Preparation and Performance Evaluation of Castor Oil-Based Asphalt Regeneration Agent.

Regeneration agents play a critical role in modifying the mechanical properties and durability of RAP asphalt mixtures. This paper aimed to develop a castor oil-based asphalt regeneration agent. The effects of this regeneration agent on the pavement performance of laboratory-aged asphalt and an RAP asphalt mixture were comparatively studied by a series of laboratory tests. For the developed castor oil-based asphalt regeneration agent, the weight ratio of the castor oil to dibutyl phthalate was determined as 1:4. Moreover, the regeneration effectiveness of the castor oil-based regeneration agent was tested on three laboratory-aged asphalt binders and an RAP asphalt binder; the penetration, softening point and ductility of the RAP asphalt binder recovered to 83 dmm, 50.3 °C, and more than 100 cm, respectively. The optimum content of the regeneration agent was 5% by the weight of the aged asphalt binder. Furthermore, the castor oil-based regeneration agent could effectively restore the pavement performance of an RAP asphalt mixture. In this study, the RAP percentage can reach up to 60% by the weight of the HMA mixture using the castor oil-based asphalt regeneration agent according to the Chinese specification.

Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.

Type VII secretion system extracellular protein B targets STING to evade host anti-Staphylococcus aureus immunity.

Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.

Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone.

BACKGROUND: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression. METHODS: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis. FINDINGS: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone. INTERPRETATION: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer. FUNDING: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.

Metal-organic frameworks as candidates for tumor sonodynamic therapy: Designable structures for targeted multifunctional transformation.

Sonodynamic therapy (SDT), utilizing ultrasound (US) as the trigger, has gained popularity recently as a therapeutic approach with significant potential for treating various diseases. Metal-organic frameworks (MOFs), characterized by structural flexibility, are prominently emerging in the SDT realm as an innovative type of sonosensitizer, offering functional tunability and biocompatibility. However, due to the inherent limitations of MOFs, such as low reactivity to reactive oxygen species and challenges posed by the complex tumor microenvironment, MOF-based sonosensitizers with singular functions are unable to demonstrate the desired therapeutic efficacy and may pose risks of toxicity, limiting their biological applications to superficial tissues. MOFs generally possess distinctive crystalline structures and properties, and their controlled coordination environments provide a flexible platform for exploring structure-effect relationships and guiding the design and development of MOF-based nanomaterials to unlock their broader potential in biological fields. The primary focus of this paper is to summarize cases involving the modification of different MOF materials and the innovative strategies developed for various complex conditions. The paper outlines the diverse application areas of functionalized MOF-based sonosensitizers in tumor synergistic therapies, highlighting the extensive prospects of SDT. Additionally, challenges confronting SDT are briefly summarized to stimulate increased scientific interest in the practical application of MOFs and the successful clinical translation of SDT. Through these discussions, we strive to foster advancements that lead to early-stage clinical benefits for patients. STATEMENT OF SIGNIFICANCE: 1. An overview for the progresses in SDT explored from a novel and fundamental perspective. 2. Different modification strategies to improve the MOFs-mediated SDT efficacy are provided. 3. Guidelines for the design of multifunctional MOFs-based sonosensitizers are offered. 4. Powerful tumor ablation potential is reflected in SDT-led synergistic therapies. 5. Future challenges in the field of MOFs-based SDT in clinical translation are suggested.

Utilizing a structure-based virtual screening approach to discover potential LSD1 inhibitors.

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.

Associations of incident female breast cancer with long-term exposure to PM2.5 and its constituents: Findings from a prospective cohort study in Beijing, China.

This study aimed to investigate the association between long-term exposure to fine particulate matter (PM2.5) and its constituents (black carbon (BC), ammonium (NH4+), nitrate (NO3-), organic matter (OM), inorganic sulfate (SO42-)) and incident female breast cancer in Beijing, China. Data from a prospective cohort comprising 85,504 women enrolled in the National Urban Cancer Screening Program in Beijing (2013-2019) and the Tracking Air Pollution in China dataset are used. Monthly exposures were aggregated to calculate 5-year average concentrations to indicate long-term exposure. Cox models and mixture exposure models (weighted quantile sum, quantile-based g-computation, and explanatory machine learning model) were employed to analyze the associations. Findings indicated increased levels of PM2.5 and its constituents were associated with higher breast cancer risk, with hazard ratios per 1-µg/m3 increase of 1.02 (95% confidence interval (CI): 1.01, 1.03), 1.39 (95% CI: 1.16, 1.65), 1.28 (95% CI: 1.12, 1.46), 1.15 (95% CI: 1.05, 1.24), 1.05 (95% CI: 1.02, 1.08), and 1.15 (95% CI: 1.07, 1.23) for PM2.5, BC, NH4+, NO3-, OM, and SO42-, respectively. Exposure-response curves demonstrated a monotonic risk increase without an evident threshold. Mixture exposure models highlighted BC and SO42- as key factors, underscoring the importance of reducing emissions of these pollutants.

Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

One-stage secondary debulking procedure: A unique technique to restore the differential contour of digit after groin flap reconstruction.

BACKGROUND: Pedicled groin flap is a reliable reconstructive method for digits. However, problems with the contour, mobility, and sensation, especially while providing strict thin skin coverage still exist. PATIENTS AND METHODS: A total of 17 cases with 36 digits injured by trauma were identified. One-stage secondary debulking procedure was adopted for flap revision. The skin over the flap was harvested as a full-thickness graft. At the dorsal side of the reconstructed digit, the subcutaneous tissue and fat were debulked till the deep fascial layer. At the volar side, the flap was debulked till the superficial fascial layer. The skin was then re-grafted. The outcomes were reviewed after 12 months follow-up. RESULTS: The average timing for debulking procedure after flap reconstruction was 116 days. After removal of bolster dressing 7 days after debulking, all the grafted skin took well. A mean length of 2.5 cm of digit was preserved for the non-replantable digits. The reconstructed digits achieved comparable diameter and contour with that of the contralateral side. The two-point discrimination of the injured digits of adults was 10.4 ± 1.6 mm. Using a 5-point Likert scale, post-debulking digits showed statistically significant improvement compared to pre-debulking digits. The evaluation of the patients' satisfactory outcomes of the reconstructed digits was judged as "very satisfying" in 12 patients (75 %) and "good" in 4 patients (25 %). CONCLUSIONS: One-stage secondary debulking procedure resulted in excellent functional and esthetic outcomes for digits according to different structures of the dorsal and volar sides. LEVEL OF EVIDENCE: IV, Retrospective.

Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis.

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor ß (IR-ß) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-ß phosphorylation, ultimately resulting in IR-ß inactivation. This inactivation of IR-ß suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

[Evaluation of the feasibility of endoscopic tympanoplasty in two-person three-hand operation].

Objective:To study the difference of postoperative efficacy between two-person three-hand ear endoscopy and microscopic tympanoplasty in patients with chronic suppurative otitis media, and to explore the advantages and disadvantages of two-person three-hand ear endoscopy. Methods:A retrospective study was conducted on 100 patients who underwent tympanoplasty in the Department of Otolaryngology and Head and Neck Surgery of Hunan People's Hospital from April 2019 to March 2023, and they were divided into 2 groups with 50 cases each according to random number table method. Among them, 50 cases underwent endoscopic tympanoplasty in two-person three-hand（group A） and 50 cases underwent routine microscopic tympanoplasty（group B）. The operation and postoperative conditions of the two groups were followed up. Results:In group A, the mean operation time was（65.78±18.21） min, the mean intraoperative blood loss was（12.94±4.46） mL, the postoperative pain score was（1.82±0.60） points, and the mean postoperative hospital stay was（2.76±0.72） d. The mean operation time of group B was（89.45±20.38） min, the mean intraoperative blood loss was（22.78±5.74） mL, the postoperative pain score was（2.98±0.85） points, and the mean postoperative hospital stay was（3.82±0.75） d, which with statistical significance between the two groups（P<0.05）. Hearing in both groups was significantly improved 6 months after surgery, and the difference was statistically significant before and after surgery（P<0.05）, but there was no significant difference between the two groups before surgery and 6 months after surgery（P>0.05）. There were 2 cases in group A（4%） and 1 case in group B（2%） complicated with tympanic cord injury during operation, and the difference was not statistically significant（P>0.05）. There were 47 cases of A group（94%） of one-time healing of tympanic membrane after operation, 48 cases（96%） of group B, and the difference was not statistically significant（P>0.05）. Conclusion:There is no significant difference in cure rate and hearing improvement between two-person three-hand ear endoscopic tympanoplasty and conventional microscope surgery, and the operation time is significantly shortened, the amount of blood loss is less, and the postoperative recovery is faster. It has the advantages of clear operating field, two-person three-hand operation, minimally invasive, and can reach the range of middle ear tympanic sinus and mastoid apex, and the surgical complications are seldom, which is worth promoting.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

[Retracted] Tremella polysaccharides inhibit cellular apoptosis and autophagy induced by Pseudomonas aeruginosa lipopolysaccharide in A549 cells through sirtuin 1 activation.

[This retracts the article DOI: 10.3892/ol.2018.8554.].

A case report of atypical chronic myeloid leukemia with complete hematological and major molecular response to Venetoclax/Azacitidine treatment.

Atypical Chronic Myeloid Leukemia (aCML), a myeloproliferative neoplasm with poor prognosis, was reclassified as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the WHO 2022 classification. Due to the heterogeneity of its clinical features and the lack of unique biomarkers, as well as limited treatment options, aCML currently lacks a standardized treatment protocol. In this case report, we reviewed a young man diagnosed with aCML who achieved complete clinical and hematologic remission subsequent to receiving a therapeutic regimen combining Venetoclax and Azacitidine.

Domino Michael/Oxa-Michael Reactions of the Unsymmetric Double Michael Acceptor for Access to Bicyclic Furo[2,3-b]pyrrole.

By creating an unsymmetric double Michael acceptor 1, we were able to synthesize the nonaromatic-fused bicyclic furo[2,3-b]pyrrole nucleus using a domino Michael/oxa-Michael reaction. Adopting benzoyl acetonitrile 2d (CN as the electron-withdrawing group) as a substrate, we discovered a (DHQ)2AQN-catalyzed method for high diastereo- and enantioselectivity of those products. The reaction path has been determined by isolating the reaction intermediates, and density functional theory calculations support these findings. Beyond providing a synthetic approach, this work illustrated the compounds' possible use in antitumor activity.

Constructing 2D Polyphenols-Based Crosslinked Networks for Ultrafast and Selective Uranium Extraction from Seawater.

The role of tannins (TA), a well-known abundant and ecologically friendly chelating ligand, in metal capture has long been studied. Different kinds of TA-containing adsorbents are synthesized for uranium capture, while most adsorbents suffer from unfavorable adsorption kinetics. Herein, the design and preparation of a TA-containing 2D crosslinked network adsorbent (TANP) is reported. The ≈1.8-nanometer-thick TANP films curl up into micrometer-scale pores, which contribute to fast mass transfer and full exposure of active sites. The coordination environment of uranyl (UO2 2+) ions is explored by integrated analysis of U L3-edge XANES and EXAFS. Density functional theory calculations indicate the energetically favorable UO2 2+ binding. Consequently, TANP with excellent adsorption kinetics presents a high uranium capture capacity (14.62 mg-U g-Ads-1) and a high adsorption rate (0.97 mg g-1 day-1) together with excellent selectivity and biofouling resistance. Life cycle assessment and cost analysis demonstrate that TANP has tremendous potential for application in industrial-scale uranium extraction from seawater.

A CT-based radiomics nomogram for predicting histologic grade and outcome in chondrosarcoma.

OBJECTIVE: The preoperative identification of tumor grade in chondrosarcoma (CS) is crucial for devising effective treatment strategies and predicting outcomes. The study aims to build and validate a CT-based radiomics nomogram (RN) for the preoperative identification of tumor grade in CS, and to evaluate the correlation between the RN-predicted tumor grade and postoperative outcome. METHODS: A total of 196 patients (139 in the training cohort and 57 in the external validation cohort) were derived from three different centers. A clinical model, radiomics signature (RS) and RN (which combines significant clinical factors and RS) were developed and validated to assess their ability to distinguish low-grade from high-grade CS with area under the curve (AUC). Additionally, Kaplan-Meier survival analysis was applied to examine the association between RN-predicted tumor grade and recurrence-free survival (RFS) of CS. The predictive accuracy of the RN was evaluated using Harrell's concordance index (C-index), hazard ratio (HR) and AUC. RESULTS: Size, endosteal scalloping and active periostitis were selected to build the clinical model. Three radiomics features, based on CT images, were selected to construct the RS. Both the RN (AUC, 0.842) and RS (AUC, 0.835) were superior to the clinical model (AUC, 0.776) in the validation set (P = 0.003, 0.040, respectively). A correlation between Nomogram score (Nomo-score, derived from RN) and RFS was observed through Kaplan-Meier survival analysis in the training and test cohorts (log-rank P < 0.050). Patients with high Nomo-score tumors were 2.669 times more likely to suffer recurrence than those with low Nomo-score tumors (HR, 2.669, P < 0.001). CONCLUSIONS: The CT-based RN performed well in predicting both the histologic grade and outcome of CS.

Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS: Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS: Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION: The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING: This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).

A novel simple laser guidance puncture system for intracerebral hematoma.

OBJECTIVE: Accurate localization and real-time guidance technologies for cerebral hematomas are essential for minimally invasive procedures, including minimally invasive hematoma puncture and drainage, as well as neuroendoscopic-assisted hematoma removal. This study aims to evaluate the precision and safety of a self-developed laser-guided device in localizing and guiding hematoma punctures in minimally invasive surgery for intracerebral hemorrhage (ICH). METHODS: We present the components of the device and its operational procedures. Subsequently, surgeons with different titles conduct hematoma puncture experiments using the device on skull models, comparing it to freehand puncture methods and recording the offset distance from the puncture needle tip to the hematoma center. Additionally, we report the application of this device in 10 patients with ICH, assessing its accuracy and safety in comparison with a neuro-navigation system. RESULTS: In simulated puncture experiments, the accuracy of the laser-guided group surpasses that of the freehand puncture group, with a significant statistical difference observed between the two groups (P < 0.05). In the laser-guided group, there is no statistically significant difference in puncture accuracy among the surgeons (P > 0.05). In clinical experiments, no relevant surgical complications were observed. The offset distance for the laser-guided group was 0.61 ± 0.18 cm, while the neuro-navigation group was 0.48 ± 0.13 cm. There was no statistically significant difference between the two groups in terms of offset distance (P > 0.05). However, there was a significant difference in surgical duration (P < 0.05), with the former being 35.0 ± 10.5 minutes and the latter being 63.8 ± 10.5 minutes. CONCLUSION: The current study describes satisfactory results from both simulated experiments and clinical applications, achieved through the use of a novel laser-guided hematoma puncture device. Furthermore, owing to its portability, affordability, and simplicity, it holds significant importance in advancing surgical interventions for ICH, especially in underdeveloped regions.