A randomized trial of early cardiotoxicity in breast cancer patients receiving postoperative IMRT with or without serial cardiac dose constraints.

Optimal cardiac dose constraints in breast cancer (BC) patients undergoing postoperative intensity-modulated radiation therapy (IMRT) are unclear, although as low as possible is recommended. This trial proposes serial cardiac dose constraint to optimize cardiac safety. Postoperative BC patients eligible for anthracycline/taxanes-based chemotherapy or HER2-targeted therapy were randomized to cardiac safety arm with prespecified mean heart dose (MHD) (≤6 Gy), V30 (≤20%), and V10 (≤50%) constraints, or to a control arm with in-house protocol (mainly MHD ≤8 Gy). The primary endpoint was cumulative incidence of newly onset cardiac events within 1-year post-RT. An exploratory analysis examined the relationship between whole heart dose metrics and those of substructures. Of 199 participants, 93 were in the cardiac safety and 106 in the control arm. The cardiac safety group showed lower MHD, V10, and V30. The 1-year cardiac event incidence was slightly lower in the cardiac safety group (19.4%) compared to controls (24.9%). The LVEF and diastolic dysfunction rates were 0% and 5.4% in the study arm, and 1.9% and 8.8% in the control arm, respectively. The LAD, LV, and RV received the highest doses for left-sided patients. For right-sided patients, RA, RCA, and RV were most irradiated. The MHD, V10, and Dmax of heart significantly correlated with all substructure doses in either laterality. Our study supports the early cardiac safety profile using IMRT in BC patients receiving cardiac-toxic systemic therapy, with serial cardiac dose constraints. Combined constraints on MHD and dose-volume parameters are representative of the cardiac substructure dose.

Association of chronic obstructive pulmonary disease with risk of lung cancer in individuals aged 40 years and older: A cross-sectional study based on NHANES 2013-2018.

BACKGROUND: It remains unclear whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer after excluding confounding factors such as smoking, age, sex, body mass index (BMI), comorbidities, etc. METHODS: Data from 11,440 participants (≥ 40 years old) in the National Health and Nutrition Examination Survey (NHANES) 2013-2018 were analyzed. Weighted multivariable logistic regression models were used to assess the association between COPD and lung cancer risk. Subgroup analyses were based on age, sex, BMI, and smoking. RESULTS: This study included 660 patients with COPD and 10,780 participants without COPD. The prevalence of lung cancer was significantly higher in patients with COPD compared to participants without COPD (3.39% vs 0.14%). After adjusting for confounding factors, COPD was associated with a significantly increased risk of lung cancer (OR, 12.24, 95% CI, 4.99-30.06, p < 0.001). This association remained significant in all subgroups, particularly in individuals aged > 65 years (OR, 20.05, 95% CI, 6.85-58.72, p < 0.001), smokers (OR, 19.38, 95% CI, 2.02-185.66, p = 0.010), males (OR, 17.39, 95% CI, 5.28-57.31, p < 0.001), individuals who quit smoking within 10 years (OR, 12.86, 95% CI, 2.59, 63.99, p = 0.002), and individuals with a BMI > 25 kg/m2 (OR, 14.56, 95% CI, 3.88-54.69, p < 0.001). CONCLUSIONS: COPD is an independent risk factor for lung cancer, especially in certain subgroups. The combination of COPD and smoking greatly amplifies the lung cancer risk. These findings highlight the importance of early lung cancer screening in patients with COPD.

An in vitro study of irrigation rate, operator duty cycle and intrarenal temperature in superpulse fiber thulium laser lithotripsy.

OBJECTIVE: The present study aimed to examine the relationship between irrigation velocity, operator duty cycle (ODC), and intrarenal temperature during retrograde intrarenal surgery with a superpulse fiber thulium laser. METHODS: Place the stones into the fresh isolated porcine kidneys, use puncture needle to place the temperature probe 2 mm around the stones, and place the pressure probes in the upper calyx, lower calyx, and renal pelvis. Place the entire setup in a 37 °C constant temperature water bath to simulate the human body environment. The laser power varies between 10 and 30 W, and the irrigation speed is 10-30 ml/min. Additionally, at a laser power of 20 W and an irrigation speed of 10 ml/min, different On-Duty Cycles (ODC) are set. Monitor the changes in temperature and pressure. RESULTS: A direct proportionality of temperature in the kidney to the rate of irrigation has been reported between 10 W and 30 W laser powers. The percentage ratio of the rate of irrigation and power in the laser is 1:1, which can keep the temperature in the kidney at a safe level. At a laser power of 20 W and irrigation of 10 ml/min, the temperature inside the kidney increases sharply with the increase in ODC. By decreasing the ratio of ODC, the increase of temperature inside the kidney can be brought to a great reduction. CONCLUSION: Maintaining a 1:1 ratio between laser power and irrigation speed can effectively prevent thermal damage or injury to kidney tissue.Additionally, by adjusting the On-Duty Cycle (ODC) ratio, the intrarenal temperature can also be reduced.

Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons.

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor-ß (TGF-ß) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor-1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Endothelial cells derived extracellular vesicles promote diabetic arterial calcification via circ_0008362/miR-1251-5p/Runx2 axial.

INTRODUCTION: Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification. RESULTS: The results showed that EVs derived from HG induced ECs (ECHG-EVs) exhibited a bilayer structure morphology with a mean diameter of 74.08 ± 31.78 nm, expressing EVs markers including CD9, CD63 and TSG101, but not express calnexin. ECHG-EVs was internalized by VSMCs and induced VSMC calcification by increasing Runx2 expression and mineralized nodule formation. The circ_0008362 was enriched in ECHG-EVs, and it can be transmitted to VSMCs to promote VSMC calcification both in vitro and in vivo. Mechanistically, miR-1251-5p might be one of the targets of circ_0008362 and they were co-localization in the cytoplasm of VSMCs. Runx2 was identified as the downstream target of miR-1251-5p, and circ_0008362 acted as a sponge, enhancing Runx2 expression and then promoted VSMC calcification. Besides, circ_0008362 could directly interact with Runx2 to aggravate VSMC calcification. Notably, DiR-labelled ECHG-EVs was detected in the vessels of mice. Meanwhile, the level of circ_0008362 and Runx2 were increased significantly, while the expression of miR-1251-5p was decreased significantly in calcified artery tissues of mice. However, inhibiting the release of EVs by GW4869 attenuated arterial calcification in diabetic mice. Finally, the level of circulation of plasma EVs circ_0008362 was significantly higher in patients with DM compared with normal controls. Elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. CONCLUSIONS: Our findings suggested that circ_0008362 was enriched in EVs derived from ECs and promoted VSMC calcification under HG conditions, both by sponging miR-1251-5p to upregulate Runx2 expression and through direct interaction with Runx2. Furthermore, elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. These results may serve as a potential prevention and therapeutic target for diabetic arterial calcification.

Comparison of Oliceridine to Remifentanil for Optimal Analgesia in Mechanical Ventilation (CO-ROAM): Study Protocol for a Multicenter Randomized Controlled Trial.

INTRODUCTION: Critically ill patients often endure pain, a distressing experience that can trigger diverse pathophysiological consequences. While remifentanil, with its rapid kinetics, is commonly used for analgesia in intensive care units (ICU), it frequently leads to opioid-related adverse effects. A promising alternative has emerged in oliceridine, a novel G protein-biased µ-opioid receptor agonist. This new drug offers the potential for effective pain relief with fewer side effects. However, its efficacy and safety profile in mechanically ventilated ICU patients remain to be fully elucidated. METHODS: This is a multicenter, prospective, randomized, single-blind, active-controlled trial conducted across 24 ICUs in China. A total of 292 mechanically ventilated patients requiring analgesia and sedation will be randomly assigned in a 1:1 ratio to either the oliceridine or remifentanil group. The oliceridine group will receive oliceridine (2-20 µg/kg/h), while the remifentanil group will receive remifentanil (1.5-12 µg/kg/h). Both groups will receive propofol for sedation if necessary. The target for analgesia is Critical-Care Pain Observation Tool (CPOT) < 3, and for sedation is Richmond Agitation-Sedation Scale (RASS) - 2 to 0. PLANNED OUTCOMES: The primary outcome will be the percentage of time within target analgesia during study drug administration. Secondary outcomes will include gastrointestinal dysfunction, respiratory depression, sedative usage, mechanical ventilation duration, ICU stay length, extubation failure rate, etc. TRIAL REGISTRATION: NCT06454292. Registered on June 11, 2024.

Task-space tracking for networked heterogeneous robotic systems via adaptive neural fixed-time control.

The task-space distributed adaptive neural network (NN) fixed-time tracking problem is studied for networked heterogeneous robotic systems (NHRSs). In order to address this complex problem, we propose a NN-based fixed-time hierarchical control approach that transforms the problem into two sub-problems: a distributed fixed-time estimation problem and a local fixed-time tracking problem, respectively. Specifically, distributed estimators are constructed so that each follower can acquire the dynamic leader's state in a fixed time. Then, the neural networks (NNs) are employed to approximate the compounded uncertainty consisting of the unknown dynamics of robotic systems and the boundary of the compounded disturbance. More importantly, to guarantee that the tracking errors can converge into a small neighborhood of equilibrium in a fixed time independent of the initial state, the adaptive neural fixed-time local tracking controller is proposed. Another merit of the proposed controller is that the approximation errors are addressed in a novel way, eliminating the need for prior precise knowledge of uncertainties and improving the robustness and convergence speed of unknown robotic systems. Finally, the experimental results demonstrate the effectiveness and advantages of the proposed control method.

Vapor flux induced by temperature gradient is responsible for providing liquid water to hypoliths.

Commonly comprised of cyanobacteria, algae, bacteria and fungi, hypolithic communities inhabit the underside of cobblestones and pebbles in diverse desert biomes. Notwithstanding their abundance and widespread geographic distribution and their growth in the driest regions on Earth, the source of water supporting these communities remains puzzling. Adding to the puzzle is the presence of cyanobacteria that require liquid water for net photosynthesis. Here we report results from six-year monitoring in the Negev Desert (with average annual precipitation of ~ 90 mm) during which periodical measurements of the water content of cobblestone undersides were carried out. We show that while no effective wetting took place following direct rain, dew or fog, high vapor flux, induced by a sharp temperature gradient, took place from the wet subsurface soil after rain, resulting in wet-dry cycles and wetting of the cobblestone undersides. Up to 12 wet-dry cycles were recorded following a single rain event, which resulted in vapor condensation on the undersides of the cobblestones, with the daily wet phase lasting for several hours during daylight. This 'concealed mechanism' expands the distribution of photoautotrophic organisms into hostile regions where the abiotic conditions limit their growth, and provides the driving force for important evolutionary processes not yet fully explored.

DMSO-Catalyzed Double P-O Bond or Double P-S Bond Formations of Phosphinic Acids.

A DMSO-catalyzed double P-O bond or double P-S bond formation of phosphinic acid with an O- or S-containing nucleophile has been developed. Under metal-free and mild conditions, this simple procedure provides a compatible and rapid access to a variety of phosphonates and dithiophosphates. The DFT calculation of stabilization energy (SE) and the mechanism studies demonstrated that the "just right" Lewis base property and the relatively "soft" interaction strength with the phosphenium-dication ensure the unique catalytic activity of DMSO in this transformation.

Three dimensional-printed artificial disc replacement for single-level cervical spondylosis: a cohort study.

PURPOSE: To compare the clinical efficacy of 3D-printed artificial discs with that of ACDF for treating cervical spondylosis. METHODS: This was a retrospective analysis of 73 patients with single-level cervical spondylosis who met the inclusion criteria between January 2020 and December 2022 at XX Hospital. The patients were divided: 38 patients in the ACDF group and 35 patients in the CADR group. Patient general information, including operation time and intraoperative blood loss, was collected. The clinical effect of the combination therapy was evaluated by the VAS, JOA, and NDI. The radiological effect was evaluated using the ROM test. Ethics No. 201,606,009. RESULTS: The average follow-up times in the ACDF and CADR groups were 28.24 ± 4.65 and 29.11 ± 5.06 months, respectively (P = 0.443). Clinical symptoms (evaluated by VAS, NDI, and JOA) are significantly improved in both the ACDF and CADR groups with similar efficacy. The preoperative ROM of the ACDF group was 40.03 ± 8.79, while that of the CADR group was 42.11 ± 7.98 (P = 0.293). However, the postoperative ROM in the ACDF group was 35.29 ± 7.23, which was lower than that in the CADR group (40.43 ± 6.98) (P = 0.003). Furthermore, only one patient in the ACDF group experienced mild dysphagia after surgery, and the patient recovered within three days. ASD occurred in nine patients in the ACDF group and in two patients in the CADR group (Χ²=4.597, P = 0.032). CONCLUSIONS: Compared with ACDF, 3D-printed artificial discs for treating single-level cervical spondylosis have proven to be clinically effective; it associated with less blood loss and a lower incidence of ASD, and maintain a better cervical ROM.

Hypoxia-induced DTL promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through ubiquitin-mediated degradation of SLTM and subsequent Notch pathway activation.

Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort (n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.

Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of monoamine oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxidative stress associated with PD. In this study, we report the novel use of an azastilbene-based compound library for screening human (h)MAO-B, followed by optimization of initial hits to obtain compounds with low nanomolar inhibitory potencies (compound 9, IC50 = 42 nM) against hMAO-B. To ensure specificity and minimize false positives due to non-specific hydrophobic interactions, we performed comprehensive selectivity profiling against hMAO-A, butyrylcholinesterase (hBChE) and acetylcholinesterase (hAChE) - enzymes with hydrophobic active sites that are structurally distinct from hMAO-B. Docking analysis with Glide provided valuable insights into the binding interactions between the inhibitors and hMAO-B and also explained the selectivity against hMAO-A. In the cell-based model of Parkinson's disease, one of the compounds significantly reduced rotenone-induced accumulation of reactive oxygen species. In addition, these compounds showed a protective effect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction in PD model mice and reduced MPTP-induced loss of striatal tyrosine hydroxylase-positive neurons in the substantia nigra. These results make azastilbene-based compounds a promising new class of hMAO-B inhibitors with potential therapeutic applications in Parkinson's disease and related neurodegenerative disorders.

Characteristic activation pattern and network connectivity of prefrontal cortex in patients with type 2 diabetes mellitus and major depressive disorder during a verbal fluency task: A functional near-infrared spectroscopy study based on network-based statistic prediction.

INTRODUCTION: Type 2 diabetes (T2DM) and major depressive disorder (MDD) together occur frequently among the elderly population. However, the inconsistency in assessments and limited medical resources in the community make it challenging to identify depression in patients with T2DM. This cross-sectional study aimed to investigate the activation pattern and network connectivity of prefrontal cortex (PFC) during a verbal fluency task (VFT) in patients with T2DM and MDD using functional near-infrared spectroscopy (fNIRS). METHODS: Three parallel groups (T2DM with MDD group, T2DM group, and healthy group) with 100 participants in each group were included in the study. Recruitment took place from August 1, 2020, to December 31, 2023. Due to the close association between the PFC and depressive emotions, fNIRS was used to monitor brain activation and network connectivity of PFC in all participants during a task of Chinese-language phonological VFT. Network-based statistic prediction (NBS-predict) was adopted as data analysis method. RESULTS: Patients in the T2DM with MDD group showed characteristic activation pattern and network connectivity in contrast with patients with T2MD and healthy controls, including decreased activation in PFC, and decreased network connectivity of right dorsolateral prefrontal cortex (DLPFC). Furthermore, the network connectivity of the right DLPFC in patients with T2DM and MDD was negatively correlated with scores of Hamilton Depression Scale-24 (HAMD-24). CONCLUSIONS: There was a distinctive activation pattern and network connectivity of the prefrontal cortex in patients with T2DM and MDD. The right DLPFC could serve as a potential target for the diagnosis and intervention of MDD in patients with T2DM.

Impact of computed tomography/magnetic resonance imaging registration on rehabilitation after percutaneous endoscopic decompression for lumbar stenosis: Retrospective study.

BACKGROUND: Percutaneous endoscopic lumbar decompression (PELD) shows promise for lumbar spinal stenosis (LSS) treatment, but its use is limited by the disease's complexity and procedural challenges. AIM: In this study, the effects of preoperative planning and intraoperative guidance with computed tomography (CT)/magnetic resonance imaging (MRI) registration techniques on PELD for LSS and postoperative rehabilitation outcomes were evaluated. METHODS: This retrospective study was conducted with data from patients who underwent PELD for LSS between January 2021 and December 2023. Patients were assigned to preoperative CT/MRI registration and control groups. Data collected included the operative time, length of hospital stay, visual analog scale (VAS) scores for low back and leg pain, and the Japanese Orthopaedic Association (JOA) lumbar spine score. Differences between groups were assessed using Student's t test. RESULTS: Data from 135 patients (71 in the CT/MRI registration group, 64 in the control group) were analyzed. The operative time was significantly shorter in the CT/MRI registration group (P = 0.007). At 2 months postoperatively, both groups showed significant reductions in VAS leg and low back pain scores (all P < 0.001) and improvements in the JOA score (both P < 0.001). No complication or death occurred. Preoperatively, pain and JOA scores were similar between groups (P = 0.830, P = 0.470, and P = 0.287, respectively). At 2 months postoperatively, patients in the CT/MRI registration group reported lower leg and low back pain levels (P < 0.001 and P = 0.001, respectively) and had higher JOA scores (P = 0.004) than did patients in the control group. CONCLUSION: Preoperative CT/MRI registration for PELD for LSS reduced the operative time and VAS pain scores at 2 months and improved JOA scores, demonstrating enhanced effectiveness and safety.

Small particle drug-eluting beads-transarterial chemoembolization combined with targeted therapy in the clinical treatment of unresectable liver cancer.

BACKGROUND: Liver cancer is a highly malignant tumor with significant clinical impact. Chemotherapy alone often yields suboptimal outcomes in both the short and long term, characterized by high rates of local recurrence and distant metastasis, leading to a poor long-term prognosis. AIM: To evaluate the clinical efficacy of small particle drug-eluting beads-transarterial chemoembolization (DEB-TACE) combined with targeted therapy for the treatment of unresectable liver cancer. METHODS: We analyzed clinical data from 74 patients with unresectable liver cancer admitted between January 2019 and December 2020. Based on the different treatment regimens administered, patients were divided into the control (36 patients receiving sorafenib alone) and joint (38 patients receiving small particle DEB-TACE combined with sorafenib) groups. We compared liver function indicators [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB)] and serum tumor markers [alpha fetoprotein (AFP)] before and after treatment in both groups. Short-term efficacy measures [complete response (CR), partial response, progression disease, stable disease, objective response rate (ORR), and disease control rate (DCR)] were assessed post-treatment. Long-term follow-up evaluated median overall survival (OS), progression-free survival (PFS), and adverse reaction rates between the two groups. RESULTS: One month post-treatment, the joint group demonstrated significantly higher rates of CR, ORR, and DCR compared to the control group (P < 0.05). Three days after treatment, the joint group showed elevated levels of ALT, AST, and TBIL but reduced levels of ALB and AFP compared to the control group (P < 0.05). The median OS was 18 months for the control group and 25 months for the joint group, while the median PFS was 15 months for the control group and 22 months for the joint group, with significant differences observed (log-rank: χ 2 = 7.824, 6.861, respectively; P = 0.005, 0.009, respectively). The incidence of adverse reactions was not significantly different between the groups (P > 0.05). CONCLUSION: The combination of small particle DEB-TACE and sorafenib significantly improves both short- and long-term outcomes in the treatment of unresectable liver cancer while preserving liver function.

Quality problems in clinical practice guidelines and guideline appraisal studies: Should we tolerate or eradicate?

BACKGROUND: Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument have been widely used by scholars around the world to assess the methodological quality of clinical practice guidelines (CPGs). We sought to identify items or domains that are commonly scored low in the assessment, and to systematically review the issues that emerged when evaluators used the AGREE II tool for guideline quality assessment. METHODS: A systematic search was conducted to identify articles published in medically relevant databases from 2022 to 2023 regarding the use of the AGREE II tool for the assessment of CPGs. We extracted six quality domains and overall quality assessment data of CPGs included in the literature, and processed the data using descriptive statistical analysis, difference analysis, regression analysis, and correlation analysis. A seven-point Likert scale was used to assess the reporting quality of the included articles. RESULTS: 151 relevant publications were identified, including 2081 guidelines published between 1990 and 2022. The results of the regression analysis showed a statistically significant impact of all domains on overall guideline quality (p < 0.001; R2 = 0.777). Domain 1, 2, 3, 4, and 6 scores differed significantly over time (p < 0.001) and were increasing. The score was good for Domain 4 (median 78.00 [IQR: 62.75-89.00]; mean 74.34 [SD 18.85]) and Domain 1 (median 78.00 [IQR: 61.00-90.00]; mean 73.57 [SD 21.12]). Scores were generic for Domain 6 (median 58.33 [IQR: 25.00-83.33]; mean 53.98 [SD 34.13]), Domain 2 (median 53.00 [IQR: 33.30-72.10]; mean 53.30 [SD 24.52]) and Domain 3 (median 51.00 [IQR: 26.02-73.00]; mean 50.44 [SD 27.19]). The score was poor for Domain 5 (median 36.20 [IQR: 20.20-58.32]; mean 40.21 [SD 24.90]). In addition, the quality evaluation results of the included articles showed that 33.1% were evaluated as low and 11.9% as very low. CONCLUSIONS: AGREE II tools have facilitated the development of methodological quality for CPGs. Although the quality of CPGs has improved over time, some general low-quality problems still exist, and solving these problems will be an effective way for developers to upgrade the quality of guidelines. In addition, addressing critical issues in the evaluation of guidelines to present high-quality study reports would be another way to guide guideline development.

Hyaluronic acid-functionalized nanoparticles for ulcerative colitis-targeted therapy: a comparative study of oral administration and intravenous injection.

Targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for selectively alleviating the symptoms of ulcerative colitis (UC), while minimizing adverse effects. Herein, we aimed to compare the in vivo pharmacokinetics and therapeutic outcomes of macrophage-targeted nanoparticles (NPs) via oral administration and intravenous injection. Polymeric NPs were employed to load an anti-inflammatory drug (curcumin, CUR), followed by surface functionalization with hyaluronic acid (HA). The resulting HA-CUR-NPs had an average diameter of 281 nm and a negatively charged surface. These NPs showed excellent biocompatibility and a significantly higher cell internalization efficiency in RAW 264.7 macrophages compared with their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-CUR-NPs). Moreover, HA-CUR-NPs exhibited a dramatically stronger capacity to inhibit the mRNA expression levels of the typical pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-CUR-NPs. In vivo experiments revealed that HA-CUR-NPs after i.v. injection could improve the pharmacokinetics of CUR, and that it showed much better UC therapeutic outcomes compared with the oral administration way. Collectively, in comparison with HA-CUR-NPs (oral), HA-CUR-NPs (i.v.) possess a higher CUR delivery efficiency to the colitis mucosa, which can be developed as an efficient platform for UC treatment.

Cuproptosis-based layer-by-layer silk fibroin nanoplatform-loaded PD-L1 siRNA combining photothermal and chemodynamic therapy against metastatic breast cancer.

Cuproptosis is a newly identified form of copper-dependent cell death that differs from other known pathways. This discovery provides a new way to explore copper-based nanomaterial applications in cancer therapy. This study used a layer-by-layer self-assembling method to load Cu2-xS nanoparticle (NP) cores with the siRNA of the PD-L1 immune escape-related gene and wrap a silk fibroin (SF) shell to form a multifunctional copper-based SF nanoplatform, denoted as CuS-PEI-siRNA-SFNs. CuS-PEI-siRNA-SFNs induced cuproptosis and exerted an antitumor effect via multiple mechanisms, including photothermal therapy (PTT), chemodynamic therapy (CDT), and immune activation. The presence of significant dihydrolipoamide S-acetyltransferase (DLAT) oligomers in 4T1 cells treated with CuS-PEI-siRNA-SFNs indicated the triggering of cuproptosis. Furthermore, in vivo experimental results showed that CuS-PEI-siRNA-SFNs efficiently accumulated in the tumor tissues of 4T1 tumor-bearing mice inhibited primary tumor and lung metastasis, and displayed excellent biosafety and antitumor activity. This study demonstrated that the synergistic effect of cuproptosis, PTT, CDT, and immune activation showed promise for treating metastatic breast cancer.