Clinical Use Research Articles

SP9.8 - Assessing the quality of guidelines for the management of Gastro-Intestinal Stromal Tumour

Abstract Introduction Gastro Intestinal Stromal Tumours (GISTs) are tumours of the gastro-intestinal tract that arise from connective tissue and they have potential for malignancy. A number of guidelines exist in their management. The aim of this study is to assess the quality of these guidelines. Methods A search of the literature was undertaken for appropriate guidelines pertaining to the diagnosis and management of GISTs. The AGREE II checklist was used to assess the current GIST guidelines. Results A total of nine guidelines were included in this study. The overall median score across all guidelines was 68% (lowest; 50%, highest 89%). Guidelines tended to score highly in Domain IV (Clarity of Presentation, median score 76%) as well as Domain VI (Editorial Independence, 67%) and Domain I (Scope and Purpose, 61%). However, lower scores were noted in the Domain V (Applicability, 39%), Domain III (Rigor of Development, 52%) and Domain II (Stakeholder Involvement, 56%). None of the guidelines scored a unanimous ‘Yes’ vote for clinical usage, and all needed some level of modifying. Conclusion Whilst some of the current guidelines for the management of GISTs is of a high quality, there is a need for improvement with regards to the quality of the methodology used to formulate the guidelines and how they can be implemented in daily clinical use.

Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain

CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.

Effect of polishing process on torque loss ratio and microgap of selective laser melting abutment: an in vitro study

BackgroundThe purpose of this in vitro study was to investigate the effect of polishing post-treatment process on the torque loss ratio and microgap of Selective Laser Melting (SLM) abutments before and after mechanical cycling test through improving the surface roughness of the implant-abutment interface.Materials and methodsForty SLM abutments were fabricated, with 20 underwent minor back-cutting, designated as polishing, in the implant-abutment interface. The abutments were divided into three groups: SLM abutments (group A), original abutments (group B), and polished SLM abutments (group C), each containing 20 abutments. Surface roughness was evaluated using a laser microscope. Implant-abutment specimens were subjected to mechanical cycling test, and disassembly torque values were measured before and after. Scanning electron microscope (SEM) was used to measure microgap after longitudinal sectioning of specimens. Correlation between surface roughness, torque loss ratio, and microgap were evaluated. LSD’s test and Tamhane’s T2 comparison were used to analyze the data (α = 0.05).ResultsThe Sz value of polished SLM abutments (6.86 ± 0.64 μm) demonstrated a significant reduction compared to SLM abutments (26.52 ± 7.12 μm). The torque loss ratio of polished SLM abutments (24.16%) was significantly lower than SLM abutments (58.26%), while no statistically significant difference that original abutments (18.23%). The implant-abutment microgap of polished SLM abutments (2.38 ± 1.39 μm) was significantly lower than SLM abutments (8.69 ± 5.30 μm), and this difference was not statistically significant with original abutments (1.87 ± 0.81 μm). A significant positive correlation was identified between Sz values and the ratio of torque loss after cycling test (r = 0.903, P < 0.01), as well as Sz values and the microgap for all specimens in SLM abutments and polished SLM abutments (r = 0.800, P < 0.01).ConclusionThe findings of this study indicated that the polishing step of minor back-cutting can lead to a notable improvement in the roughness of SLM abutments interface, which subsequently optimized the implant-abutment fit. It can be seen that the application of minor back-cutting method has advanced the clinical use of SLM abutments.

Investigating Therapies Targeting Druggable Targets of Mitochondria: Exploring the Efficacy for the Treatment of Cancer

AbstractCancer is a growing problem that has not yet been fully harnessed. Frequent mutations make this a highly variable and challenging pathology. Interestingly, mitochondria have currently emerged as a new target for cancer therapy. A group of agents with anticancer activity, termed mitocans that encourage apoptosis through mitochondrial disruption is currently important in research. From conventional glycolytic inhibitors to recent radiolabeled compounds, mitochondrial‐targeted therapies have marked their presence in cancer. Several TCA cycle and OXPHOS inhibitors are being established for their possible anticancer properties. There are so many distinctive differences in mitochondrial structure and function between normal and cancer cells that offer the potential for the clinical use of mitochondria as targets for novel and site‐specific anticancer agents. Mitochondrial targeting can be made possible if the bioactive molecule is specifically and selectively delivered to the mitochondria of the correct cell type using cell‐specific ligands and mitochondriotropic molecules.

Comparative Predictive Modeling for PICC Line Complications in Oncology: A Retrospective Study

Aims/Background Peripherally inserted central catheter (PICC) are increasingly used in cancer treatment, offering significant therapeutic benefits while also posing risks for complications such as infection, thrombosis, and catheter migration. Effective prediction and management of these complications are crucial to optimizing patient outcomes and reducing healthcare costs. Methods This retrospective study analyzed PICC line insertion in 266 cancer patients implemented from January 2019 to December 2023 at a regional healthcare facility in China. Using least absolute shrinkage and selection operator (LASSO) logistic regression, we identified key factors influencing PICC line complications and developed a tailored nomogram for individual risk assessment. The efficacy of the model was compared with support vector machine (SVM), random forest, and gradient boosting machine (GBM) using receiver operating characteristic (ROC) and decision curve analysis (DCA) metrics. Results Factors such as body mass index (BMI), diabetic status, and age were found to be significant predictors of PICC line complications. The LASSO model demonstrated superior predictive capability (area under the curve, AUC = 0.79) over SVM (AUC = 0.40), random forest (AUC = 0.70), and GBM (AUC = 0.64). A tailored nomogram was developed for clinical use, enabling personalized risk evaluation. Conclusion The study underscores the utility of LASSO logistic regression in the personalized risk evaluation of PICC line complications, recommending its integration into clinical practice. The tailored nomogram provides a practical tool for clinicians to enhance care customization for patients requiring PICC lines, thereby improving treatment outcomes and patient safety.

High-Impact AMPAkines Elevate Calcium Levels in Cortical Astrocytes by Mobilizing Endoplasmic Reticular Calcium Stores

Ampakines—positive allosteric modulators of AMPA-type glutamate receptors (AMPARs)—are drug candidates that have shown substantial promise in pre-clinical models of various neurodegenerative and neuropsychiatric diseases. Much of the study of ampakines has focused on how these drugs modulate neuronal AMPARs to achieve certain therapeutic effects. However, astrocytes also express functional AMPARs and their physiology may be sensitive to modulation by ampakines. Herein, we investigate the effects of multiple ampakines on calcium levels in cortical astrocytes. We find that ampakines augment cytosolic calcium elevations in astrocytes to an extent far greater than that achieved by AMPA alone. This effect is amenable to competitive AMPAR blockade. Furthermore, calcium induction is sensitive to phospholipase Cβ antagonism and blockade of inositol triphosphate receptors located on the endoplasmic reticulum. Low-impact ampakines exerted weaker effects on cytosolic calcium levels in astrocytes and higher concentrations were required to observe an effect. Furthermore, high doses of the low-impact ampakine, CX717, were not toxic to cortical astrocytes at high concentrations, which may serve to differentiate low-impact ampakines from classical AMPAR positive modulators like cyclothiazide. As ampakines are further developed for clinical use, it would be prudent to determine the extent to and manner by which they affect astrocytes, as these effects may also underpin their therapeutic utility in CNS pathologies.

Towards New Delivery Agents for Boron Neutron Capture Therapy: Synthesis and In Vitro Evaluation of a Set of Fluorinated Carbohydrate Derivatives.

Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, we expand upon our previous GLUT-targeting approach by synthesizing and evaluating the potential embedded in a representative set of fluorinated carbohydrates bearing a boron cluster. Our findings indicate that these species may have advantages over the boron delivery agents in current clinical use, e.g., significantly improved boron delivery capacity at the cellular level. Simultaneously, the carbohydrate delivery agents were found to bind strongly to plasma proteins, which may be a concern requiring further action before progression to in vivo studies. Altogether, this work brings new insights into factors which need to be accounted for if attempting to develop theranostic agents for BNCT based on carbohydrates in the future.

Approaches for posaconazole therapeutic drug monitoring and their clinical benefits.

This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.

Prediction of EGFR-TP53 genes co-mutations in patients with lung adenocarcinoma (LUAD) by 18F-FDG PET/CT radiomics.

This retrospective study was undertaken to assess the predictive efficacy of 18F-FDG PET/CT -derived radiomic features concerning the co-mutation status of epidermal growth factor receptor (EGFR) and TP53 in LUAD. A cohort of 150 LUAD patients underwent pretreatment 18F-FDG PET/CT scans with known mutation status of EGFR and TP53 were collected. The feature extraction based on their PET/CT images utilized the Pyradiomics packagebased on the 3D Slicer. The optimal radiomic features were selected through correlation analysis and the Gradient Boosting Decision Tree (GBDT) algorithm, followed by the construction of the radiomic model. The clinical model incorporated meaningful clinical variables, whereas the complex model integrated both the radiomic and clinical models. The area under the receiver operating characteristic curve (AUC) facilitated the comparison of prediction performance across the three models. The DCA gauged the clinical utility of these models. The patient cohort was randomly allocated into a training set (n = 105) and a validation set (n = 45) in a 7:3 ratio. Eleven PET and eleven CT optimal radiomic features were selected to construct the radiomic model. The model showed a good ability to discriminate the co-occurrence of EGFR and TP53, with AUC equal to 0.850 in the training set, and 0.748 in the validation set, compared with 0.750 and 0.626 for the clinical model. The complex model exhibited the highest AUC values, with 0.880 and 0.794 in both sets, but there were no significant differences compared to the radiomic model. The DCA revealed favorable clinical value.

Vaginal microbiota of pregnant women with Ureaplasma urealyticum and Mycoplasma hominis infections

BackgroundThe association between preterm birth and Mycoplasma species such as Mycoplasma hominis and Ureaplasma urealyticum has been extensively investigated. In a clinical setting, conventional diagnostic methods for them involve culture methods for Mycoplasma spp. and Ureaplasma spp., along with PCR tests. However, the clinical utility of these tests remains controversial, highlighting the necessity for more robust and reliable methods for identifying and understanding Mycoplasma infections.ObjectiveThis study aimed to assess the distribution of microbiota in pregnant women with Mycoplasma hominis and Ureaplasma urealyticum infection by the comparison of conventional diagnostic methods with vaginal microbial community analysis.Study DesignThis prospective case–control study involved 228 Korean pregnant women and utilized vaginal microbial community analysis, Ureaplasma/Mycoplasma culture, and 12-multiplex PCR for sexually transmitted diseases. Cross-correlation analysis in SPSS 27 compared the results of two conventional methods with vaginal microbial community analysis. R software generated box plots depicting the relative abundance of microorganisms. Network analysis was conducted using Cytoscape.ResultsPositive Ureaplasma urealyticum culture findings were observed in 60.2% of patients, with 76.4% positive for Ureaplasma parvum PCR and 13.2% positive for Ureaplasma urealyticum PCR. Mycoplasma hominis culture was positive only in two patients, while Mycoplasma hominis PCR was positive in eight women. Vaginal microbial community analysis identified significant differences in relative abundances of Gardnerella species type I and Fannyhessea vaginae between the Ureaplasma urealyticum PCR positive and negative groups. Mycoplasma hominis PCR positive patients exhibited significant differences in 11 bacterial species, including Gardnerella species I and Fannyhessea vaginae.ConclusionThis study suggests that STD-PCR may be more accurate than Ureaplasma/Mycoplasma culture for the diagnosis of Mycoplasma hominis and Ureaplasma urealyticum infection. Also, the presence of Gardnerella species I and Fannyhessea vaginae implies their potential influences on Ureaplasma urealyticum and Mycoplasma hominis infections based on results of vaginal microbial community analysis. Therefore, vaginal microbial community analysis may give the more information of their pathophysiology.

A retrospective propensity-score-matched cohort study of the impact of procalcitonin testing on antibiotic use in hospitalized patients during the first wave of COVID-19.

Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK. Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups. Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020. Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections. Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility. ISRCTN66682918.

A Scoping Review of the Clinical Utility of Laparoscopic Vasectomy

A Scoping Review of the Clinical Utility of Laparoscopic Vasectomy

Molecular diagnostic yield of exome sequencing in a Chinese cohort of 512 fetuses with anomalies

BackgroundCurrently, whole exome sequencing has been performed as a helpful complement in the prenatal setting in case of fetal anomalies. However, data on its clinical utility remain limited in practice. Herein, we reported our data of fetal exome sequencing in a cohort of 512 trios to evaluate its diagnostic yield.MethodsIn this retrospective cohort study, the couples performing prenatal exome sequencing were enrolled. Fetal phenotype was classified according to ultrasound and magnetic resonance imaging findings. Genetic variants were analyzed based on a phenotype-driven followed by genotype-driven approach in all trios.ResultsA total of 97 diagnostic variants in 65 genes were identified in 69 fetuses, with an average detection rate of 13.48%. Skeletal and renal system were the most frequently affected organs referred for whole exome sequencing, with the highest diagnostic rates. Among them, short femur and kidney cyst were the most common phenotype. Fetal growth restriction was the most frequently observed phenotype with a low detection rate (4.3%). Exome sequencing had limited value in isolated increased nuchal translucency and chest anomalies.ConclusionsThis study provides our data on the detection rate of whole exome sequencing in fetal anomalies in a large cohort. It contributes to the expanding of phenotypic and genotypic spectrum.

Clinical utility of a novel anchor pronged clips for mucosal defect closure after colorectal endoscopic submucosal dissection (with video)

Background: The MANTIS Clip (Boston Scientific) is a novel anchor pronged clip designed to enhance tissue grasping and facilitate the closure of defects in the gastrointestinal tract. This study evaluates the feasibility and effectiveness of the MANTIS Clip for closing mucosal defects following colorectal endoscopic submucosal dissection (C-ESD). Methods: A retrospective single-center study was conducted on patients who underwent C-ESD with MANTIS Clip closure from May 2023 to April 2024. The primary outcome measured was the complete closure success rate. Secondary outcomes included defect size, sustained closure rate, closure time, number of clips used, adverse events, and hospital stay duration. Results: The MANTIS Clip was used in 52 cases. The complete closure rate was 98.1% (51/52), with a sustained closure rate of 96.1% (49/51). The median closed defect size was 32 mm, with the largest being 62 mm. The median closure time was 8 minutes. Typically, one MANTIS Clip per defect was used, with only one lesion requiring two clips. The median number of additional clips used was seven. Adverse events included one case of bleeding (1.9%) and one case of post-ESD coagulation syndrome (1.9%), both managed without extending hospital stays. The median CRP level on the first day post-ESD was 0.35 mg/dl, and the median hospital stay was 5 days. Conclusions: The MANTIS Clip is effective and practical for mucosal defect closure post-C-ESD, demonstrating high success and sustained closure rates with minimal complications. Future multi-center randomized trials are needed to further assess its efficacy and safety.

The effect of fluence rate and wavelength on the formation of protoporphyrin IX photoproducts.

Photodynamic diagnosis and therapy (PDD and PDT) are emerging techniques for diagnosing and treating tumors and malignant diseases. Photoproducts of protoporphyrin IX (PpIX) used in PDD and PDT may be used in the diagnosis and treatment, making a detailed analysis of the photoproduct formation under various treatment and diagnosis conditions important.Spectroscopic and mass spectrometric analysis of photoproduct formation from PpIX dissolved in dimethyl sulfoxide were performed under commonly used irradiation conditions for PDD and PDT, i.e., wavelengths of 405 and 635nm and fluence rates of 10 and 100 mW/cm2. Irradiation resulted in the formation of hydroxyaldehyde photoproduct (photoprotoporphyrin; Ppp) and formyl photoproduct (product II; Pp II) existing in different quantities with the irradiation wavelength and fluence rate. Ppp was dominant under 635nm irradiation of PpIX, with a fluorescence peak at 673nm and a protonated monoisotopic peak at m/z 595.3. PpIX irradiation with 405nm yielded more Pp II, with a fluorescence peak at 654nm. A higher photoproduct formation was observed at a low fluence rate for irradiation with 635nm, while irradiation with 405nm indicated a higher photoproduct formation at a higher fluence rate.The photoproduct formation with the irradiation conditions can be exploited for dosimetry estimation and may be used as an additional photosensitizer to improve the diagnostics and treatment efficacies of PDD and PDT. Differences in environmental conditions of the present study from that of a biological environment may result in a variation in the photoproduct formation rate and may limit their clinical utilization in PDD and PDT. Thus, further investigation of photoproduct formation rates in more complex biological environments, including in vivo, is necessary. However, the results obtained in this study will serve as a basis for understanding reaction processes in such biological environments.

HPV 16/18 E7 oncoprotein detection as a promising triage strategy for HPV 16/18-positive patients: A prospective multicenter study with a 2-year follow up.

To explore the effectiveness of HPV 16/18 E7 oncoprotein in detecting high-grade cervical intraepithelial neoplasia (CIN) and predicting disease outcomes in HPV 16/18-positive patients. The present study was a cross-sectional study with a 2-year follow up. We collected 915 cervical exfoliated cell samples from patients who tested positive for HPV 16/18 in gynecologic clinics of three tertiary hospitals in Beijing from March 2021 to October 2022 for HPV 16/18 E7 oncoprotein testing. Subsequently, 2-year follow up of 408 patients with baseline histologic CIN1 or below were used to investigate the predictive role of HPV 16/18 E7 oncoprotein in determining HPV persistent infection and disease progression. The positivity rate of the HPV 16/18 E7 oncoprotein assay was 42.06% (249/592) in the inflammation/CIN 1 group and 85.45% (277/324) in the CIN2+ group. For CIN2+ detection, using the HPV 16/18 E7 oncoprotein assay combined with HPV 16/18 testing, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.45%, 57.94%, 52.57%, and 87.95%, respectively. During the 2-year follow up, the sensitivity, specificity, PPV, and NPV for predicting persistent HPV infection were 48.44%, 58.21%, 34.64%, and 71.18% in the baseline inflammation and CIN1 group. As a triage method for high-grade CIN screening in HPV 16/18-positive patients, HPV 16/18 E7 oncoprotein demonstrated a relatively high NPV, making it suitable for clinical use in triaging HPV 16/18-positive cases and potentially reducing the colposcopic referral rate. HPV 16/18 E7 oncoprotein exhibited a preferably predictive value in determining HPV infection outcomes and disease progression.

The clinical utility of autologous tumor lysate-loaded dendritic cell vaccination for patients with glioma: A systematic review and meta-analysis.

Dendritic cell (DC) vaccines show promise for glioma treatment, but optimal use remains uncertain. This meta-analysis examined DC vaccine efficacy and safety for gliomas. This systematic review and meta-analysis study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. From the date of inception to October 23, 2023, electronic databases PubMed, Embase, Web of Science, and Scopus have been thoroughly evaluated. A total of 12 studies with 998 patients and a mean age ranging from 40.2 to 56 years were included. Across 12 articles, DC vaccine 6-month overall survival (OS) was 100% [95% confidence interval {95%CI}: 100%-100%]. Respectively, 12-month OS reported 75% [95%CI: 65%-85%] but declined to 32% [95%CI: 20%-43%] for 24-month OS. 6- and 12-month progression-free survival reached 49% [95%CI: 21%-77%] and 19% [95%CI:8%-30%]. Studying radiological outcomes shows that complete response and partial response rates were 13% [95%CI: 17%-42%], and 26% [95%CI: 10%-42%], though stable disease reached 33% [95%CI: 15%-51%], suggesting predominant antineoplastic effects. The progressive disease rate also was 24% [95%CI: 9%-57%]. In gliomas, DC vaccinations show a temporary efficacy; stability is more prevalent than regression. Impacts favor decreased resistance to early disease. Enhancing efficacy remains critical. Early therapy can be enhanced by appropriate supplementary therapy integration.

Analysis of the CPZ/Wnt4 osteogenic pathway for high-bonding-strength composite-coated magnesium scaffolds through transcriptomics

Magnesium (Mg)-based scaffolds are garnering increasing attention as bone repair materials owing to their biodegradability and mechanical resemblance to natural bone. Their effectiveness can be augmented by incorporating surface coatings to meet clinical needs. However, the limited bonding strength and unclear mechanisms of these coatings have impeded the clinical utility of scaffolds. To address these issues, this study introduces a composite coating of high-bonding-strength polydopamine-microarc oxidation (PDA-MHA) on Mg-based scaffolds. The results showed that the PDA-MHA coating achieved a bonding strength of 40.56 ± 1.426 MPa with the Mg scaffold surface, effectively enhancing hydrophilicity and controlling degradation rates. Furthermore, the scaffold facilitated bone regeneration by influencing osteogenic markers such as RUNX-2, OPN, OCN, and VEGF. Transcriptomic analyses further demonstrated that the PDA-MHA/Mg scaffold upregulated carboxypeptidase Z expression and activated the Wnt-4/β-catenin signaling pathway, thereby promoting bone regeneration. Overall, this study demonstrated that PDA can synergistically enhance bone repair with Mg scaffold, broadening the application scenarios of Mg and PDA in the field of biomaterials. Moreover, this study provides a theoretical underpinning for the application and clinical translation of Mg-based scaffolds in bone tissue engineering endeavors.

Reversible chemoresistance of pancreatic cancer grown as spheroids

Better in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Plasma metabolic profiling reveals that crude and processed Polygonatum cyrtonema hua extract ameliorates myocardial ischemia-induced damage by regulating branched-chain amino acid and energy metabolism

Polygonatum cyrtonema Hua and its processed products have demonstrated cardio-protective effects, though the underlying mechanisms remain unclear. In this study, plasma metabolic profiling and pattern recognition were employed to explore the cardio-protective mechanisms of both crude and processed P. cyrtonema in a myocardial ischemia model induced by ligation, using gas chromatography-mass spectrometry. Post-modeling, plasma levels of creatine kinase-MB, lactate dehydrogenase, troponin T, and malondialdehyde were significantly elevated but were notably reduced after treatment. Conversely, plasma levels of glutathione peroxidase and superoxide dismutase, which were significantly decreased post-modeling, were restored following treatment. Hematoxylin-eosin (HE) and Masson staining revealed that both crude and processed P. cyrtonema effectively reduced inflammatory infiltration and fibrosis in cardiac tissue. Metabolic profiling identified 34 differential endogenous metabolites in the treatment groups, with 19 confirmed using standard compounds. The linear correlation coefficients (R2) for these standards ranged from 0.9960 to 0.9996, indicating high accuracy. The method exhibited excellent precision and repeatability, with relative standard deviation (RSD) values below 8.57%. Recovery rates were between 95.02% and 105.15%, and the stability of the standard compounds was confirmed after three freeze–thaw cycles, with RSD values under 4.42%. Both crude and processed P. cyrtonema were found to alleviate myocardial ischemia symptoms by regulating branched-chain amino acid metabolism and energy metabolism. These findings provide a solid foundation for the potential clinical use of this herb and its processed products in treating heart disease.