DLM-GelMA/tumor slice sandwich structured tumor on a chip for drug efficacy testing.

The in vitro recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better preserve the complex tumor architecture and phenotypic activity of native cells, but are limited by their exposure to fluid shear and gradual degradation under perfusion culture. Here, we established a decellularized liver matrix (DLM)-GelMA "sandwich" structure and a perfusion-based microfluidic platform to support long-term culture of tumor slices with excellent structural integrity and cell viability over 7 days. The DLM-GelMA was able to secrete cytokines and growth factors while providing shear protection to the tumor slice via the sandwich structure, leading to the preservation of the tumor microenvironment where immune cells (CD3, CD8, CD68), tumor-associated fibroblasts (α-SMA), and extracellular matrix components (collagen I, fibronectin) were well maintained. Furthermore, this chip presented anti-tumor efficacy at cisplatin (20 µM) on tumor patients, demonstrating our platform's efficacy to design patient-specific treatment regimens. Taken together, the successful development of this DLM-GelMA sandwich structure on the chip could faithfully reflect the tumor microenvironment and immune response, accelerating the screening process of drug molecules and providing insights for practical medicine.

The significance of serum SLC7A11 levels in the occurrence of vascular calcification in maintenance peritoneal dialysis patients.

AIM: This research aimed to explore the serum levels of solute carrier family 7 member 11 (SLC7A11) in patients with maintenance peritoneal dialysis (MPD) and its correlation with vascular calcification (VC) and clinical results. METHODS: This present prospective observational cohort study enrolled 189 patients with MPD who were undergoing regular peritoneal dialysis for over 3 months in our hospital from February 2020 to July 2022. The abdominal aortic calcification score was used to assess the VC condition of MPD patients. The serum SLC7A11, interleukin (IL)-6, IL-1ß and C-reactive protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Demographic and clinical statistics were collected. All patients were followed up for 1 year and the overall survival time (OS) of all patients were recorded. All data used SPSS 18.0 for statistical analyses. RESULTS: Patients with moderate/severe calcification in MPD had a longer duration of dialysis, higher serum levels of phosphate (P) and calcium (Ca) and lower serum levels of SLC7A11. Spearman's analysis revealed a negative correlation between serum SLC7A11 levels and the levels of P, Ca and IL-1ß. Additionally, we observed an association between serum SLC7A11 levels and clinical prognosis as well as the extent of VC in MPD patients. Multivariate logistic regression analysis indicated that dialysis duration, SLC7A11, and P were risk factors for VC in MPD patients. CONCLUSION: The serum SLC7A11 levels decreased remarkably in MPD patients with moderate/severe calcification. This study may provide new targets and comprehensive approach to cardiovascular protection in patients with chronic kidney disease.

Short-term effects of temperature-related indices on emergency ambulance dispatches due to mental and behavioral disorders in Shenzhen, China.

Introduction: The precise associations between temperature-related indices and mental and behavioral disorders (MBDs) have yet to be fully elucidated. Our study aims to ascertain the most effective temperature-related index and assess its immediate impact on emergency ambulance dispatches (EADs) due to MBDs in Shenzhen, China. Methods: EADs data and meteorological data from January 1, 2013, to December 31, 2020, in Shenzhen were collected. Distributed lag non-linear models (DLNMs) were utilized to examine the non-linear and lagged effects of temperature-related indices on EADs due to MBDs. The Quasi Akaike Information criterion (QAIC) was used to determine the optimal index after standardizing temperature-related indices. After adjusting for confounding factors in the model, we estimated the immediate and cumulative effects of temperature on EADs due to MBDs. Results: The analysis of short-term temperature effects on EADs due to MBDs revealed Humidex as the most suitable index. Referring to the optimal Humidex (3.2th percentile, 12.00°C), we observed a significant effect of Humidex over the threshold (34.6th percentile, 26.80°C) on EADs due to MBDs at lag 0-5. The cumulative relative risks for high temperature (90th percentile, 41.90°C) and extreme high temperature (99th percentile, 44.20°C) at lag 0-5 were 1.318 (95% CI: 1.159-1.499) and 1.338 (95% CI: 1.153-1.553), respectively. No significant cold effect was observed on EADs due to MBDs. Conclusion: High Humidex was associated with more EADs due to MBDs in subtropical regions. Health authorities should implement effective measures to raise public awareness of risks related to high temperature and protect vulnerable populations.

Causality between serum uric acid and diabetic microvascular complications - a mendelian randomization study.

BACKGROUND: The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method. METHODS: We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10- 8), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran's Q test, and polytropy was assessed using the MR‒Egger intercept. RESULTS: MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07-1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07-1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94-1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84-1.40, p = 0.549]. CONCLUSIONS: This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.

Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.

In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

A novel nomogram model to predict in-hospital mortality in patients with acute type A aortic dissection after surgery.

BACKGROUND: Acute type A aortic dissection is a dangerous disease that threatens public health. In recent years, with the progress of medical technology, the mortality rate of patients after surgery has been gradually reduced, leading that previous prediction models may not be suitable for nowadays. Therefore, the present study aims to find new independent risk factors for predicting in-hospital mortality and construct a nomogram prediction model. METHODS: The clinical data of 341 consecutive patients in our center from 2019 to 2023 were collected, and they were divided into two groups according to the death during hospitalization. The independent risk factors were analyzed by univariate and multivariate logistic regression, and the nomogram was constructed and verified based on these factors. RESULTS: age, preoperative lower limb ischemia, preoperative activated partial thromboplastin time (APTT), preoperative platelet count, Cardiopulmonary bypass (CPB) time and postoperative acute kidney injury (AKI) independently predicted in-hospital mortality of patients with acute type A aortic dissection after surgery. The area under the receiver operating characteristic curve (AUC) for the nomogram was 0.844. The calibration curve and decision curve analysis verified that the model had good quality. CONCLUSION: The new nomogram model has a good ability to predict the in-hospital mortality of patients with acute type A aortic dissection after surgery.

Chloride Corrosion Process of Concrete with Different Water-Binder Ratios under Variable Temperature Drying-Wetting Cycles.

In this paper, four water-binder ratios (w/b) of 0.29, 0.33, 0.39, and 0.46 were designed. A variable test temperature was implemented in the drying-wetting cycle test according to the temperature fluctuations in the actual service environment, and the constant temperature test was established as the control group. The mechanical properties and chloride corrosion resistance of concrete with different w/b ratios under variable temperature drying-wetting cycles, as well as the microstructure changes, phase composition, and damage mechanism inside the concrete, were investigated. The results showed that the mechanical properties of concrete increased first and then decreased with drying-wetting cycles increasing, whereas the chloride corrosion resistance continued to decline. A higher w/b exacerbated the deterioration of the concrete performance. A higher w/b increased the porosity, chloride diffusion depth, and chloride content, thus reducing the resistance of chloride corrosion. Compared with w/b = 0.29, the compressive strength, splitting tensile strength, mass, and relative dynamic elasticity modulus of w/b = 0.46 exposed to 60 drying-wetting cycles decreased by 54.50%, 52.44%, 0.96%, and 6.50%, respectively, while the porosity, peak chloride content, and erosion depth increased by 45.12%, 70.45%, and 45.00%. Compared with the drying-wetting cycle with a constant temperature, the cumulative damage caused by the drying-wetting cycle with a variable temperature was greater, resulting in more severe deterioration of concrete performance. The increase in the test temperature significantly accelerated the diffusion rate, penetration depth, and chemical binding capacity of chloride ions. After 60 drying-wetting cycles, the peak chlorine content and erosion depth of w/b = 0.46 under variable temperature cycles were 15.38% and 10.32% higher than those under a constant temperature, while the compressive strength, splitting tensile strength, mass, and relative dynamic elastic modulus were reduced by 7.76%, 14.81%, 0.33%, and 2.40%, respectively. Microscopic analysis confirmed that higher w/b and variable temperature cycles accelerated the decay of mechanical properties and the decline of chloride corrosion resistance. According to the numerical fitting analysis, the w/b should be 0.29~0.39 under the condition that the mechanical properties and chloride corrosion resistance of concrete are met.

Metal-organic frameworks-based moisture responsive essential oil hydrogel beads for fresh-cut pineapple preservation.

The preservation of fresh-cut fruits and vegetables has attracted attention to the shelf-life reduction caused by high humidity. Herein, alginate/copper ions cross-linking, in-situ growth and self-assembly techniques of metal-organic frameworks (MOFs) were utilized to prepare a moisture responsive hydrogel bead (HKUST-1@ALG). As the multistage porous structure formation, tea tree essential oil (TTO) load capacity in hydrogel bead (TTO-HKUST-1@ALG) was increased from 6.1% to 21.6%. TTO-HKUST-1@ALG had excellent moisture response performance, and the release rates of TTO increased from 33.89% to 70.98% with moisture increasing from 45% to 95%. Besides, TTO-HKUST-1@ALG exhibited excellent antimicrobial, antioxidant capacity, and biocompatibility. During storage, TTO-HKUST-1@ALG effectively improved the cell membrane integrity by maintaining the balance of reactive oxygen species metabolism. The degradation of cell wall structure and tissue softening were delayed by inhibiting the cell wall-degrading enzymes activity. Briefly, TTO-HKUST-1@ALG improved the storage quality and extended shelf-life of fresh-cut pineapple, which was a promising preservative.

PD-1 and LAG-3 positive T cells are related with the prognosis of patients with chronic kidney disease.

OBJECTIVE: Our objective was to study the frequency of circulating LAG-3+ and PD-1+ T cells in chronic kidney disease (CKD) patients and their correlation with cytokines and patient prognosis. METHODS: A total of 83 patients with CKD between June 2020 and June 2022 were enrolled. We measured serum levels of IL-6, CRP, IL-1ß, and TNF-α by ELISA. The frequency of PD-1+ and LAG-3+ T cells was measured using flow cytometry. All patients were followed up for 1 year, and the occurrence of any of the following conditions during the follow-up period was considered as major adverse cardiac events (MACE) indicating poor prognosis. RESULTS: The frequencies of LAG-3+PD-1+, LAG-3+ and PD-1+ cells were significantly increased in CKD group compared to healthy volunteers. Additionally, CKD patients had remarkably enhanced levels of cytokines. Compared to the non-MACE group, MACE group had significantly higher frequencies of LAG-3PD-1, LAG-3 and PD-1 expression on CD8 and CD4. Positive correlations were observed between IL-1ß, IL-6 and frequencies of PD-1+LAG-3+. CD4+LAG-3+PD-1+ frequency displayed the highest diagnostic value for CKD patients with MACE. Moreover, CD8+LAG-3+, CD4+LAG-3+PD-1+, CD4+PD-1+, IL-1ß and IL-6 were identified as risk factors for the occurrence of MACE in patients with CKD. CONCLUSION: In summary, the present research showed that the frequencies of LAG-3+ and PD-1+ T cells were remarkably enhanced in CKD patients. These findings offer novel insights and potential therapeutic targets for the management of CKD.

TIGIT Blockade Reshapes the Tumor Microenvironment Based on the Single-cell RNA-Sequencing Analysis.

SUMMARY: Immune checkpoint blockade therapy is a pivotal approach in treating malignant tumors. TIGIT has emerged as a focal point of interest among the diverse targets for tumor immunotherapy. Nonetheless, there is still a lack of comprehensive understanding regarding the immune microenvironment alterations following TIGIT blockade treatment. To bridge this knowledge gap, we performed single-cell sequencing on mice both before and after the administration of anti-TIGIT therapy. Our analysis revealed that TIGIT was predominantly expressed on T cells and natural killer (NK) cells. The blockade of TIGIT exhibited inhibitory effects on Treg cells by downregulating the expression of Foxp3 and reducing the secretion of immunosuppressive cytokines. In addition, TIGIT blockade facilitated the activation of NK cells, leading to an increase in cell numbers, and promoted cDC1 maturation through the secretion of XCL1 and Flt3L. This activation, in turn, stimulated the TCR signaling of CD8 + T cells, thereby enhancing their antitumor effect. Consequently, anti-TIGIT therapy demonstrated substantial potential for cancer immunotherapy. Our research provided novel insights into future therapeutic strategies targeting TIGIT for patients with cancer.

A robust approach for multi-type classification of brain tumor using deep feature fusion.

Brain tumors can be classified into many different types based on their shape, texture, and location. Accurate diagnosis of brain tumor types can help doctors to develop appropriate treatment plans to save patients' lives. Therefore, it is very crucial to improve the accuracy of this classification system for brain tumors to assist doctors in their treatment. We propose a deep feature fusion method based on convolutional neural networks to enhance the accuracy and robustness of brain tumor classification while mitigating the risk of over-fitting. Firstly, the extracted features of three pre-trained models including ResNet101, DenseNet121, and EfficientNetB0 are adjusted to ensure that the shape of extracted features for the three models is the same. Secondly, the three models are fine-tuned to extract features from brain tumor images. Thirdly, pairwise summation of the extracted features is carried out to achieve feature fusion. Finally, classification of brain tumors based on fused features is performed. The public datasets including Figshare (Dataset 1) and Kaggle (Dataset 2) are used to verify the reliability of the proposed method. Experimental results demonstrate that the fusion method of ResNet101 and DenseNet121 features achieves the best performance, which achieves classification accuracy of 99.18 and 97.24% in Figshare dataset and Kaggle dataset, respectively.

Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study.

AIMS: To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS: Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS: Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS: In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.

Efficacy and safety of Mazdutide on weight loss among diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials.

Background: Overweight and obesity are increasing global public health problems. Mazdutide is a new dual agonist drug that can potentially reduce weight and blood glucose levels simultaneously. However, the synthesis of evidence on the efficacy and safety of this drug is scarce. Therefore, this study aimed to synthesize evidence on the efficacy and safety of Mazdutide compared to placebo on weight reduction among adults with and without diabetes. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Data were retrieved from six electronic databases: PubMed, Web of Science, Scopus, Cochrane Library, ClinicalTrial.gov, and Google Scholar, and manually searched from the included references. The data were synthesized using a random effect model. This analysis was performed in the R programming language using the Meta package. Results: A total of seven RCTs involving 680 participants were included in this study. Mazdutide was more effective in reducing body weight (mean difference [MD]= -6.22%, 95% confidence interval [CI]: -8.02% to -4.41%, I2 = 90.0%), systolic blood pressure (MD = -7.57 mmHg, 95% CI: -11.17 to -3.98 mmHg, I2 = 46%), diastolic blood pressure (MD = -2.98 mmHg, 95% CI: -5.74 to -0.22 mmHg, I2 = 56%), total cholesterol (MD = -16.82%, 95% CI: -24.52 to -9.13%, I2 = 61%), triglycerides (MD = -43.29%, 95% CI: -61.57 to -25.01%, I2 = 68%), low-density lipoprotein (MD= -17.07%, 95% CI: -25.54 to -8.60%, I2 = 53%), and high-density lipoprotein (MD = -7.54%, 95% CI: -11.26 to -3.83%, I2 = 0%) than placebo. Mazdutide was associated with reduced hemoglobin A1c (HbA1c) and fasting plasma glucose in participants with type 2 diabetes. In the subgroup and meta-regression analyses, weight reduction was more significant in non-diabetics compared to diabetics, and in those who received a longer treatment duration (24 weeks) than in those on shorter durations (12-20 weeks). Participants who received Mazdutide had a higher risk of transient mild or moderate gastrointestinal side effects. Conclusion: Mazdutite appears to be effective in weight reduction among patients with and without diabetes, and it has an advantage over other associated comorbidities. However, it was associated with mild or moderate gastrointestinal side effects. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=403859, identifier CRD42023403859.

Precursor exhausted CD8+T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness.

Exhausted CD8+T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8+T cells, termed Tpex cells, which are characterized as TCF-1+PD-1+CD8+T cells. Elevated Tpex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating Tpex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of Tpex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between Tpex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for Tpex cell detection using mIHC technology but also confirmed that assessing Tpex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of Tpex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.

Inkjet-Printed Dielectric Layer for the Enhancement of Electrowetting Display Devices.

Electrowetting with a dielectric layer is commonly preferred in practical applications. However, its potential is often limited by factors like the properties of the dielectric layer and its breakdown, along with the complexity of the deposition method. Fortunately, advancements in 3D inkjet printing offer a more adaptable solution for making patterned functional layers. In this study, we used a negative photoresist (HN-1901) to create a new dielectric layer for an electrowetting display on a 3-inch ITO glass using a Dimatix DMP-2580 inkjet printer. The resulting devices performed better due to their enhanced resistance to dielectric breakdown. We meticulously investigated the physical properties of the photoresist material and printer settings to achieve optimal printing. We also controlled the uniformity of the dielectric layer by adjusting ink drop spacing. Compared to traditional electrowetting display devices, those with inkjet-printed dielectric layers showed significantly fewer defects like bubbles and electrode corrosion. They maintained an outstanding response time and breakdown resistance, operating at an open voltage of 20 V. Remarkably, these devices achieved faster response times of ton 22.3 ms and toff 14.2 ms, surpassing the performance of the standard device.

Acetyllevocarnitine Hydrochloride for the Treatment of Diabetic Peripheral Neuropathy: A Phase 3 Randomized Clinical Trial in China.

Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type 2 diabetes (T2D) for which no effective treatment is available. In this multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, patients with T2D with DPN received acetyllevocarnitine hydrochloride (ALC; 1,500 mg/day; n = 231) or placebo (n = 227) for 24 weeks, during which antidiabetic therapy was maintained. A significantly greater reduction in modified Toronto clinical neuropathy score (mTCNS) as the primary end point occurred in the ALC group (-6.9 ± 5.3 points) compared with the placebo group (-4.7 ± 5.2 points; P < 0.001). Effect sizes (ALC 1.31 and placebo 0.85) represented a 0.65-fold improvement in ALC treatment efficacy. The mTCNS values for pain did not differ significantly between the two groups (P = 0.066), whereas the remaining 10 components of mTCNS showed significant improvement in the ALC group compared with the placebo group (P < 0.05 for all). Overall results of electrophysiological measurements were inconclusive, with significant improvement in individual measurements limited primarily to the ulnar and median nerves. Incidence of treatment-emergent adverse events was 51.2% in the ALC group, among which urinary tract infection (5.9%) and hyperlipidemia (7.9%) were most frequent.

Fast Label-Free Metabolic Profile Recognition Identifies Phenylketonuria and Subtypes.

Phenylketonuria (PKU) is the most common inherited metabolic disease in humans. Clinical screening of newborn heel blood samples for PKU is costly and time-consuming because it requires multiple procedures, like isotope labeling and derivatization, and PKU subtype identification requires an additional urine sample. Delayed diagnosis of PKU, or subtype identification can result in mental disability. Here, plasmonic silver nanoshells are used for laser desorption/ionization mass spectrometry (MS) detection of PKU with label-free assay by recognizing metabolic profile in dried blood spot (DBS) samples. A total of 1100 subjects are recruited and each DBS sample can be processed in seconds. This platform achieves PKU screening with a sensitivity of 0.985 and specificity of 0.995, which is comparable to existing clinical liquid chromatography MS (LC-MS) methods. This method can process 360 samples per hour, compared with the LC-MS method which processes only 30 samples per hour. Moreover, this assay enables precise identification of PKU subtypes without the need for a urine sample. It is demonstrated that this platform enables high-performance and fast, low-cost PKU screening and subtype identification. This approach might be suitable for the detection of other clinically relevant biomarkers in blood or other clinical samples.

Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway.

BACKGROUND: Diabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear. AIM: This study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved. METHODS: C57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses. RESULTS: After a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels. CONCLUSION: Treatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.