Intermedin Alleviates Diabetic Cardiomyopathy by Up-Regulating CPT-1ß through Activation of the Phosphatidyl Inositol 3 Kinase/Protein Kinase B Signaling Pathway.

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with myocardial fatty acid metabolism. Carnitine palmitoyltransferase-1ß (CPT-1ß) is the rate-limiting enzyme responsible for ß-oxidation of long-chain fatty acids. Intermedin (IMD) is a pivotal bioactive small molecule peptide, participating in the protection of various cardiovascular diseases. However, the role and underlying mechanisms of IMD in DCM are still unclear. In this study, we investigated whether IMD alleviates DCM via regulating CPT-1ß. A rat DCM model was established by having rats to drink fructose water for 12 weeks. A mouse DCM model was induced by feeding mice a high-fat diet for 16 weeks. We showed that IMD and its receptor complexes levels were significantly down-regulated in the cardiac tissues of DCM rats and mice. Reduced expression of IMD was also observed in neonatal rat cardiomyocytes treated with palmitic acid (PA, 300 µM) in vitro. Exogenous and endogenous IMD mitigated cardiac hypertrophy, fibrosis, dysfunction, and lipid accumulation in DCM rats and IMD-transgenic DCM mice, whereas knockout of IMD worsened these pathological processes in IMD-knockout DCM mice. In vitro, IMD alleviated PA-induced cardiomyocyte hypertrophy and cardiac fibroblast activation. We found that CPT-1ß enzyme activity, mRNA and protein levels, and acetyl-CoA content were increased in T2DM patients, rats and mice. IMD up-regulated the CPT-1ß levels and acetyl-CoA content in T2DM rats and mice. Knockdown of CPT-1ß blocked the effects of IMD on increasing acetyl-CoA content and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. IMD receptor antagonist IMD17-47 and the phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 reversed the effects of IMD on up-regulating CPT-1ß and acetyl-CoA expression and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. We revealed that IMD alleviates DCM by up-regulating CPT-1ß via calcitonin receptor-like receptor/receptor activity-modifying protein (CRLR/RAMP) receptor complexes and PI3K/Akt signaling. IMD may serve as a potent therapeutic target for the treatment of DCM.

Rational Design and Modification of NphB for Cannabinoids Biosynthesis.

The rapidly growing field of cannabinoid research is gaining recognition for its impact in neuropsychopharmacology and mood regulation. However, prenyltransferase (NphB) (a key enzyme in cannabinoid precursor synthesis) still needs significant improvement in order to be usable in large-scale industrial applications due to low activity and limited product range. By rational design and high-throughput screening, NphB's catalytic efficiency and product diversity have been markedly enhanced, enabling direct production of a range of cannabinoids, without the need for traditional enzymatic conversions, thus broadening the production scope of cannabinoids, including cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), and cannabigerovarinic acid (CBGVA). Notably, the W3 mutant achieved a 10.6-fold increase in CBG yield and exhibited a 10.3- and 20.8-fold enhancement in catalytic efficiency for CBGA and CBGV production, respectively. The W4 mutant also displayed an 9.3-fold increase in CBGVA activity. Molecular dynamics simulations revealed that strategic reconfiguration of the active site's hydrogen bonding network, disulfide bond formation, and enhanced hydrophobic interactions are pivotal for the improved synthetic efficiency of these NphB mutants. Our findings advance the understanding of enzyme optimization for cannabinoid synthesis and lay a foundation for the industrial-scale production of these valuable compounds.

Comparing the Self-Reported Acceptability of Discrete Choice Experiment and Best-Worst Scaling: An Empirical Study in Patients with Type 2 Diabetes Mellitus.

Purpose: Discrete choice experiment (DCE) and profile case (case 2) best-worst scaling (BWS) present uncertainties regarding the acceptability of quantifying individual healthcare preferences, which may adversely affect the validity of responses and impede the reflection of true healthcare preferences. This study aimed to assess the acceptability of these two methods from the perspective of patients with type 2 diabetes mellitus (T2DM) and examine their association with specific characteristics of the target population. Patients and Methods: This cross-sectional study was based on a nationally representative survey; data were collected using a multistage stratified cluster-sampling procedure between September 2021 and January 2022. Eligible adults with confirmed T2DM voluntarily participated in this study. Participants completed both the DCE and case 2 BWS (BWS-2) choice tasks in random order and provided self-reported assessments of acceptability, including task completion difficulty, comprehension of task complexity, and response preference. Logistic regression and random forest models were used to identify variables associated with acceptability. Results: In total, 3286 patients with T2DM were included in the study. Respondents indicated there was no statistically significant difference in completion difficulty between the DCE and BWS-2, although the DCE scores were slightly higher (3.07 ± 0.68 vs 3.03 ± 0.67, P = 0.06). However, 1979 (60.2%) respondents found the DCE easier to comprehend. No significant preferences were observed between the two methods (1638 (49.8%) vs 1648 (50.2%)). Sociodemographic factors, such as residence, monthly out-of-pocket costs, and illness duration were significantly associated with comprehension complexity and response preference. Conclusion: This study yielded contrasting results to most of previous studies, suggesting that DCE may be less cognitively demanding and more suitable for patients with T2DM from the perspective of self-reported acceptability of DCE and BWS. This study promotes a focus on patient acceptability in quantifying individual healthcare preferences to inform tailored optimal stated-preference method for a target population.

Stated preference methodologies such as the discrete choice experiment (DCE) and case 2 best-worst scaling (BWS-2) are gaining popularity as methods for quantifying individual preferences in healthcare. However, the acceptability of the two methods to participants must be considered in practice to reduce cognitive burden and ensure the validity of preference elicitation.DCE was perceived to be less cognitively burdensome than BWS-2. In contrast to patients who thought that DCE was more acceptable, BWS-2 was more accepted by rural patients, patients who lived with the disease for a longer period, and those who had lower monthly out-of-pocket costs.These findings demonstrate potential differences in the acceptability of DCE and BWS-2 for patients with type 2 diabetes mellitus. To improve efficiency, it would be useful for researchers to consider the optimal stated preference method for identifying target populations according to sociodemographic and disease-related characteristics.

Identification of Two Linear Epitopes on MGF_110-13L Protein of African Swine Fever Virus with Monoclonal Antibodies.

African swine fever caused by African swine fever virus (ASFV) is an acute, highly contagious swine disease with high mortality. To facilitate effective vaccine development and find more serodiagnostic targets, fully exploring the ASFV antigenic proteins is urgently needed. In this study, the MGF_110-13L was identified as an immunodominant antigen among the seven transmembrane proteins. The main outer-membrane domain of MGF_110-13L was expressed and purified. Two monoclonal antibodies (mAbs; 8C3, and 10E4) against MGF_110-13L were generated. The epitopes of two mAbs were preliminary mapped with the peptide fusion proteins after probing with mAbs by enzyme-linked immunosorbent assay (ELISA) and Western blot. And the two target epitopes were fine-mapped using further truncated peptide fusion protein strategy. Finally, the core sequences of mAbs 8C3 and 10E4 were identified as 48WDCQDGICKNKITESRFIDS67, and 122GDHQQLSIKQ131, respectively. The peptides of epitopes were synthesized and probed with ASFV antibody positive pig sera by a dot blot assay, and the results showed that epitope 10E4 was an antigenic epitope. The epitope 10E4 peptide was further evaluated as a potential antigen for detecting ASFV antibodies. To our knowledge, this is the first report of antigenic epitope information on the antigenic MGF_110-13L protein of ASFV.

[Advances in using artificial intelligence for predicting protein-ligand binding affinity].

The binding of proteins and ligands is a crucial aspect of life processes. The calculation of the protein-ligand binding affinity (PLBA) offers valuable insights into protein function, drug screening targets protein receptors, and enzyme modifications. In recent years, artificial intelligence (AI) has experienced rapid advancements, becoming widely used in PLBA prediction. This is attributed to its robust feature extraction ability, superior algorithm accuracy, and speedy calculations. Our paper aims to provide a comprehensive overview of AI predication process, associated resources, application scenarios, challenges, and potential solutions, serving as a valuable reference for the relevant research endeavors.

Real-world cost- effectiveness analysis: Tumor Treating Fields for newly diagnosed glioblastoma in China.

BACKGROUND: Glioblastoma (GBM) stands as the most aggressive and prevalent primary brain malignancy. Tumor Treating Fields (TTFields), an innovative therapy complementing chemotherapy for GBM treatment, which can significantly enhance overall survival, disease progression-free survival, and patient's quality of life. However, there is a dearth of health economics evaluation on TTFields therapy both domestically and internationally. OBJECTIVE: The study aims to assess the cost-effectiveness of TTFields + temozolomide (TMZ) in comparison to TMZ alone for newly diagnosed GBM patients. The intent is to provide robust economic evidence to serve as a foundation for policymaking and decision-making processes in GBM treatment. METHODS: We estimated outcomes for newly diagnosed GBM patients over a lifetime horizon using a partitioned survival model with three states: Progression-Free Survival, Progression Disease, and Death. The survival model was derived from a real-world study in China, with long-term survival data drawn from GBM epidemiology literature. Adverse event rates were sourced from the EF-14 trial data. Cost data, validated by expert consultation, was obtained from public literature and databases. Utility values were extracted from published literature. Using Microsoft Excel, we calculated expected costs and quality-adjusted life years (QALYs) over 15 years from a health system perspective. The willingness-to-pay threshold was set at three times the Chinese per capita Gross Domestic Product (GDP) in 2022, amounting to CN¥242,928 (US$37,655) /QALY. A 5% discount rate was applied to costs and utilities. Results underwent analysis through single factor and probability sensitivity analyses. RESULTS: TTFields + TMZ demonstrated a mean increase in cost by CN¥389,326 (US$57,859) and an increase of 2.46 QALYs compared to TMZ alone. The incremental cost-effectiveness ratio (ICER) was CN¥157,979 (US$23,474) per QALY gained. The model exhibited heightened sensitivity to changes in the discount rate. Probability sensitivity analysis indicates that, under the existing threshold, the probability of TTFields + TMZ being economical is 95.60%. CONCLUSIONS: This cost-effectiveness analysis affirms that incorporating TTFields into TMZ treatment proves to be cost-effective, given a threshold three times the Chinese per capita GDP.

Cardiomyopathy in Patients With Acute Ischemic Stroke and Methamphetamine Use: Relevance for Cardioembolic Stroke and Outcome.

BACKGROUND: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke. METHODS AND RESULTS: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P<0.001), included more men (78.3% versus 52.8%; P<0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P<0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P<0.01) or hyperlipidemia (28.3% versus 51.7%; P<0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P<0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P<0.05). CONCLUSIONS: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain.

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

Patient preferences and willingness to pay for central venous access devices in breast cancer: A multicenter discrete choice experiment.

BACKGROUND: Despite being a significant management decision in clinical or nursing practice, there is limited understanding of the preferences regarding risks, benefits, costs, and other attributes of patients with breast cancer when selecting peripherally inserted central catheters or totally implanted ports. The objective of this study is to investigate the preferences of patients with breast cancer who require chemotherapy when selecting an optimal central venous access device. METHODS: Data on patients' preferences for central venous access devices were collected using a face-to-face discrete choice experiment from the oncology departments of three public hospitals in China representing the eastern (Zhejiang province), central (Henan province), and western (Sichuan province) regions. The study used six attributes to describe the preferences of breast cancer patients for central venous access devices, including out-of-pocket cost, limitations in activities of daily living, catheter maintenance frequency, risk of catheter-related thrombosis, risk of catheter-related infection, and size of incision. Data were analyzed using a conditional logit model and mixed logit model. The marginal willingness to pay (mWTP) was calculated by assessing the ratio of the preference for other attributes to the preference for out-of-pocket cost. RESULTS: A total of 573 respondents completed the survey. The discrete choice experiment results showed that respondents strongly preferred a central venous access device with a catheter maintenance frequency of one time a month (vs four times a month, ß = 1.188, p < 0.001), the lower risk of catheter-related thrombosis (2 % vs 10 %, ß = 1.068; p < 0.001) and lower risk of catheter-related infection (2 % vs 8 % risk: ß = 0.824; p < 0.001). Respondents were willing to pay CNY ¥11,968.1 (US$1776.5) for a central venous access device with a catheter maintenance frequency of one time a month rather than four times a month, ¥10,753.6 (US$1596.2) for a central venous access device with 2 % thrombosis risk over one with 10 %, and ¥8302.0 (US$1232.3) for a central venous access device with 2 % infection risk over one with 8 %. Respondents with longer travel time to the hospital, younger than 50 years old, and with urban employee basic medical insurance were willing to pay more for an improvement in the attributes. CONCLUSIONS: These findings suggest that patients with breast cancer were mainly concerned with the out-of-pocket cost, catheter maintenance frequency, risk of catheter-related thrombosis and risk of catheter-related infection when choosing a central venous access device for the delivery of chemotherapy. In clinical or nursing practice, when making central venous access device recommendation for young patients and those who live far from hospitals, totally implanted ports may be a preferable choice.

Identification and Validation of Magnolol Biosynthesis Genes in Magnolia officinalis.

Bacterial infections pose a significant risk to human health. Magnolol, derived from Magnolia officinalis, exhibits potent antibacterial properties. Synthetic biology offers a promising approach to manufacture such natural compounds. However, the plant-based biosynthesis of magnolol remains obscure, and the lack of identification of critical genes hampers its synthetic production. In this study, we have proposed a one-step conversion of magnolol from chavicol using laccase. After leveraging 20 transcriptomes from diverse parts of M. officinalis, transcripts were assembled, enriching genome annotation. Upon integrating this dataset with current genomic information, we could identify 30 laccase enzymes. From two potential gene clusters associated with magnolol production, highly expressed genes were subjected to functional analysis. In vitro experiments confirmed MoLAC14 as a pivotal enzyme in magnolol synthesis. Improvements in the thermal stability of MoLAC14 were achieved through selective mutations, where E345P, G377P, H347F, E346C, and E346F notably enhanced stability. By conducting alanine scanning, the essential residues in MoLAC14 were identified, and the L532A mutation further boosted magnolol production to an unprecedented level of 148.83 mg/L. Our findings not only elucidated the key enzymes for chavicol to magnolol conversion, but also laid the groundwork for synthetic biology-driven magnolol production, thereby providing valuable insights into M. officinalis biology and comparative plant science.

Optimizing Trilobatin Production via Screening and Modification of Glycosyltransferases.

Trilobatin (TBL) is a key sweet compound from the traditional Chinese sweet tea plant (Rubus suavissimus S. Lee). Because of its intense sweetness, superior taste profile, and minimal caloric value, it serves as an exemplary natural dihydrochalcone sweetener. It also has various health benefits, including anti-inflammatory and glucose-lowering effects. It is primarily produced through botanical extraction, which impedes its scalability and cost-effectiveness. In a novel biotechnological approach, phloretin is used as a precursor that is transformed into TBL by the glycosyltransferase enzyme ph-4'-OGT. However, this enzyme's low catalytic efficiency and by-product formation limit the large-scale synthesis of TBL. In our study, the enzyme Mdph-4'-OGT was used to screen 17 sequences across species for TBL synthesis, of which seven exhibited catalytic activity. Notably, PT577 exhibited an unparalleled 97.3% conversion yield within 3 h. We then optimized the reaction conditions of PT577, attaining a peak TBL bioproduction of 163.3 mg/L. By employing virtual screening, we identified 25 mutation sites for PT577, thereby creating mutant strains that reduced by-products by up to 50%. This research enhances the enzymatic precision for TBL biosynthesis and offers a robust foundation for its industrial-scale production, with broader implications for the engineering and in silico analysis of glycosyltransferases.

Identification and Optimization of more Efficient Olivetolic Acid Synthases.

Introduction: Olivetolic acid (OLA) is a key intermediate in cannabidiol (CBD) synthesis, and cannabinoids are important neuroactive drugs. However, the catalytic activity of olivetolic acid synthase (OLS), the key enzyme involved in OLA biosynthesis, remains low and its catalytic mechanism is unclear. Materials and Methods: In this study, we conducted a scrupulous screening of the pivotal rate-limiting enzyme and analyzed its amino acid sites that are critical to enzyme activity as validated by experiments. Results: Through stringent enzyme screening, we pinpointed a highly active OLS sequence, OLS4. Then, we narrowed down three critical amino acid sites (I258, D198, E196) that significantly influence the OLS activity. Conclusions: Our findings laid the groundwork for the efficient biosynthesis of OLA, and thereby facilitate the biosynthesis of CBD.

Mapping of health technology assessment in China: a comparative study between 2016 and 2021.

BACKGROUND: Health Technology Assessment (HTA) in China has recently expanded from purely academic research to include policy or decision-oriented practice, especially after HTA evidence was used to update the National Reimbursement Drug List for the first time in 2017. This study aims to identify the progress and challenges of HTA development from 2016 to 2021 and inform policies and decisions to promote further HTA development in China. METHODS: We conducted a cross-sectional web-based survey with policy makers, researchers and industry-providers in China in 2016 and 2021 respectively. The 'Mapping of HTA Instrument', was utilized to assess the HTA development across eight domains: Institutionalization, Identification, Priority setting, Assessment, Appraisal, Reporting, Dissemination of findings and conclusions, and Implementation in policy and practice. To reduce the influence of confounders and compare the mapping outcomes between the 2016 and 2021 groups, we conducted 1:1 Propensity Score Matching (PSM). Univariate analysis was conducted to compare the differences between the two groups. The overall results were further compared with those of a mapping study that included ten countries. RESULTS: In total, 212 and 255 respondents completed the survey in 2016 and 2021, respectively. The total score of the HTA development level in China in 2021 was higher than that in 2016 before PSM (89.38 versus 83.96). Following PSM, 183 respondents from the 2016 and 2021 groups were matched. Overall, the mean scores for most indicators in the Institutionalization domain and Dissemination domain in 2021 were higher than those in 2016 (P < 0.05). The Appraisal domain in 2021 was more explicit, transparent and replicable than that in 2016 (t = -3.279, P < 0.05). However, the mean scores of most indicators in the Assessment domain were higher in 2016 than those in 2021 (P < 0.05). CONCLUSIONS: Our study suggest that the level of HTA development in China progressed significantly from 2016 to 2021. However, before engaging in HTA activities, further efforts are required to enhance the assessment process. For instance, it is important to establish a clear goal and scope for HTA; adapt standardized methodologies for evaluating the performance of systematic reviews or meta-analyses; and provide comprehensive descriptions of the safety, clinical effectiveness, cost, and cost-effectiveness of the assessed technologies, thus improving the development of HTA in China.

A literature review on Epimedium, a medicinal plant with promising slow aging properties.

Ethnopharmacological relevance: Aging is related to many factors, such as genes, oxidative damage, metabolic abnormalities, immune regulation and sex hormones. This article reviews the pharmacological mechanism of Epimedium on slow aging from six aspects: gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, the regulation of sex hormone, and clinical efficacy.Aim of the studyThrough literature review, to discover the potential pharmacological mechanism of Epimedium for slow aging. Materials and methods: We reviewed the literature on the applications of Epimedium in multiple systems and the potential underlying mechanisms with systematic and comprehensive illustrations. The review includes the following aspects: gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, the regulation of sex hormone, clinical efficacy and safety. Results: The slow aging active components of Epimedium may be flavonoids, such as Epimedins A, B, C and icariin The slow aging effect of Epimedium may be related to gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, and the regulation of sex hormone. No severe adverse reaction has been reported. Conclusions: Epimedium has potential slow aging effect and been widely used in the clinic for aging-related diseases in the real world in China; however, large-scale studies are still needed.

Propranolol or Beta-Blockers for Cerebral Cavernous Malformation: a Systematic Review and Meta-analysis of Literature in Both Preclinical and Clinical Studies.

Cerebral cavernous malformation (CCM), either sporadic or familial, is a devastating vascular malformation affecting the central nervous system that can present with intracerebral hemorrhage, seizure, and new focal neurologic deficits resulting in substantial morbidity and mortality. To date, there is no effective evidence-based preventive regimen. There have been several preclinical and clinical studies investigating the potential mechanisms and benefits of beta-blockers, especially on propranolol. We aimed to conduct a systematic review on the published literature investigating the use of beta-blockers in the treatment of CCM, including both preclinical and clinical studies between 2008 and 2023 using public databases. A total of 2 preclinical studies and 6 clinical studies met the inclusion/exclusion criteria and were included. Data was extracted and synthesized from 5 clinical studies for meta-analysis. The meta-analysis failed to demonstrate a statistically significant protective effect of beta-blockers in preventing intracerebral hemorrhage or developing focal neurologic deficits in subjects with CCM (overall effect = 0.78 (0.20, 3.11), p = 0.73). Overall, there was a paucity of high quality clinical trials, partially due to limited cases of CCM. Addressing this gap may require collaborative efforts at a national or international level. In this review, we summarized all barriers and opportunities on this topic. Additionally, we proposed establishing an evidence-based approach on the use of beta-blockers in preventing recurrent hemorrhage and focal neurological deficits in patients with CCM.

Intermedin alleviates diabetic vascular calcification by inhibiting GLUT1 through activation of the cAMP/PKA signaling pathway.

BACKGROUND AND AIMS: Vascular calcification (VC) is regarded as an independent risk factor for cardiovascular events in type 2 diabetic patients. Glucose transporter 1 (GLUT1) involves VC. Intermedin/Adrenomedullin-2 (IMD/ADM2) is a cardiovascular protective peptide that can inhibit multiple disease-associated VC. However, the role and mechanism of IMD in diabetic VC remain unclear. Here, we investigated whether IMD inhibits diabetic VC by inhibiting GLUT1. METHODS AND RESULTS: It was found that plasma IMD concentration was significantly decreased in type 2 diabetic patients and in fructose-induced diabetic rats compared with that in controls. Plasma IMD content was inversely correlated with fasting blood glucose level and VC severity. IMD alleviated VC in fructose-induced diabetic rats. Deficiency of Adm2 aggravated and Adm2 overexpression attenuated VC in high-fat diet-induced diabetic mice. In vitro, IMD mitigated high glucose-induced calcification of vascular smooth muscle cells (VSMCs). Mechanistically, IMD reduced advanced glycation end products (AGEs) content and the level of receptor for AGEs (RAGE). IMD decreased glucose transporter 1 (GLUT1) levels. The inhibitory effect of IMD on RAGE protein level was blocked by GLUT1 knockdown. GLUT1 knockdown abolished the effect of IMD on alleviating VSMC calcification. IMD receptor antagonist IMD17-47 and cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) inhibitor H89 abolished the inhibitory effects of IMD on GLUT1 and VSMC calcification. CONCLUSIONS: These findings revealed that IMD exerted its anti-calcification effect by inhibiting GLUT1, providing a novel therapeutic target for diabetic VC.

Patient preferences and shared decision making for the traditional Chinese medicine treatment of lung cancer: A discrete choice experiment study.

Background: Traditional Chinese Medicine (TCM), integrating patient preferences into decision-making process, has been widely used in the multimodality therapy of lung cancer. This study aimed to estimate patient preferences for treatment and shared decision-making (SDM) modes concerning inpatient TCM treatment of lung cancer in Shanghai in order to provide a basis for clinical decision-making process on TCM therapy for lung cancer. Methods: This study was conducted among patients (n = 347) from nine tertiary hospitals in Shanghai by discrete-choice experiment (DCE) survey and Shared Decision-Making Questionnaire-patient version (SDM-Q-9) survey. The DCE was developed with the inclusion of the most relevant attributes at appropriate levels for the TCM treatment of lung cancer. The empirical data analyses of patients were performed using mixed logit models. Additionally, subgroup analysis was conducted. Results: In total, 347 respondents completed the questionnaire. All attributes' coefficients were statistically significant for patients' preferences. Patients showed strong preferences for increasing disease control rate, relieving nausea and vomiting, reducing the risk of side effects, and were concerned about monthly out-of-pocket costs. Subgroup analysis indicated that patients with a lower SDM-Q-9 score and those who were satisfied with medical services emphasized more importance of higher disease control rate. Furthermore, most of the patients (90.20%) self-reported a high willingness to use SDM during the decision-making process. Conclusion: In Shanghai, patients mainly preferred SDM and considered disease control rate as the most essential attribute in the TCM treatment of lung cancer. The study findings could underscore the importance of considering patients' preferences and promote SDM.

MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas.

Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in millions of women worldwide. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyomas that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant MED12 (mut-MED12) versus WT-MED12 leiomyomas. Integration of cistromic and transcriptomics data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene that was significantly upregulated in mut-MED12 leiomyomas when compared with adjacent myometrium and WT-MED12 leiomyomas. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyomas. Treatment of primary mut-MED12 leiomyoma cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis, and induced AHR-target gene expression, whereas blocking the TDO2/kynurenine/AHR pathway by siRNA or pharmacological treatment abolished these effects. Progesterone receptors regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for leiomyoma growth. In summary, activation of the TDO2/kynurenine/AHR pathway selectively in mut-MED12 leiomyomas promoted tumor growth and may inform the future development of targeted treatments and precision medicine.

Quantifying Benefit-Risk Trade-Offs Toward Prophylactic Treatment Among Adult Patients With Hemophilia A in China: Discrete Choice Experiment Study.

BACKGROUND: Hemophilia A is a chronic condition that requires meticulous treatment and management. Patient preferences for prophylactic treatment can substantially influence adherence, outcomes, and quality of life, yet these preferences remain underexplored, particularly in China. OBJECTIVE: This study aimed to investigate the preferences for prophylactic treatment among Chinese adult patients with hemophilia A without inhibitors, considering clinical effectiveness, side effects, dosing mode, and dosing frequency. METHODS: A discrete choice experiment was used to elicit patient preferences for prophylactic treatment of hemophilia. The study was conducted across 7 provinces in China with socioeconomic and geographical diversity. Subgroup analysis was performed according to education level, geographic location, and treatment type, alongside the exploration of benefit-risk trade-offs. RESULTS: A total of 113 patients completed the discrete choice experiment questionnaire, and we included 102 responses for analysis based on predetermined exclusion criteria. The study found that patients prioritized reducing annual bleeding times and avoiding the risk of developing inhibitors over treatment process attributes. Subgroup analysis revealed that lower-educated patients and those from rural areas attached more importance to the dosing mode, likely due to barriers to self-administration. Patients demonstrated a clear understanding of benefit-risk trade-offs, exhibiting a willingness to accept an increased risk of developing inhibitors for improved clinical outcomes. CONCLUSIONS: This study provides valuable insights into the preferences of patients with hemophilia A for prophylactic treatment in China. Understanding these preferences can enhance shared decision-making between patients and clinicians, fostering personalized prophylactic treatment plans that may optimize adherence and improve clinical outcomes.