Drug Treatment Research Articles

Vanillin, ferulic acid and their 1:1 combination inhibit lipid accumulation in 3T3 L1 adipocytes and 3D spheroids

BackgroundObesity is poised to be a major healthcare crisis worldwide. Genetic predisposition, inadequate activity, changing lifestyle and dietary patterns are cited as major causes for obesity. Even as a number of anti-obesity medications hit the market, there is still an ongoing quest to explore natural compounds, which are perceived as safer alternatives, for their anti-obesity activity. This study explores the anti-obesity potential of dietary polyphenols vanillin, ferulic acid and their combination using 3T3 L1 adipocytes and their 3D spheroids. MethodsStudies were conducted on differentiated 3T3 L1 adipocytes and their 3D spheroids. Assays conducted on 3T3 L1 adipocytes include Oil red O, fluorescent Nile Red staining and triglyceride quantification to assess effect on lipid droplet accumulation. 2 NBDG was used to assess glucose uptake following drug treatment. 3D spheroid cultures were generated and triglyceride content was quantified. Effect of drug treatment on gene expression was analysed using qRT-PCR. Results of monolayer culture were compared with 3D spheroid models. ResultsVanillin, ferulic acid and their combination lower intracellular triglyceride content and lipid droplet accumulation, inhibiting glucose uptake and conversion to triglycerides in 3T3 L1 adipocytes and their 3D spheroids. Compounds and their combination downregulated mRNA expression of C/EBP α and PPAR ɣ, FAS, ACC1, GLUT4, LPL, aP2. Vanillin treatment upregulated leptin mRNA expression. ConclusionVanillin, ferulic acid and their combination lower lipid accumulation and glucose uptake in 3T3 L1 adipocytes and 3D spheroids.

Acupuncture treatment is associated with a decreased risk of dementia in patients with rheumatoid arthritis in Taiwan: a propensity-score matched cohort study

BackgroundThe purpose of this study was to understand whether acupuncture can decrease the risk of dementia in patients with rheumatoid arthritis (RA). MethodsUsing the registry from the National Health Insurance Research Database of Taiwan, we carried out a 1:1 propensity-score matched cohort study to analyze patients with RA diagnosed between 2000 and 2010. The patients who received acupuncture therapy were grouped as acupuncture users (n=9,919), while the others were grouped as non-acupuncture users (n=19,331). After propensity-score matching, the final sample included 9,218 matched participants in both groups, and these participants were followed up until the end of 2011. We used a Cox regression model to adjust for age, sex, comorbidiy, and conventional drugs and compared the hazard ratios (HRs) of developing dementia in the acupuncture and non-acupuncture groups. ResultsAcupuncture users tended to be more female-dominant and younger than non-acupuncture users. After propensity-score matching, both groups have comparable demographic characteristics. Acupuncture users had a lower risk of dementia than non-acupuncture users (adjusted HR: 0.55, 95% CI: 0.46-0.66). The cumulative incidence of dementia in the acupuncture group was significantly lower than that in the non-acupuncture group (log-rank test, p < 0.001). Patients who received the combinational treatment of conventional drugs and acupuncture had a significantly lower risk of developing dementia (adjusted HR: 0.64, 95% CI: 0.56-0.73) compared to those who only received conventional drugs. ConclusionAcupuncture therapy is associated with a reduced risk of dementia in patients with RA. Further clinical and mechanistic studies are needed.

Anticoagulant therapy in venous thromboembolism and bleeding risk: focus on the use of predictive scores.

The standard treatment for venous thromboembolism (Vte) is anticoagulation. Drug selection and treatment duration will depend on the clinical presentation, the existence of provoking factors, bleeding risk, and the patient's preferences. Anticoagulation therapy is indicated for 3-6 months in all patients with acute Vte but may be extended, even indefinitely in some cases. The most severe side effect of anticoagulation is bleeding, with the highest risk occurring during the 1st months of therapy. Balancing the risk of bleeding and the risk of recurrence in patients with Vte remain a major issue. There are, currently, no simple and validated predictive scores to estimate the long-term bleeding risk in patients undergoing anticoagulant treatment and to safely select those patients with higher bleeding risk. In this review we will examine some of these scores, including the RIETE scores, the HAS-BLED SCORE, the VTE-BLEED score, the VTE- PREDICT and the ACCP guidelines and the timing for their application in the patient's population treated for Vte as well as the initial and long-term management and evaluation of thromboembolic disease.

Research priorities for progressive pulmonary fibrosis in the UK

IntroductionHealth research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial...

A Facile, Transfection-Free Approach to siRNA Delivery in In Vitro 3D Spheroid Models.

Cell culture has long been essential for preclinical modeling of human development and disease. However, conventional two-dimensional (2D) cell culture fails to faithfully model the complexity found in vivo, and novel drug candidates that show promising results in 2D models often do not translate to the clinic. More recently, three-dimensional (3D) cell culture models have gained popularity owing to their greater physiological relevance to in vivo biology. In particular, 3D spheroid models are becoming widely used due to their ability to mimic solid tumors, both in architecture and gradation of nutrients distributed from the outer, proliferative layers into the inner, quiescent layers of cells. Similar to in vivo tumors, cell lines grown in 3D spheroid models tend to be more resistant to antitumor drug treatments than their 2D cultured counterparts, though distinct signaling pathways and gene targets conferring this resistance have yet to be fully explored. RNA interference (RNAi) is an effective tool to elucidate gene function and discover novel druggable targets in 2D models; however, only a few studies have successfully performed RNAi in complex 3D models to date. Here, we demonstrate efficient RNAi-mediated knockdown using "transfection-free" Dharmacon Accell siRNAs in three spheroid culture models, in the presence or absence of the extracellular matrix. This methodology has the potential to be scaled up for complex arrayed screening experiments, which may aid in the identification of novel druggable targets with greater clinical relevance than those identified in 2D experiments. © 2024 Dharmacon, Inc. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of 3D spheroids in matrix-free ULA plates Alternate Protocol 1: Generation of Matrigel matrix-embedded 3D spheroids Alternate Protocol 2: Generation of GrowDex hydrogel-embedded 3D spheroids Basic Protocol 2: Delivery of siRNA and collection of matrix-free 3D spheroids Alternate Protocol 3: Delivery of siRNA and collection of matrix-embedded spheroids Basic Protocol 3: RNA and protein extraction from spheroids for characterization of gene knockdown.

Pain Interference in Juvenile Idiopathic Arthritis.

Despite treatment advances, pain remains a serious problem for many children with juvenile idiopathic arthritis (JIA). To better understand pain in children with JIA and identify potentially modifiable factors, this study evaluated Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference (PI) and its relationships with other pain measures and demographic, clinical, psychosocial, and functional variables. This cross-sectional, observational, multicenter study used descriptive statistics and a mix of bivariate and multivariable analyses to describe PI and characterize relationships with other measures and variables. Among 355 children with JIA, 27% reported moderate or severe PI and 13.3% reported daily pain. PI correlated with other pain measures. Increasing age, decreasing disease duration, and increasing number of active joints, as well as presence of active disease, steroid treatment, and biologic treatment, were associated with greater PI. All PROMIS psychosocial and functional measures were associated with PI in the expected direction except for PROMIS Pediatric Physical Activity, which showed no association. In multivariable analyses, only PROMIS Fatigue, PROMIS Mobility, and the exploratory interaction of PROMIS Anxiety and disease-modifying antirheumatic drug treatment were significant. Moderate and severe PI was prevalent in this sample of children with JIA. PI increased with age and indicators of disease activity, but was more strongly associated with increasing fatigue and decreasing mobility. Findings support the use of PI as a short, easily administered multidimensional pain measure as part of routine clinical care. Fatigue, mobility, and disease activity should be assessed further when PI is high.

A thermoresponsive metabolic nanomodulator for achieving photochemotherapy-sensitized cancer immunotherapy

The largest obstacle that impedes the successful clinical use of anticancer nanodrugs lies in their unsatisfactory therapeutic performance even if multiple drug treatments are applied, which may cause tumor relapse and drug resistance. Therefore, it is challenging to develop effective nanodrugs that can eradicate tumors with only single injection. Herein, we construct a metabolic nanomodulator (denoted as ISM liposome), where the phototherapeutic dye IR825-NH2, the chemodrug shikonin, and the mitochondrial respiration inhibitor metformin are encapsulated, to closely synergize phototherapy, chemotherapy, and immunotherapy via the laser-triggered on-demand metabolism regulation for realizing robust anticancer potency after only single injection and irradiation. Upon near-infrared laser irradiation, IR825-NH2 can generate reactive oxygen species and mild heat to enable the phototherapeutic cytotoxcity and thermoresponsive release of the loaded drugs. Then, cellular oxygen can be spared by the released metformin via metabolic modulation and be utilized by shikonin to further amplify the oxidative stress in cancer cells. More importantly, the ISM liposome-mediated photochemotherapy can subsequently elicit a strong immunogenic cell death (ICD) effect and sensitize the immunosupressive tumor to the ICD-induced immunotherapy, thereby achieving strong tumor inhibition and even eradication. The metabolic nanomodulator-based photochemotherapy-sensitized cancer immunotherapy may represent a new solution to fight against cancer.

Drug response-based precision therapeutic selection for tamoxifen-resistant triple-positive breast cancer

Breast cancer adaptability to the drug environment reduces the chemotherapeutic response and facilitates acquired drug resistance. Cancer-specific therapeutics can be more effective against advanced-stage cancer than standard chemotherapeutics. To extend the paradigm of cancer-specific therapeutics, clinically relevant acquired tamoxifen-resistant MCF-7 proteome was deconstructed to identify possible druggable targets (N = 150). Twenty-eight drug inhibitors were used against identified druggable targets to suppress non-resistant (NC) and resistant cells (RC). First, selected drugs were screened using growth-inhibitory response against NC and RC. Seven drugs were shortlisted for their time-dependent (10–12 days) cytotoxic effect and further narrowed to three effective drugs (e.g., cisplatin, doxorubicin, and hydroxychloroquine). The growth-suppressive effectiveness of selected drugs was validated in the complex spheroid model (progressive and regressive). In the progressive model, doxorubicin (RC: 83.64 %, NC: 54.81 %), followed by cisplatin (RC: 76.66 %, NC: 68.94 %) and hydroxychloroquine (RC: 68.70 %, NC: 61.78 %) showed a significant growth-suppressive effect. However, in fully grown regressive spheroid, after 4th drug treatment, cisplatin significantly suppressed RC (84.79 %) and NC (40.21 %), while doxorubicin and hydroxychloroquine significantly suppressed only RC (76.09 and 76.34 %). Our in-depth investigation effectively integrated the expression data with the cancer-specific therapeutic investigation. Furthermore, our three-step sequential drug-screening approach unbiasedly identified cisplatin, doxorubicin, and hydroxychloroquine as an efficacious drug to target heterogeneous cancer cell populations. Significance statementHormonal-positive BC grows slowly, and hormonal-inhibitors effectively suppress the oncogenesis. However, development of drug-resistance not only reduces the drug-response but also increases the chance of BC aggressiveness. Further, alternative chemotherapeutics are widely used to control advanced-stage BC. In contrast, we hypothesized that, compared to standard chemotherapeutics, cancer-specific drugs can be more effective against resistant-cancer. Although cancer-specific treatment identification is an uphill battle, our work shows proteome data can be used for drug selection. We identified multiple druggable targets and, using ex-vivo methods narrowed multiple drugs to disease-condition-specific therapeutics. We consider that our investigation successfully interconnected the expression data with the functional disease-specific therapeutic investigation and selected drugs can be used for effective resistant treatment with higher therapeutic response.

Targeting RNA Helicase DDX3X with a Small Molecule Inhibitor for Breast Cancer Bone Metastasis Treatment

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

3D-printed individual template brachytherapy for the treatment of intractable central pelvic recurrent cervical cancer: A single institution experience

OBJECTIVEThe prognosis of recurrent cervical cancer tends to be poor and there are limited effective treatments currently available for these patients. This study was developed to find a safe and effective treatment for patients with central pelvic recurrent cervical cancer. MATERIALS AND METHODSThis retrospective study analyzed patients with central pelvic recurrent cervical cancer who received 3D-printed individual template (3D-PIT) brachytherapy between February 2019 and June 2023. Analyses of dosimetric parameters, toxicity-related complications, and survival were conducted based on the data of these patients. RESULTSTwenty-one patients with central pelvic recurrent cervical cancer patients were enrolled. All of them received 3D-printed individual template (3D-PIT) brachytherapy. The mean respective adjusted cumulative HRCTV-D90 and HRCTV-D98 values for these patients were 86.9 Gy and 75.4 Gy. And the local control (LC) rate of these patients was 57.1%. In these 21 patients, only 2 (9.5%) of them experienced grade 3–4 rectal adverse reactions, while 7 (33.3%) patients experienced grade 3–4 bladder adverse reactions. 5(23.8%) patients had fistula, while 3 of these 5 patients had undergone prior anti-VEGF targeted drug treatment which is a risk factor of fistula. The respective 2-year rates of overall and progression-free survival (OS and PFS) for these patients were 72.9% and 57.4%, with a 26-month median PFS. CONCLUSIONSThese single-institution data highlight the potential viability of 3D-PIT brachytherapy as an approach to managing intractable central pelvic recurrent cervical cancer following first-line treatment.

Benzothiazole derivatives in the design of antitumor agents.

Benzothiazoles are a class of heterocycles with multiple applications as anticancer, antibiotic, antiviral, and anti-inflammatory agents. Benzothiazole is a privileged scaffold in drug discovery programs for modulating a variety of biological functions. This review focuses on the design and synthesis of new benzothiazole derivatives targeting hypoxic tumors. Cancer is a major health problem, being among the leading causes of death. Tumor-hypoxicareas promote proliferation, malignancy, and resistance to drug treatment, leading to the dysregulation of key signaling pathways that involve drug targets such as vascular endothelial growth factor, epidermal growth factor receptor, hepatocyte growth factor receptor, dual-specificity protein kinase, cyclin-dependent protein kinases, casein kinase2, Rho-related coil formation protein kinase, tunica interna endothelial cell kinase, cyclooxygenase-2, adenosine kinase, lysophosphatidic acid acyltransferases, stearoyl-CoA desaturase, peroxisome proliferator-activated receptors, thioredoxin, heat shock proteins, and carbonic anhydrase IX/XII. In turn, they regulate angiogenesis, proliferation, differentiation, and cell survival, controlling the cell cycle, inflammation, the immune system, and metabolic alterations. A wide diversity of benzothiazoles were reported over the last years to interfere with various proteins involved in tumorigenesis and, more specifically, in hypoxic tumors. Many hypoxic targets are overexpressed as a result of the hypoxia-inducible factor activation cascade and may not be present in normal tissues, providing a potential strategy for selectively targeting hypoxic cancers.

Patient-reported preferences for subcutaneous or intravenous administration of parenteral drug treatments in adults with immune disorders: a systematic review and meta-analysis.

Aim: Several studies have found subcutaneous (SC) and intravenous (IV) administration of similar drugs for long-lasting immunological and autoimmune diseases to have similar clinical effectiveness, meaning that what patients report they prefer is, or should be, a major factor in treatment choices. Therefore, it is important to systematically compile evidence regarding patient preferences, treatment satisfaction and health-related quality of life (HRQL) using SC or IV administration of the same drug. Materials & methods: PubMed database searches were run on 15 October 2021. Studies involving patients with experience of both home-based SC and hospital-based IV administration of immunoglobulins or biological therapies for the treatment of any autoimmune disease or primary immunodeficiencies (PIDs) were included. The outcomes assessed were patient preferences, treatment satisfaction and HRQL. Preference data were meta-analyzed using a random-effects model. Results: In total, 3504 citations were screened, and 46 publications describing 37 studies were included in the review. There was a strong overall preference for SC over IV administration, with similar results seen for PIDs and autoimmune diseases: PID, 80% (95% confidence interval [CI], 64-94%) preferred SC; autoimmune diseases, 83% (95% CI: 73-92%); overall, 82% (95% CI: 75-89%). The meta-analysis also found that 84% (95% CI: 75-92%) of patients preferred administration at home to treatment in hospital. Analysis of treatment satisfaction using the life quality index found consistently better treatment interference and treatment setting scores with SC administration than with IV administration. Conclusion: Compared with IV infusions in hospital, patients tend to prefer, to be more satisfied with and to report better HRQL with SC administration of the same drug at home, primarily due to the greater convenience. This study contributes to evidence-based care of patients with autoimmune diseases or PIDs.

Review and prospect of the diagnosis and treatment of head and neck paragangliomas

ead and neck paraganglioma（HNPGL） often originates from the parasympathetic ganglia and is a highly invasive benign tumor. The diagnosis and treatment of this disease with strong heterogeneity is still a challenge. In the future, deep exploration is needed in genetic typing, grading diagnosis and treatment decisions, protection of cranial nerves and new drug treatments to better treat this disease.

Research Mechanism and Progress of the Natural Compound Curcumin in Treating Alzheimer´s Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. AD patients usually present symptoms, such as cognitive dysfunction, progressive memory loss, and other manifestations. With the increasing number of AD cases worldwide, there is an urgent need to develop effective drug treatments. Currently, drugs targeting AD symptoms may not change or prevent the progression of the disease. Curcumin, a polyphenol extracted from the turmeric herb, has been used for the treatment of AD. In this review, we summarized both cellular and animal studies and described the mechanism of action of curcumin in altering the pathological features of AD. Curcumin attenuates the formation of amyloid-β plaques and promotes its decomposition, reduces the phosphorylation of tau, improves its clearance rate, and binds with copper to reduce cholesterol. It changes the activity of microglia, suppresses acetylcholinesterase, regulates insulin signal transduction, and exhibits antioxidant properties. Studies have found that curcumin can promote nerve repair and has a significant effect on AD. However, the low bioavailability of curcumin may hinder its use as a therapeutic agent. If this limitation can be overcome, curcumin may emerge as a promising drug for the treatment of AD.

SOX-5 Transcription Factor: a Novel Psoriatic Autoantigen Preferentially Found in Women.

Adaptive immunity mediates psoriatic disease pathogenesis. We aimed to identify novel psoriatic autoantigens and their phenotypic associations in deeply characterized patient cohorts. Sera from psoriatic arthritis (PsA) patients were used for autoantibody discovery. Immunoprecipitations performed with cell lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence and clinical features associated with anti-SRY-Box transcription factor-D (SOX-D) antibodies were determined by screening discovery cohorts of patients with PsA (n = 135), patients with psoriasis without PsA (n = 24), and healthy controls (n = 41). A PsA validation cohort (n = 325) and disease control samples of individuals with rheumatoid arthritis (RA; n = 66) and systemic lupus erythematosus (SLE, n = 66) were assayed for anti-SOX5 antibodies. Disease characteristics were compared by antibody status. Longitudinal data were analyzed using linear mixed-effects models with patient-specific intercept to ascertain associations. We also tested PsA sera for the recently described anti-ADAMTS-L5 autoantibody in PsA. The novel autoantigens identified were SOX-D transcription factors, with SOX-5 being the focus of this analysis. Anti-SOX5 antibodies were present in 8.9% (12 of 135) and 4.3% (14 of 323) of patients in the PsA discovery and validation cohorts, respectively, 12.5% of patients (3 of 24) in the psoriasis group, 2.4% (1 of 41) of healthy controls, and 7.6% (5 of 66) each of patients in the RA and SLE groups. Anti-SOX5 were associated with female sex in both PsA cohorts (discovery: 15.7% women, 2.6% men, P = 0.006; validation: 6.3% women, 1.4% men, P = 0.049). In a longitudinal analysis adjusted for sex, anti-SOX5 associated with biologic disease-modifying antirheumatic drug treatment (95% vs 61%; P = 0.001; n = 96) and with differences in estimated treatment effects by mechanism of action. Anti-ADAMTS-L5 autoantibodies were identified in 8 of 124 patients (6.5%) in the PsA group. SOX-D transcription factors are novel psoriatic autoantigens. Anti-SOX5 antibodies were preferentially found in women with PsA and associated with specific clinical and treatment characteristics, suggesting that anti-SOX5 antibodies may identify mechanistic subgroups. We independently validated anti-ADAMTS-L5 autoantibodies in PsA.

Multi-task deep latent spaces for cancer survival and drug sensitivity prediction.

Cancer is a very heterogeneous disease that can be difficult to treat without addressing the specific mechanisms driving tumour progression in a given patient. High-throughput screening and sequencing data from cancer cell-lines has driven many developments in drug development, however, there are important aspects crucial to precision medicine that are often overlooked, namely the inherent differences between tumours in patients and the cell-lines used to model them in vitro. Recent developments in transfer learning methods for patient and cell-line data have shown progress in translating results from cell-lines to individual patients in silico. However, transfer learning can be forceful and there is a risk that clinically relevant patterns in the omics profiles of patients are lost in the process. We present MODAE, a novel deep learning algorithm to integrate omics profiles from cell-lines and patients for the purposes of exploring precision medicine opportunities. MODAE implements patient survival prediction as an additional task in a drug-sensitivity transfer learning schema and aims to balance autoencoding, domain adaptation, drug-sensitivity prediction, and survival prediction objectives in order to better preserve the heterogeneity between patients that is relevant to survival. While burdened with these additional tasks, MODAE performed on par with baseline survival models, but struggled in the drug-sensitivity prediction task. Nevertheless, these preliminary results were promising and show that MODAE provides a novel AI-based method for prioritizing drug treatments for high-risk patients. https://github.com/UEFBiomedicalInformaticsLab/MODAE.

To Explore the Rule and Mechanism of Traditional Chinese Medicine in the Treatment of Postmenopausal Osteoporosis Based on Data Mining, Network Pharmacology and Molecular Docking Technology

Postmenopausal osteoporosis (PMOP) is an important part of primary osteoporosis, and the current clinical treatment program for PMOP is easily limited by side effects and adverse reactions, so it is particularly important to seek more efficient, safe, and economical drug treatment for PMOP. In recent years, with the change of disease treatment mode and the gradual deepening of Traditional Chinese medicine (TCM) research on PMOP, a review of the literature reveals that there is a huge number of studies on the use of TCM in the treatment of PMOP, but there are no relevant systematic studies on the rules of its formulas and the specific mechanisms by which the core drugs exert their therapeutic effects. Therefore, in this study, we collected a total of 141 formulas used by TCM clinicians to treat PMOP, statistically analyzed their high-frequency medications, Four Qi, Five Flavors, meridians, and efficacies, and analyzed the core medications based on the association rules, which were Rehmanniae Radix Praeparata, Epimedium, Eucommia ulmoides, Rhizoma Drynariae, Angelica sinensis, Achyranthes, Astragalus propinquus, Psoralen, Cornus officinalis and licorice. A total of 87 drug pairs were obtained from the correlation analysis, and a total of 8 groups of potential core combination drugs and 4 potential new prescriptions were derived based on the cluster analysis. Subsequently, a network pharmacological analysis of the core drugs was conducted to obtain 173 active ingredients in the core drugs, including kaempferol, β-sitosterol, quercetin, etc. 298 targets of action, including MAPK3, STAT1, HSP90AA1, etc. 170 signaling pathways including AGE-RAGE, PI3 K/Akt, TNF, HIF-1 and others. The molecular docking results showed that 11 key active ingredients in the core drugs had stable binding to the target targets. This study showed that TCM treatment of PMOP is mainly based on “reinforcing liver and kidney, warmly invigorating spleen and stomach, activating blood and resolving stasis.” Core drugs therapy for PMOP is a comprehensive intervention through multi-component, multi-target, and multi-pathway approaches. The minimum binding energies between the 11 key active ingredients and the 11 key targets were calculated in a comprehensive analysis, which shows that the core drugs have good binding activities to their therapeutic targets, proving that the predictions of this study are reliable. In the future, it will provide certain medication basis and data support for TCM treatment of PMOP.

Non-canonical olfactory pathway activation induces cell fusion of cervical cancer cells

Multinucleation occurs in various types of advanced cancers and contributes to their malignant characteristics, including anticancer drug resistance. Therefore, inhibiting multinucleation can improve cancer prognosis; however, the molecular mechanisms underlying multinucleation remain elusive. Here, we introduced a genetic mutation in cervical cancer cells to induce cell fusion-mediated multinucleation. The olfactory receptor OR1N2 was heterozygously mutated in these fused cells; the same OR1N2 mutation was detected in multinucleated cells from clinical cervical cancer specimens. The mutation-induced structural change in the OR1N2 protein activated protein kinase A (PKA), which, in turn, mediated the non-canonical olfactory pathway. PKA phosphorylated and activated furin protease, resulting in the cleavage of the fusogenic protein syncytin-1. Because this cleaved form of syncytin-1, processed by furin, participates in cell fusion, furin inhibitors could suppress multinucleation and reduce surviving cell numbers after anticancer drug treatment. The improved anticancer drug efficacy indicates a promising therapeutic approach for advanced cervical cancers.

P124 CARDIOVASCULAR RISK RE-CLASSIFICATION BY IMPLEMENTING CAROTID ULTRASONOGRAPHY IN PRIMARY CARE

Background and Objective: The accurate assessment of the total cardiovascular risk (CVR) using risk calculation algorithms in individuals with CVR factors in the primary prevention setting is essential for optimal management decisions, including drug treatment initiation and treatment goals. The aim of this study was to evaluate the contribution of ultrasonographic identification of asymptomatic carotid atherosclerosis in the re-classification of the CVR assessed with the reference SCORE2/2-OP algorithm. Methods: In individuals aged ≥40 years without established cardiovascular disease, the 10-year CVR was calculated using the SCORE2/2-OP algorithm (3 risk categories: low/moderate, high, and very high). Carotid ultrasound study was applied using a portable handheld device (Lumify, Philips) to classify CVR as follows: (i) low/moderate (absence of atherosclerotic plaque), (i) high (atherosclerotic plaque with &lt;50% stenosis), (iii) very high (atherosclerotic plaque with ≥50% stenosis). Results: Data from 332 participants were analysed [age 59±7.5 years, men 41%, current smokers 26%, body mass index 28±5 kg/m2, office blood pressure 125±15/77±10 mmHg (systolic/diastolic), LDL-cholesterol 111±33 mg/dl]. Based on SCORE2/2-OP, 49/46/5% participants were categorised as of low/moderate, high, and very high CVR, respectively. Based on carotid ultrasound, the rates were 39/59/2%, respectively. 44% of individuals categorized as of low/moderate CVR based on SCORE2/2-OP were re-classified into a higher CVR category based on carotid ultrasound. The agreement between the 2 methods (ultrasound versus algorithms) in categorizing low/moderate and high CVR was 67% (kappa 0.35, P&lt;0.001) and 61% (kappa 0.23, P&lt;0.001), respectively. Among 204 participants categorized as of high/very high CVR according to carotid ultrasound, only 15 (7%) had LDL-cholesterol levels &lt;70 mg/dl. Conclusions: These findings suggest that carotid ultrasonography using a portable handheld device may significantly contribute to assess CVR more accurately in primary care, especially in individuals classified as of low/moderate CVR using reference algorithms.

See the power in kidney cells with ATP biosensor

Yamamoto etal. developed an exciting technical advance to examine intracellular adenosine triphosphate levels with single-cell resolution in intact living kidney tissue, including in tubular and vascular segments that lie deep under the kidney surface. The work is a significant advance on prior invivo biosensor studies, and it allows for mechanistic investigation of alterations in cell metabolism, kidney disease pathobiology, and the effects of drug treatments on energy sources in different kidney cell types.