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Behavioral larval zebrafish screens leverage a high-throughput small molecule discovery format to find neuroactive molecules relevant to mammalian physiology. We screen a library of 650 central nervous system active compounds in high replicate to train deep metric learning models on zebrafish behavioral profiles. The machine learning initially exploited subtle artifacts in the phenotypic screen, necessitating a complete experimental re-run with rigorous physical well-wise randomization. These large matched phenotypic screening datasets (initial and well-randomized) provide a unique opportunity to quantify and understand shortcut learning in a full-scale, real-world drug discovery dataset. The final deep metric learning model substantially outperforms correlation distance-the canonical way of computing distances between profiles-and generalizes to an orthogonal dataset of diverse drug-like compounds. We validate predictions by prospective in vitro radio-ligand binding assays against human protein targets, achieving a hit rate of 58% despite crossing species and chemical scaffold boundaries. These neuroactive compounds exhibit diverse chemical scaffolds, demonstrating that zebrafish phenotypic screens combined with metric learning achieve robust scaffold hopping capabilities.

Chikungunya virus is an emerging mosquito-borne alphavirus that causes febrile illness and arthritic disease. Chikungunya virus is endemic in 110 countries and the World Health Organization estimates that it has caused more than 2 million cases of crippling acute and chronic arthritis globally since it re-emerged in 2005. Chikungunya virus outbreaks have occurred in Africa, Asia, Indian Ocean islands, South Pacific islands, Europe, and the Americas. Until recently, no specific countermeasures to prevent or treat chikungunya disease were available. To address this need, multiple vaccines are in human trials. These vaccines use messenger RNA-lipid nanoparticles, inactivated virus, and viral vector approaches, with a live-attenuated vaccine VLA1553 and a virus-like particle PXVX0317 in phase III testing. In November 2023, the US Food and Drug Administration (FDA) approved the VLA1553 live-attenuated vaccine, which is marketed as IXCHIQ. In June 2024, Health Canada approved IXCHIQ, and in July 2024, IXCHIQ was approved by the European Commission. On August 13, 2024, the US FDA granted priority review for PXVX0317. The European Medicine Agency is considering accelerated assessment review of PXVX0317, with potential for approval by both agencies in 2025. In this review, we summarize published data from pre-clinical and clinical trials for the IXCHIQ and PXVX0317 vaccines. We also discuss unanswered questions including potential impacts of pre-existing chikungunya virus immunity on vaccine safety and immunogenicity, whether long-term immunity can be achieved, safety in children, pregnant, and immunocompromised individuals, and vaccine efficacy in people with previous exposure to other emerging alphaviruses in addition to chikungunya virus.

UNLABELLED: Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease. IMPORTANCE: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

Microgravity has been shown to lead to both muscle atrophy and impaired muscle regeneration. The purpose was to study the efficacy of microgravity to model impaired muscle regeneration in an engineered muscle platform and then to demonstrate the feasibility of performing drug screening in this model. Engineered human muscle was launched to the International Space Station National Laboratory, where the effect of microgravity exposure for 7 days was examined by transcriptomics and proteomics approaches. Gene set enrichment analysis of engineered muscle cultured in microgravity, compared to normal gravity conditions, highlighted a metabolic shift toward lipid and fatty acid metabolism, along with increased apoptotic gene expression. The addition of pro-regenerative drugs, insulin-like growth factor-1 (IGF-1) and a 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH-i), partially inhibited the effects of microgravity. In summary, microgravity mimics aspects of impaired myogenesis, and the addition of these drugs could partially inhibit the effects induced by microgravity.

BackgroundRestraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.MethodsUsing Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.ResultsWe developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.ConclusionsOur method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity. RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity. CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

Cardiovascular organ-on-a-chip (OoC) devices are composed of engineered or native functional tissues that are cultured under controlled microenvironments inside microchips. These systems employ microfabrication and tissue engineering techniques to recapitulate human physiology. This review focuses on human OoC systems to model cardiovascular diseases, to perform drug screening, and to advance personalized medicine. We also address the challenges in the generation of organ chips that can revolutionize the large-scale application of these systems for drug development and personalized therapy.

PurposeModels to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes.Experimental designMatched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model.ResultsPDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden.ConclusionsThe variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.

Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel NaV1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to NaV1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery.

Patients with epilepsy often require long‐term treatment with antiseizure medications, and their impact on daily activities, particularly driving, is of significant concern. The recently published “Guideline for Evaluating Effects of Psychotropic Drugs on the Performance to Drive a Motor Vehicle” in Japan provides a framework that can be referred to for not only the evaluation of new drugs but also the reevaluation of approved drugs. This study conducted a literature review regarding the effects of carbamazepine, valproate, lamotrigine, lacosamide, and levetiracetam, which are frequently prescribed for epilepsy, on driving performance following the guideline's tiered evaluation approach. Analyses of pharmacological, pharmacodynamic, and adverse events suggested that these drugs primarily affect arousal function. Driving studies showed that acute administration of carbamazepine, but not chronic monotherapy with carbamazepine, valproate, lamotrigine, and levetiracetam, significantly impairs driving performance. Epidemiological studies have not identified a definitive association between these drugs and traffic accidents. Initial administration of these five antiseizure medications may affect driving performance, warranting special attention, but the influence appears to diminish with continued use. Nevertheless, while long‐term administration of these five drugs may not have a clinically meaningful effect on driving performance, safe driving is not guaranteed for each individual patient, and appropriate individualized guidance is important in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To conduct a comprehensive evaluation of PD-1 inhibitors for the treatment of advanced non-small cell lung cancer on the market in China, using A Quick Guideline for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition), and to provide a reference for the selection of and decision-making on clinical drugs in hospitals. Method: The Sanzhi drug evaluation and selection system was used to evaluate the PD-1 inhibitors for the treatment of advanced non-small cell lung cancer on the market in China, according to five characteristics: pharmaceutical characteristics, efficiency, safety, economy, and others. Results: Based on the above evaluation criteria, the scores of all PD-1 inhibitors were above 61 points. The main difference among the five characteristics were efficiency and economy. The difference between the other characteristics was relatively small. Sintilimab injection had the highest score due to the advantages among characteristics except the other attributes. Nivolumab injection (100 mg/10 mL (10 mg/mL)) had the lowest total score due to its low effectiveness and economy scores. Conclusion: PD-1 inhibitors are effective therapeutic drugs for immunotherapy in patients with advanced nonsmall cell lung cancer. Different PD-1 inhibitors have different advantages in clinical treatment. The comprehensive evaluation of PD-1 inhibitors for the treatment of advanced non-small cell lung cancer on the market in China through A Quick Guide for Drug Evaluation and Selection of Chinese Medical Institutions (Second Edition) can provide a basis for drug selection and scientific, reasonable, and safe drug use in medical institutions. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

Objective: To establish a mice model that is more in line with the human immunocompromised state, and to investigate the regulatory effect of Rosa laevigata Michx., probiotics and their combination on their immune function. Methods: Immunosuppressive model of mice was established by using cyclophosphamide with different dosage, time and end point, and compared with immunosuppressive model induced by hydrocortisone and cyclosporine A, immunosuppressive model of mice was established by injecting 25 mg/kg cyclophosphamide 7 times every other day, without recovery period; changes in the proportion of lymphocytes in spleen （CD4+T cells, CD8+T cells, CD19+B cells） were analyzed by flow cytometry; qRT-PCR was used to detect expression levels of inflammatory factors （IL-1β and IL-6） mRNA in spleen. Results: After continuous injection of 80 mg/kg cyclophosphamide for 3 days, the thymus was atrophied, the spleen was significantly swelling, proportion of immune cells CD4+T cells, CD8+T cells and CD19+B cells in spleen were significantly decreased, while mRNA expressions of IL-1β and IL-6 were up-regulated. After 7 injections of 25 mg/kg cyclophosphamide every other day, the thymus and the spleen were significantly atrophied, proportion of CD4+T cells and CD8+T cells in spleen showed an increasing trend, and mRNA expressions of IL-1β and IL-6 were up-regulated; after 1 week or 2 weeks recovery period from cyclophosphamide injection, weight and index of immune organs, proportion of spleen lymphocytes and mRNA expressions of inflammatory cytokines in spleen were significantly reversed; Rosa laevigata Michx. combined with probiotics could significantly reverse the up-regulation of CD4+T cells and inflammatory factor IL-1β caused by cyclophosphamide. Conclusion: In this study, an immunocompromised mice model has been established with 7 injections of 25 mg/kg cyclophosphamide every other day and without recovery period. And a certain positive immunomodulatory effect of the combination of Rosa laevigata Michx. and probiotics has been found. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effectiveness and safety of quadruple regimen in preventing multi-day cisplatinbased chemotherapy-induced nausea and vomiting (CINV). Methods A total of 112 patients with malignant tumors who underwent cisplatin-based chemotherapy. According to the random number table method, patients were divided into the experimental group and the control group, with 56 cases in each group. The control group received cisplatin-based chemotherapy and triple therapy of fosapreitant dimeglumine, ondansetron hydrochloride and dexamethasone tablets. On this basis, the experimental group was given quadruple therapy containing olanzapine tablets. The occurrence of nausea and vomiting, as well as changes in FLIE and HAD scores were observed in both groups. Results The incidence of nausea and vomiting was lower from day 1 (D1) to day 9 (D9) after the beginning of chemotherapy in the experimental group than that in the control group (P＜0.05). The incidence of nausea and vomiting in the experimental group was lower than that in the control group . On D9 after the beginning of chemotherapy, the nausea score, vomiting score and total score of FILE were higher in the experimental group than those in the control group (P＜0.05). There were no significant differences in depression or anxiety score and incidence of adverse reactions on D1 and D9 after the beginning of chemotherapy between the two groups (P＞0.05). Conclusion The quadruple antiemetic regimen can improve the control rate of CINV induced by multi-day cisplatin-based chemotherapy, especially for the control of delayed nausea and vomiting, and improve the quality of life of patients during chemotherapy, with good safety. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O2) and standard (21% O2) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, this work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening.

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.

Zeyu Xie, Jia Hu, Mengting Li, Xiao Hu, Jisheng Chen Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Jisheng Chen, Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, People’s Republic of China, Tel +86 20-87622305, Fax +86 20-61321967, Email cjslym@163.comPurpose: This study provides a reference for healthcare organizations in the selection and rational use of glucagon-like peptide-1 receptor agonists (GLP-1RAs), based on the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition).Methods: According to the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition) released in 2023, relevant databases such as PubMed, Cochrane, and Embase, drug labels, and clinical guidelines were searched for drug information. We systematically evaluated 7 GLP-1RAs marketed in China for safety, efficacy, economy, pharmacological properties, and other attributes using a percentage scoring method.Results: The final assessment result scores from highest to lowest were semaglutide (71.5 points), dulaglutide (68.9 points), liraglutide (68.7 points), exenatide (62.5 points), lixisenatide (59.9 points), polyethylene glycol loxenatide (55.9 points), and benaglutide (45.1 points).Conclusion: When a healthcare organization introduces GLP-1RAs to their hospital, they can refer to the assessment results and use the top three recommended medications: semaglutide, dulaglutide, and liraglutide.Keywords: glucagon-like peptide-1 receptor agonist, health technology assessment, type 2 diabetes mellitus, drug evaluation

High throughput drug screening is an established approach to investigate tumor biology and identify therapeutic leads. Traditional platforms use two-dimensional cultures which do not accurately reflect the biology of human tumors. More clinically relevant model systems such as three-dimensional tumor organoids can be difficult to scale and screen. Manually seeded organoids coupled to destructive endpoint assays allow for the characterization of treatment response, but do not capture transitory changes and intra-sample heterogeneity underlying clinically observed resistance to therapy. We present a pipeline to generate bioprinted tumor organoids linked to label-free, time-resolved imaging via high-speed live cell interferometry (HSLCI) and machine learning-based quantitation of individual organoids. Bioprinting cells gives rise to 3D structures with unaltered tumor histology and gene expression profiles. HSLCI imaging in tandem with machine learning-based segmentation and classification tools enables accurate, label-free parallel mass measurements for thousands of organoids. We demonstrate that this strategy identifies organoids transiently or persistently sensitive or resistant to specific therapies, information that could be used to guide rapid therapy selection.

OBJECTIVE: To evaluate the four kinds of interleukin biological agents of ustekinumab, ixekizumab, secukinumab and guselkumab, so as to provide scientific basis for drug selection and clinical rational drug use in medical institutions. METHODS: According to the Selection and Evaluation Form of Drug Use (Chemical Drugs) List in the Tertiary Public Medical Institutions in Hebei Province published by Hebei Provincial Health Commission, four kinds of interleukin biological agents were comprehensively evaluated from effectiveness, pharmaceutical characteristics, safety, economy and other properties. RESULTS: The total scores of ustekinumab, ixekizumab, secukinumab and guselkumab were 79. 3, 77. 8, 68. 3 and 76. 3 points respectively. Guselkumab could achieve complete clearing of skin lesions, and the drug retention rate was high. Ustekinumab was the “ dual-targeted ” interleukin-12 and interleukin-23 inhibitor for moderately to severely active Crohn’ s disease in addition to psoriasis. Ixekizumab was a non-whole-human biological preparation, with the highest incidence of adverse reactions among the four types of biological preparations, yet was relatively inexpensive. Sekucizumab and ustekinumab were approved for psoriasis in children and adolescents. CONCLUSIONS: Guselkumab may be considered for patients seeking complete clearance and wishing to maintain better outcomes over time. Ustekinumab may be considered for patients with a history of inflammatory bowel disease or a family history of inflammatory bowel disease. Secukinumab and ustekinumab may be considered for pediatric psoriasis. Ixekizumab may be an option for patients wishing to achieve a rapid onset of action and who have limited ability to pay, yet patients who are susceptible to allergies and at high risk for connective tissue disease should be avoided. Ixekizumab and secukinumab may cause or aggravate inflammatory bowel disease and should be used with caution in clinic. [ABSTRACT FROM AUTHOR]

Objectives: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. Material and methods: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. Results: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). Conclusion: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. Clinical relevance statement: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. Key Points: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions. [ABSTRACT FROM AUTHOR]

Recombinant human coagulation factor Ⅷ is the first-line treatment for hemophilia A recommended by authoritative guidelines. Various recombinant human coagulation factor Ⅷ have the same mechanism of action, which can temporarily replace the missing clotting factor Ⅷ that is needed for effective hemostasis in patients. There are differences in economy, pharmaceutical characteristics and other attributes. Therefore, pharmaceutical and clinical experts are organized by the Pharmacovigilance Professional Committee of Guangdong Pharmaceutical Association to formulate the Expert Consensus on Evaluation and Selection of Recombinant Human Coagulation Factor Ⅷ in Guangdong. Multi-dimensional evaluation on 6 kinds of recombinant human coagulation factor Ⅷ marketed in China are carried out from five aspects: pharmaceutical characteristics, efficacy, safety, economy and other attributes, so as to provide scientific basis for drug selection in medical institutions and promotes rational drug use in clinic. [ABSTRACT FROM AUTHOR]

The microfluidic system is capable of recapitulating key attributes of in vivo circumstances and, therefore, becomes a valuable platform for better understanding tumor growth dynamics and evaluating drug efficiency. While numerical simulations have been envisioned as powerful tools for validating versatile performance of advanced microfluidic platforms, cell growth within these microchannels has not yet been theoretically modeled. In this paper, we developed an experimental data-driven cellular automaton model, which was adopted for simulating cell behaviors and drug responses in a microfluidic system. The boundaries of the cellular automata lattices and prohibited zones for simulation were directly converted from microscopic images of cell morphology and the microchamber configuration. The dynamic progression of tumor growth at the avascular stage was predicted by incorporating the biophysical and molecular characteristics of cells and their interactions with surrounding environment. The simulated proliferation rate of tumor cells over time demonstrated its dependency on nutrient delivery, aligning well with experimental observations in the microfluidic culture. The spatiotemporal efficacy of the chemotherapeutic compound doxorubicin (DOX) on the microfluidic culture was also simulated. The similarity between in silico simulations and in vitro tumor response upon drug interaction highlighted the potential of the computational models as complementary tools for predicting the drug treatment efficacy with acceptable accuracy before practical applications. [ABSTRACT FROM AUTHOR]

Background: Daytime hysteroscopy requires anesthesia that offers rapid onset and clearance, with minimal respiratory and cardiovascular suppression. This study compared the effects of different doses of alfentanil combined with propofol target-controlled infusion (TCI) for such procedures. Methods: We randomized 240 patients undergoing daytime hysteroscopy into three groups to receive alfentanil at doses of 5 μg/kg, 10 μg/kg, and 15 μg/kg, combined with propofol TCI. We meticulously recorded complications and perioperative vitals to evaluate the safety and efficacy of each dosage regimen. Results: The 10 μg/kg dose of alfentanil, used in conjunction with propofol, required lower propofol dosages and resulted in quicker recovery time and fewer intraoperative movements. However, higher doses of 15 μg/kg led to a significant increase in hypoxemia and instability in hemodynamics and oxygenation. Conclusion: Combining alfentanil at 10 μg/kg with propofol TCI for daytime hysteroscopy results in high effectiveness. A lower incidence of complications, a reduced propofol requirement, and rapid emergence from sedation characterize this regimen.

BackgroundAdherence to clinical practice guidelines for alcohol and drug screening, brief intervention, and referral to treatment (SBIRT) is often inadequate. Mobile apps developed as clinical translation tools could improve the delivery of high fidelity SBIRT.Methods: This study tested the effectiveness of an SBIRT mobile app conceptually aligned with the Theory of Planned Behavior (TPB) to support SBIRT delivery by health care trainees (nursing, social work, internal medicine, psychiatry, and psychology) working in clinical settings (N = 101). Bivariate analyses examined the rate of SBIRT delivery between trainees assigned to the experimental (app) and control (no app) study conditions; as well as the relationship between TPB-based constructs, intention to deliver SBIRT, and screening rates.Results: No significant differences were identified between the study conditions in SBIRT delivery. Significant correlations were found between intent to screen and TPB variables including attitudes/behavioral beliefs concerning substance use treatment (r = .49, p = .01); confidence in clinical skills (r = .36, p = .01); subjective norms (r = .54, p = .01) and perceived behavioral control over appointment time constraints (r = .42, p = .01). Also significant were correlations between percent of patients screened and confidence (r = .24, p = .05); subjective norms (r = .22, p = .05) and perceived behavioral control (r = .28, p = .01).Conclusions: The negative results of the study condition comparisons indicate the need for further investigation of strategies to optimize mobile app utilization, engagement, and effectiveness as a clinical translation tool. Findings of significant correlations between substance use screening rates and both norms and confidence support the potential value of the TPB model in explaining behavior of health care learners in SBIRT delivery.

Protein networks can be assembled in vitro for basic biochemistry research, drug screening, and the creation of artificial cells. Two standard methodologies are used: manual pipetting and pipetting robots. Manual pipetting has limited throughput in the number of input reagents and the combination of reagents in a single sample. While pipetting robots are evident in improving pipetting efficiency and saving hands-on time, their liquid handling volume usually ranges from a few to hundreds of microliters. Microfluidic methods have been developed to minimize the reagent consumption and speed up screening but are challenging in multifactorial protein studies due to their reliance on complex structures and labeling dyes. Here, we engineered a new impact-printing-based methodology to generate printed microdroplet arrays containing water-in-oil droplets. The printed droplet volume was linearly proportional (R2 = 0.9999) to the single droplet number, and each single droplet volume was around 59.2 nL (coefficient of variation = 93.8%). Our new methodology enables the study of protein networks in both membrane-unbound and -bound states, without and with anchor lipids DGS-NTA(Ni), respectively. The methodology is demonstrated using a subnetwork of mitogen-activated protein kinase (MAPK). It takes less than 10 min to prepare 100 different droplet-based reactions, using

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.

Internal validation is the most popular evaluation strategy used for drug-target predictive models. The simple random shuffling in the cross-validation, however, is not always ideal to handle large, diverse and copious datasets as it could potentially introduce bias. Hence, these predictive models cannot be comprehensively evaluated to provide insight into their general performance on a variety of use-cases (e.g. permutations of different levels of connectiveness and categories in drug and target space, as well as validations based on different data sources). In this work, we introduce a benchmark, BETA, that aims to address this gap by (i) providing an extensive multipartite network consisting of 0.97 million biomedical concepts and 8.5 million associations, in addition to 62 million drug-drug and protein-protein similarities and (ii) presenting evaluation strategies that reflect seven cases (i.e. general, screening with different connectivity, target and drug screening based on categories, searching for specific drugs and targets and drug repurposing for specific diseases), a total of seven Tests (consisting of 344 Tasks in total) across multiple sampling and validation strategies. Six state-of-the-art methods covering two broad input data types (chemical structure- and gene sequence-based and network-based) were tested across all the developed Tasks. The best-worst performing cases have been analyzed to demonstrate the ability of the proposed benchmark to identify limitations of the tested methods for running over the benchmark tasks. The results highlight BETA as a benchmark in the selection of computational strategies for drug repurposing and target discovery.

In this review, we explore the growing role of artificial intelligence (AI) in advancing the biomedical applications of human pluripotent stem cell (hPSC)-derived organoids. Stem cell-derived organoids, these miniature organ replicas, have become essential tools for disease modeling, drug discovery, and regenerative medicine. However, analyzing the vast and intricate datasets generated from these organoids can be inefficient and error-prone. AI techniques offer a promising solution to efficiently extract insights and make predictions from diverse data types generated from microscopy images, transcriptomics, metabolomics, and proteomics. This review offers a brief overview of organoid characterization and fundamental concepts in AI while focusing on a comprehensive exploration of AI applications in organoid-based disease modeling and drug evaluation. It provides insights into the future possibilities of AI in enhancing the quality control of organoid fabrication, label-free organoid recognition, and three-dimensional image reconstruction of complex organoid structures. This review presents the challenges and potential solutions in AI-organoid integration, focusing on the establishment of reliable AI model decision-making processes and the standardization of organoid research. [ABSTRACT FROM AUTHOR]

Soft actuators have played an indispensable part in the field of biosensors and soft robotics as such systems offer solutions that cannot be addressed with rigid actuators due to the lack of both flexibility and sensitivity. However, soft actuators have certain limitations when it comes to their durability and longevity. In recent years, quite a few versatile fabrication techniques and innovative solutions have been developed that have played an essential role in the development of soft robotics. An exemplary innovation involves the integration of nanomaterials into polymers that act as a host in the fabrication of inorganic/organic actuators. These actuators have shown significant enhancement both in their physical and chemical properties. Consequently, it paves the way for the development of sophisticated soft actuator-based devices that can find broader applications in the field of biomedical sciences. However, biocompatibility has been a matter of concern for inorganic/organic soft actuators. Addressing this issue, studies on the development of biomaterial-based soft actuators that incorporate nanomaterials have been conducted for biohybrid robots. This review aims to provide a comprehensive understanding of diverse stimulus-trigger actuation alongside exploring the influence of nanomaterials in inorganic/organic actuators. Further, it gives valuable insights into the implication of biomaterials in soft actuators for the development of biohybrid robot. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of sacubitril valsartan in the treatment of heart failure (HF) of midrange ejection fraction（HFmrEF）in patients after acute myocardial infarction (AMI). Methods A total of 102 patients with HFmrEF after AMI were divided into the control group and the experimental group, with 51 cases in each group. The control group was given conventional treatment for AMI and anti-HF treatment, and the angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin Ⅱ receptor blocker (ARB) was used without contraindications. The experimental group was replaced by ACEI/ARB with sacubitril valsartan on the basis of the control group. After 6 months of treatment, the total effective rates of the two groups after treatment were analyzed, and the cardiac function, N-terminal pro-brain natriuretic peptide (NT-proBNP) and serum inflammatory factor C-reactive protein (CRP) were compared before and after treatment. The occurrence of adverse reactions after treatment was recorded. Kaplan-Meier method was used to analyze the cumulative cardiovascular mortality, HF rehospitalization rate and end-event-free survival after 6 months of treatment in two groups. Results After treatment, there was no significant difference in the occurrence of adverse reactions between the two groups (P＞0.05). The total effective rate was higher in the experimental group than that of the control group (P＜0.05). Compared with before treatment, left ventricular ejection fraction (LVEF), stroke volume (SV), mitral diastolic blood flow velocity E peak and A peak ratio (E/A) and 6 min walking distance (6MWD) were increased in the two groups, and left ventricular enddiastolic diameter (LVEDD) and left atrial diameter (LAD) were decreased in the two groups after treatment (all P＜0.05). After treatment, LVEF, SV, E/A and 6MWD were higher in the experimental group than those in the control group (P＜0.05). LVEDD and LAD were lower than those in the control group (all P＜0.05). Compared with results before treatment, NT proBNP and CRP were decreased after treatment in the experiment group than those in the control group (P＜0.05). There was no significant difference in the cumulative cardiovascular mortality between the experiment group and the control group (3.9% vs. 5.9%，P=0.524). The cumulative HF rehospitalization rate was lower in the experimental group than that of the control group (9.8% vs. 23.5%，P=0.042). The cumulative end-point-free survival rate was higher in the experiment group than that of the control group (86.3% vs. 70.6%, P=0.037). Conclusion Sacubitril valsartan is safer and more effective than ACEI/ARB in the treatment of AMI patients with HFmrEF, and it is worthy of clinical promotion. [ABSTRACT FROM AUTHOR]

Drug therapies are the cornerstone of systemic treatment for pancreatic cancer patients. However, the relative outcome of drug evaluation is often hampered by the complex microenvironment of pancreatic cancer due to the lack of reasonable tumor models. Here, we proposed a novel platform that integrated pancreatic adenocarcinoma cells encapsulated into hydrogel microcapsules for three‐dimensional (3D) tumor cultivation and antitumor agent evaluation. These hydrogel microcapsules contain alginate/poly (N‐isopropyl acrylamide) (alginate/PNIPAM) shells and carboxymethyl cellulose cores, which are generated through the microfluidic electrospray technique. The microcapsules have the feature of rapid response to temperature, by which they can regulate the internal pressure environment. Besides, benefiting from good monodispersity, precise size control, and biocompatibility of these microcapsules, these wrapped tumor cells have the capacity for proliferating spontaneously and forming 3D tumor spheroids with good cell viability. We have demonstrated that pancreatic adenocarcinoma cells encapsulated in the composite microcapsules with different PNIPAM concentrations showed different drug sensitivity, which could be ascribed to the influence of external pressures environment. These results indicate that the tumor spheroids coated in these responsive microcapsules have great potential in the analysis of antitumor drug sensitivity. [ABSTRACT FROM AUTHOR]

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Age-related macular degeneration(ARMD)is the primary cause of severe visual impairment and blindness in people over 60 years old. With the aging of the global population, the incidence of the disease is also rising year by year. However, the pathogenesis and treatment strategy of ARMD need to be further explored. As a cutting-edge science and technology, microfluidic chips can build a comprehensive microsystem that simulates the condition and function of human tissues and organs, which has the advantages of less sample consumption and short analysis time. In recent years, many studies have confirmed that microfluidic chips can bring brand new technology solutions to the basic and clinical research of ARMD. This article will discuss and review the application progress of microfluidic chips in the areas of ARMD mechanism research, drug evaluation and clinical translation, providing a theoretical reference for further research on the diagnosis and treatment of ARMD.

Abstract Background Long-term drug evaluation heavily relies upon rodent models. Drug discovery methods to reduce animal models in oncology may include three-dimensional (3D) cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. Methods In this study we reconstructed a 3D tumor using an elastic polymer (acrylate-endcapped urethane-based poly(ethylene glycol) (AUPPEG)) with clinical relevant stiffness. Single cell suspensions from low-grade serous ovarian cancer (LGSOC) patient-derived early passage cultures of cancer cells and cancer-associated fibroblasts (CAF) embedded in a collagen gel were introduced to the AUPPEG scaffold. After self-organization in to a 3D tumor, this model was evaluated by a long-term (> 40 days) exposure to a drug combination of MEK and HSP90 inhibitors. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. Results The in vitro 3D scaffold LGSOC model mimics the growth ratio and spatial organization of the LGSOC. The AUPPEG scaffold approach allows to test new targeted treatments and monitor long-term drug responses. The results correlate with those of the orthotopic LGSOC xenograft mouse model. Conclusions The mechanically-tunable scaffolds colonized by a three-dimensional LGSOC allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery. Graphical Abstract

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3β and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.

Zebrafish and their mutant lines have been extensively used in cardiovascular studies. In the current study, the novel system, Zebra II, is presented for prolonged electrocardiogram (ECG) acquisition and analysis for multiple zebrafish within controllable working environments. The Zebra II is composed of a perfusion system, apparatuses, sensors, and an in-house electronic system. First, the Zebra II is validated in comparison with a benchmark system, namely iWORX, through various experiments. The validation displayed comparable results in terms of data quality and ECG changes in response to drug treatment. The effects of anesthetic drugs and temperature variation on zebrafish ECG were subsequently investigated in experiments that need real-time data assessment. The Zebra II's capability of continuous anesthetic administration enabled prolonged ECG acquisition up to 1 h compared to that of 5 min in existing systems. The novel, cloud-based, automated analysis with data obtained from four fish further provided a useful solution for combinatorial experiments and helped save significant time and effort. The system showed robust ECG acquisition and analytics for various applications including arrhythmia in sodium induced sinus arrest, temperature-induced heart rate variation, and drug-induced arrhythmia in Tg(SCN5A-D1275N) mutant and wildtype fish. The multiple channel acquisition also enabled the implementation of randomized controlled trials on zebrafish models. The developed ECG system holds promise and solves current drawbacks in order to greatly accelerate drug screening applications and other cardiovascular studies using zebrafish.

Despite many advances in infection control practices, including prophylactic antibiotics, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospitalization, and death worldwide. Our innate immune system possesses a multitude of powerful antimicrobial strategies which make it highly effective in combating bacterial, fungal, and viral infections. However, pathogens use various stealth mechanisms to avoid the innate immune system, which in turn buy them time to colonize wounds and damage tissues at surgical sites. We hypothesized that immunomodulators that can jumpstart and activate innate immune responses at surgical sites, would likely reduce infection at surgical sites. We used three immunomodulators; fMLP (formyl-Methionine-Lysine-Proline), CCL3 (MIP-1α), and LPS (Lipopolysaccharide), based on their documented ability to elicit strong inflammatory responses; in a surgical wound infection model with Pseudomonas aeruginosa to evaluate our hypothesis. Our data indicate that one-time topical treatment with these immunomodulators at low doses significantly increased proinflammatory responses in infected and uninfected surgical wounds and were as effective, (or even better), than a potent prophylactic antibiotic (Tobramycin) in reducing P. aeruginosa infection in wounds. Our data further show that immunomodulators did not have adverse effects on tissue repair and wound healing processes. Rather, they enhanced healing in both infected and uninfected wounds. Collectively, our data demonstrate that harnessing the power of the innate immune system by immunomodulators can significantly boost infection control and potentially stimulate healing. We propose that topical treatment with these immunomodulators at the time of surgery may have therapeutic potential in combating SSI, alone or in combination with prophylactic antibiotics.

SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.

Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases.

Introduction: Acanthamoeba encompasses several species of free-living ameba encountered commonly throughout the environment. Unfortunately, these species of ameba can cause opportunistic infections that result in Acanthamoeba keratitis, granulomatous amebic encephalitis, and occasionally systemic infection.Areas covered: This review discusses relevant literature found through PubMed and Google scholar published as of January 2021. The review summarizes current common Acanthamoeba keratitis treatments, drug discovery methodologies available for screening potential anti-Acanthamoeba compounds, and the anti-Acanthamoeba activity of various azole antifungal agents.Expert opinion: While several biguanide and diamidine antimicrobial agents are available to clinicians to effectively treat Acanthamoeba keratitis, no singular treatment can effectively treat every Acanthamoeba keratitis case.Efforts to identify new anti-Acanthamoeba agents include trophozoite cell viability assays, which are amenable to high-throughput screening. Cysticidal assays remain largely manual and would benefit from further automation development. Additionally, the existing literature on the effectiveness of various azole antifungal agents for treating Acanthamoeba keratitis is incomplete or contradictory, suggesting the need for a systematic review of all azoles against different pathogenic Acanthamoeba strains.

Pulmonary arterial hypertension is a clinical syndrome characterized by pulmonary vascular remodeling causing increased vascular resistance, which will lead to right heart failure and even death if left untreated. The pathogenesis of pulmonary arterial hypertension has not yet been clarified, and clinical treatments have not been effective in improving prognosis or reducing mortality. To investigate the pathogenesis of pulmonary arterial hypertension and to develop and evaluate more effective and safer drug treatments, establishing related animal disease models is very important. This paper outlines the pathological characteristics of pulmonary arterial hypertension and summarizes the various types of animal models of pulmonary arterial hypertension, as well as describes the progress of the application of these models in three therapeutic pathways and related drug research in the past five years, with a view to providing a reference for the selection of animal models of pulmonary arterial hypertension and research applications.

Abstract In this review, we explore the growing role of artificial intelligence (AI) in advancing the biomedical applications of human pluripotent stem cell (hPSC)‐derived organoids. Stem cell‐derived organoids, these miniature organ replicas, have become essential tools for disease modeling, drug discovery, and regenerative medicine. However, analyzing the vast and intricate datasets generated from these organoids can be inefficient and error‐prone. AI techniques offer a promising solution to efficiently extract insights and make predictions from diverse data types generated from microscopy images, transcriptomics, metabolomics, and proteomics. This review offers a brief overview of organoid characterization and fundamental concepts in AI while focusing on a comprehensive exploration of AI applications in organoid‐based disease modeling and drug evaluation. It provides insights into the future possibilities of AI in enhancing the quality control of organoid fabrication, label‐free organoid recognition, and three‐dimensional image reconstruction of complex organoid structures. This review presents the challenges and potential solutions in AI‐organoid integration, focusing on the establishment of reliable AI model decision‐making processes and the standardization of organoid research.

Abstract Drug therapies are the cornerstone of systemic treatment for pancreatic cancer patients. However, the relative outcome of drug evaluation is often hampered by the complex microenvironment of pancreatic cancer due to the lack of reasonable tumor models. Here, we proposed a novel platform that integrated pancreatic adenocarcinoma cells encapsulated into hydrogel microcapsules for three‐dimensional (3D) tumor cultivation and antitumor agent evaluation. These hydrogel microcapsules contain alginate/poly (N‐isopropyl acrylamide) (alginate/PNIPAM) shells and carboxymethyl cellulose cores, which are generated through the microfluidic electrospray technique. The microcapsules have the feature of rapid response to temperature, by which they can regulate the internal pressure environment. Besides, benefiting from good monodispersity, precise size control, and biocompatibility of these microcapsules, these wrapped tumor cells have the capacity for proliferating spontaneously and forming 3D tumor spheroids with good cell viability. We have demonstrated that pancreatic adenocarcinoma cells encapsulated in the composite microcapsules with different PNIPAM concentrations showed different drug sensitivity, which could be ascribed to the influence of external pressures environment. These results indicate that the tumor spheroids coated in these responsive microcapsules have great potential in the analysis of antitumor drug sensitivity.

Simple Summary: Neurofibromatosis 1 (NF1) is a genetic disorder that predisposes patients to developing nerve sheath tumors that are difficult to treat. There is currently just one drug approved for the treatment of NF1-related inoperable plexiform neurofibromas (for a limited patient population), highlighting the need for further drug discovery in this field. High-throughput screening data are used to guide drug development, but identifying and selecting promising targets can be complex. The aim of our study is to improve the value of high-throughput screening data by combining potency and effectiveness into single-value indices (S, ΔS, and ΔS mean), which are used to assess and rank drug sensitivity and drug resistance in cells exposed to potential therapeutic drugs. Our approach with S indices was applied to cell lines derived from plexiform neurofibromas of patients with NF1 gene mutations. The use of S indices provides valuable additional and independent information for discriminating among candidate compounds for follow-up pre-clinical evaluations. Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose–response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration–response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1−/− tumor cells, using immortalized non-tumor NF1+/− cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers. [ABSTRACT FROM AUTHOR]

Objective: To establish and test a clinician‐reported outcome measure of oral lichen planus (OLP): OLP Investigator global assessment (IGA). Methods: OLP IGA scale was tested with retrospective data from clinical practice and a phase II clinical trial. A comparison of the OLP IGA score with patient‐reported outcomes was completed. Results: Clinical Practice: The mean (SD) OLP IGA score (0–4) in 107 OLP patients was 1.8 (1.0) with correlation of 0.25–0.48 (p value 0.01 – <0.0001) with symptom scores. There was a significant increase in OLP symptoms based on OLP IGA score. Clinical Trial: The mean (SD) OLP IGA score in 137 research participants was 2.5 (1.2) with correlation of 0.43–0.52 (all p values <0.0001) with symptoms scores. There was a significant increase in OLP symptoms based on OLP IGA score. Forty‐seven (35%) participants in the phase 2 study had an improvement in the OLP IGA score of ≥2. There were significant improvements in all symptoms scores in relation to the change in IGA score. Conclusions: The OLP IGA is designed to assess changes in symptomatic OLP lesions and is appropriate for use across the full range of symptomatic OLP severity and represents a scale with utility in clinical practice and clinical trials. [ABSTRACT FROM AUTHOR]

Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.