Target Of Action Research Articles

Exploring the action mechanism of Gegensan in the treatment of alcoholic liver disease based on network pharmacology and bioinformatics.

Gegensan (GGS) has been reported for the treatment of alcoholic liver disease (ALD), but its therapeutic mechanism is still unclear. This paper aims to determine the therapeutic mechanism and targets of action of GGS on alcoholic liver disease utilizing network pharmacology and bioinformatics. The active ingredients in GGS were screened in the literature and databases, and common targets of ALD were then obtained from public databases to construct the network diagram of traditional Chinese medicine-active ingredient targets. Based on the common targets, Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to find target enrichment pathways, and the core targets were screened out by combining differential analysis and protein-protein interaction network analysis. Molecular docking was performed to verify the binding effect between the core targets and the corresponding active ingredients. ALD and GGS have 84 common targets, corresponding to 91 active ingredients. After subsequent differential analysis and protein-protein interaction network analysis, 10 core targets were identified. Gene Ontology and KEGG enrichment analyses showed that the main BPs corresponding to the common targets included the response to lipopolysaccharide, inflammatory response, etc. The KEGG pathways involved in the regulation of the common targets included the lipid-atherosclerosis pathway and the alcoholic liver disease pathway, etc. Further molecular docking showed that the core targets CYP1A1, CYP1A2, CXCL8, ADH1C, MMP1, SERPINE1, COL1A1, APOB, MMP1, and their corresponding 4 active ingredients, Naringenin, Kaempferol, Quercetin, and Stigmasterol, have a greater docking potential. The above results suggest that GGS can regulate lipid metabolism and inflammatory response in the ALD process, and alleviate the lipid accumulation and oxidative stress caused by ethanol. This study analyzed the core targets and mechanisms of action of GGS on ALD, which provides certain theoretical support for the further development of GGS in the treatment of ALD, and provides a reference for the subsequent research on the treatment of ALD.

Top advances of the year: Targeted therapy for lung cancer.

The past year has offered significant advancements in the field of non-small cell lung cancer (NSCLC), both in the early and advanced disease settings. The identification of guideline-recommended actionable targets has provided the foundation for developing multiple new therapeutic agents. There has been a focus on developing drugs designed to overcome acquired resistance, a limitation of tyrosine kinase inhibitor-based therapy in lung cancer. In addition, there is an emerging trend toward combination therapies for patients in the first-line setting with the goal of preventing or delaying resistance. Another promising area of development has been the use of antibody-drug conjugates, where there are the initial reports of central nervous system efficacy and activity in patients with genomic alterations. Over the past year, numerous publications and presentations have highlighted multiple therapeutic advances, offering new treatment options for patients with NSCLC. The focus of this review is to summarize the most impactful findings, emphasizing their significance in the evolving treatment landscape for NSCLC. Several landmark trials in lung cancer with practice-changing clinical implications have been presented and published in 2023. This article reviews a selection of these trials as they relate to early and advanced-stage oncogene-driven lung cancer. The ADAURA and ALINA trials, in which targeted therapy given in the adjuvant setting has demonstrated improved clinical outcomes, are reviewed. In the advanced-stage setting, recent trials in the context of specific oncogene drivers are reviewed, including EGFR, ALK, ROS1, RET, ERBB2 (HER2), BRAF, MET exon 14 skipping (METex14), and KRAS alterations. Also discussed are the results of several trials that have evaluated the use of combination therapies and resistance-mechanism agnostic treatment strategies. PLAIN LANGUAGE SUMMARY: Targeted therapy plays an important role for patients with early and advanced-stage non-small cell lung cancer carrying specific genetic alterations. New strategies that combine multiple therapies are now being studied in randomized clinical trials, with the goal of enhancing the effectiveness of targeted therapy for patients with advanced lung cancer.

A dynamic microRNA profile that tracks a chemotherapy resistance phenotype in osteosarcoma. Implications for novel therapeutics.

Osteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980s despite ongoing efforts. Overall, the five-year survival rate remains about 65%, and is much lower in patients with tumors unresponsive to methotrexate, doxorubicin, and cisplatin therapy. Genetic studies have not revealed actionable drug targets, but our group, and others, have reported that epigenomic biomarkers, including regulatory RNAs, may be useful prognostic tools for osteosarcoma. We tested if microRNA (miRNA) transcriptional patterns mark the transition from a chemotherapy sensitive to resistant tumor phenotype. Small RNA sequencing was performed using 14 patient matched pre-chemotherapy biopsy and post-chemotherapy resection high-grade osteosarcoma frozen tumor samples. Independently, small RNA sequencing was performed using 14 patient matched biopsy and resection samples from untreated tumors. Separately, miRNA specific Illumina DASL arrays were used to assay an independent cohort of 65 pre-chemotherapy biopsy and 26 patient matched post-chemotherapy resection formalin fixed paraffin embedded (FFPE) tumor samples. mRNA specific Illumina DASL arrays were used to profile 37 pre-chemotherapy biopsy and five post-chemotherapy resection FFPE samples, all of which were also used for Illumina DASL miRNA profiling. The National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments dataset, including PCR based miRNA profiling and RNA-seq data for 86 and 93 pre-chemotherapy tumor samples, respectively, was also used. Paired differential expression testing revealed a profile of 17 miRNAs with significantly different transcriptional levels following chemotherapy. Genes targeted by the miRNAs were differentially expressed following chemotherapy, suggesting the miRNAs may regulate transcriptional networks. Finally, an in vitro pharmacogenomic screen using miRNAs and their target transcripts predicted response to a set of candidate small molecule therapeutics which potentially reverse the chemotherapy resistance phenotype and synergize with chemotherapy in otherwise treatment resistant tumors. Importantly, these novel therapeutic targets are distinct from targets identified by a similar pharmacogenomic analysis of previously published prognostic miRNA profiles from pre chemotherapy biopsy specimens.

Abstract PO-022: Distinct intratumoral microbiome signatures enrichment in patients with different Anaplaplastic Large Cell Lymphoma (ALCL) subtypes

Abstract Background: The intratumoral microbiome is a tumor-specific component of the tumor microenvironment (TME), including microorganisms localized inside and around cancer cells and immune cells (Nejman Science2020), which was recently added to the “Hallmarks of Cancer” (Hanahan, Cancer Discovery 2022). Specific intratumoral microbiome signatures (IMS) can be detected using our targeted sequencing platform Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) (Prashkin Nat Comm 2023) data through the implementation of a specific bioinformatic pipeline (Vanderbilt J Mol Diagn 2022, Abate Ann Surg 2022). In lymphoma, where antigen stimulation is known to promote lymphomagenesis, studying the intratumoral microbiome might inform lymphoma biology and potentially new treatment strategies. In anaplastic large cell lymphoma (ALCL), a specific histologic phenotype can be found in a very diverse spectrum of diseases, ranging from smoldering lymphomas such as breast-implant associated (BIA-ALCL) and primary cutaneous (pcALCL) to systemic aggressive lymphomas such as ALK-positive or ALK-negative ALCL. We hypothesized that the different IMS might be present in different ALCL clinical presentations. Methods: We used metagenomic techniques to analyze IMS on MSK-IMPACT-HEME as previously described (Vanderbilt J Mol Diagn 2022) of patients with ALCL in our lymphoma database. All patients signed informed consent. We calculated the odds ratio (OR) of each intra-lymphoma IMS in one ALCL subtype compared to that of the same IMS in the other ALCL subtypes. We used several different analyses to process the data for commensals and contaminants. In this regard, we built a database of potentially pathogenic or commensal microorganisms integrated in the decontam (R package) pipeline dataset. For BIA-ALCL, we compared the IMS results with those of known components of explanted textured implant biofilm. Results: We re-analyzed the MSK-IMPACT-HEME BAM files of 58 patients with ALCL, including 12 BIA-ALCL, 11 pcALCL, and 35 systemic ALK+/- ALCL. After reviewing the data for commensals and contaminants, we could identify more than one potentially lymphoma-specific or site-specific microorganism in pcALCL (n=2) and in BIA-ALCL (n=14) (slow-growing subtypes) compared with systemic ALCL. Fewer differences were noted between pcALCL and BIA-ALCL; however, Achromobacter and Rothia were significantly enriched in BIA-ALCL compared to systemic ALCL and pcALCL (OR 14.9 p=0.001; OR=5, p=0.025) and Micromonospora in pcALCL compared to BIA-ALCL and systemic ALCL (OR=5.5, p=0.05). No specific IMS was found in systemic ALCL, as the only potentially enriched IMS (Delftiae) is likely a contaminant. Conclusions: This analysis of IMS using targeted sequencing data, highlighted some possible associations between intratumoral microorganisms and lymphoma-specific subtypes, especially in indolent subtypes of ALCL (BIA- and pc-) compared to systemic ALCL. Further analyses with more cases and confirmatory techniques might confirm these initial findings. Citation Format: Paola Ghione, Horwitz Steven, Peter Cordeiro, Maria Arcila, Natasha Galasso, Ahmet Dogan, Gilles Salles, Chad Vanderbilt. Distinct intratumoral microbiome signatures enrichment in patients with different Anaplaplastic Large Cell Lymphoma (ALCL) subtypes [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-022.

An updated review of the pharmacological effects and potential mechanisms of hederagenin and its derivatives.

Hederagenin (HG) is a natural pentacyclic triterpenoid that can be isolated from various medicinal herbs. By modifying the structure of HG, multiple derivatives with superior biological activities and safety profiles have been designed and synthesized. Accumulating evidence has demonstrated that HG and its derivatives display multiple pharmacological activities against cancers, inflammatory diseases, infectious diseases, metabolic diseases, fibrotic diseases, cerebrovascular and neurodegenerative diseases, and depression. Previous studies have confirmed that HG and its derivatives combat cancer by exerting cytotoxicity, inhibiting proliferation, inducing apoptosis, modulating autophagy, and reversing chemotherapy resistance in cancer cells, and the action targets involved mainly include STAT3, Aurora B, KIF7, PI3K/AKT, NF-κB, Nrf2/ARE, Drp1, and P-gp. In addition, HG and its derivatives antagonize inflammation through inhibiting the production and release of pro-inflammatory cytokines and inflammatory mediators by regulating inflammation-related pathways and targets, such as NF-κB, MAPK, JAK2/STAT3, Keap1-Nrf2/HO-1, and LncRNA A33/Axin2/β-catenin. Moreover, anti-pathogen, anti-metabolic disorder, anti-fibrosis, neuroprotection, and anti-depression mechanisms of HG and its derivatives have been partially elucidated. The diverse pharmacological properties of HG and its derivatives hold significant implications for future research and development of new drugs derived from HG, which can lead to improved effectiveness and safety profiles.

Molecular nociceptive mechanisms in migraine: The migraine cascade.

This review will explore the categorization of migraine-provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. Personal experience and literature. Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) that induces controlled migraine-like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP-inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP-inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine-inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies.

HDAC6 Inhibition Releases HR23B to Activate Proteasomes, Expand the Tumor Immunopeptidome and Amplify T-cell Antimyeloma Activity.

The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma.

Naringin dihydrochalcone alleviates sepsis-induced acute lung injury via improving gut microbial homeostasis and activating GPR18 receptor

Acute lung injury (ALI) is a life-threatening disease characterized by severe lung inflammation and intestinal microbiota disorder. The GPR18 receptor has been demonstrated to be a potential therapeutic target against ALI. Extracting Naringin dihydrochalcone (NDC) from the life-sustaining orange peel is known for its diverse anti-inflammatory properties, yet the specific action target remains uncertain. In the present study, we identified NDC as a potential agonist of the GPR18 receptor using virtual screening and investigated the pharmacological effects of NDC on sepsis-induced acute lung injury in rats and explored underlying mechanisms. In in vivo experiments, CLP-induced ALI model was established by cecum puncture and treated with NDC gavage one hour prior to drug administration, lung histopathology and inflammatory cytokines were evaluated, and feces were subjected to 16s rRNA sequencing and untargeted metabolomics analysis. In in vitro experiments, the anti-inflammatory properties were exerted by evaluating NDC targeting the GPR18 receptor to inhibit lipopolysaccharide (LPS)-induced secretion of TNF-α, IL-6, IL-1β and activation of inflammatory signaling pathways in MH-S cells. Our findings showed that NDC significantly ameliorated lung damage and pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) in both cells and lung tissues via inhibiting the activation of STAT3, NF-κB, and NLRP3 inflammatory signaling pathways through GRP18 receptor activation. In addition, NDC can also partly reverse the imbalance of gut microbiota composition caused by CLP via increasing the proportion of Firmicutes/Bacteroidetes and Lactobacillus and decreasing the relative abundance of Proteobacteria. Meanwhile, the fecal metabolites in the NDC treatment group also significantly were changed, including decreased secretion of Phenylalanin, Glycine, and bile secretion, and increased secretion of Lysine. In conclusion, these findings suggest that NDC can alleviate sepsis-induced ALI via improving gut microbial homeostasis and metabolism and mitigate inflammation via activating GPR18 receptor. In conclusion, the results indicate that NDC, derived from the typical orange peel of food, could significantly contribute to development by enhancing intestinal microbial balance and metabolic processes, and reducing inflammation by activating the GPR18 receptor, thus mitigating sepsis-induced ALI and expanding the range of functional foods.

Less Specific and More Comprehensive? An Analysis of How the Ocean Is Reflected in the Kunming-Montreal Global Biodiversity Framework

Abstract In response to the increasing trend of biodiversity decline globally and its consequences for the planet as a whole, the Convention on Biological Diversity Conference of the Parties adopted the Kunming-Montreal Global Biodiversity Framework (GBF) in December 2022. The Framework sets conservation, sustainability and equitable sharing of benefits from the use of genetic resources and MEAns of implementation goals to be achieved by 2050, and actionable targets to be achieved by 2030 to halt and reverse biodiversity loss. During the negotiations and even after the adoption of the GBF, much debate has surrounded how the ocean has been represented in the Framework. By addressing the scope of the GBF vis-à-vis the Convention, quantifying and comparing the use of marine-related terms in the GBF and in the previous biodiversity framework, and aligning relevant COP decisions and objectives and activities of the CBD Programme of Work on Marine and Coastal Biodiversity with the GBF targets, we conclude that the GBF does not fail to address marine and coastal biodiversity and all targets are applicable to this ecosystem.

Patient engagement in hematopoietic stem cell transplantation and cell therapy: a survey by the EBMT patient engagement task force & transplantation complications working party.

The EBMT (European Blood and Marrow Transplantation Society) aims to connect patients, the scientific community, and other stakeholders to improve hematopoietic stem cell transplantation and cellular therapy outcomes. We performed a cross-sectional online survey to understand the perceptions regarding Patient Reported Outcomes (PROs) and Patient Active Involvement in Research (PAIR) in over 800 stakeholders (n = 813). Patients (n = 278) and health care professionals (HCPs) (n = 351) were compared. We observed high openness for EBMT PRO collection (n = 680, 84.5% across stakeholders' groups; patients n = 256, 93.1% versus HCPs n = 273, 78.4% [p < 0.001]) and PAIR (n = 702, 87.3% across stakeholder groups; patients n = 256, 92.4% versus HCPs n = 296, 85.8% [p = 0.009]), with a significantly higher proportion of patients expressing interest compared to HCPs. Priority domains for PROs data-collection identified were the assessment of symptom experience, psychosocial and cognitive functioning. The most important issues for patients specifically were the data-collection of PROs reflecting cognitive function, the option of reporting data at home, the importance of identifying actionable targets to improve their recovery, and receiving feedback on their input when participating in research projects. Our multistakeholder approach suggests an added value to embracing patient engagement in the development of meaningful research and service design within the transplantation and cellular therapy community.

Targeting Tyro3, Axl, and MerTK Receptor Tyrosine Kinases Significantly Sensitizes Triple-Negative Breast Cancer to CDK4/6 Inhibition.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

First episode psychoses in people over-35 years old: uncovering potential actionable targets for early intervention services

The traditional youth-oriented design of Early Intervention Services (EIS) may lead to the exclusion of patients who have their psychotic onset later in life. A retrospective study was conducted to compare first-episode psychosis (FEP) patients who accessed treatment when aged ≤ 35 years with those ≥36+. A total of 854 patients were identified among 46,222 individuals who had access to community psychiatric services from 1991 to 2021. FEP were aged 18–65, received care between 2012 and 2021 and had a diagnosis of affective or non-affective FEP. Two groups were identified (FEP diagnosed at age ≤ 35 vs ≥ 36) and compared for sociodemographic and clinical characteristics. Most patients were diagnosed when aged ≥ 36+ (61.8%). Compared to the ≤ 35 group, older patients were more likely to be women, married and diagnosed with affective psychosis, and they were less frequently hospitalized. Long-acting injectables antipsychotics (LAI) were less frequently prescribed in the ≥ 36+ group, whereas antidepressants were more frequently prescribed compared to those aged ≤ 35. In both age groups, women were less frequently prescribed LAIs compared to men. These findings highlight the need to reorient EIS to accommodate the needs of older FEP, especially women.

Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.

Network pharmacology combined with metabolomics to reveal the anti-fibrotic mechanism of Polygoni Orientalis Fructus in CCl4-induced hepatic fibrosis rats

Polygoni Orientalis Fructus (POF), a dried ripe fruit of Polygonum orientale L., is commonly used in China for liver disease treatment. However, its therapeutic mechanism remains unclear. The aim of this study was to elucidate the effects of POF on the regulation of endogenous metabolites and identify its key therapeutic targets in hepatic fibrosis (HF) rats by integrating network pharmacology and metabolomics approaches. First, serum liver indices and histopathological analyses were used to evaluate the therapeutic effects of POF on carbon tetrachloride (CCl4)-induced HF. Subsequently, differential metabolites and potential therapeutic targets of POF were screened using plasma metabolomics and network pharmacology, respectively. The key targets of POF were identified by overlapping differential metabolite-associated targets with the potential targets and validated by molecular docking and ELISA experiments. The results showed that POF effectively alleviated HF in rats. A total of 51 metabolites related to HF were screened, and 24 were associated with POF. 232 potential therapeutic targets were identified by network pharmacology analysis. Finally, six key targets were identified through a combined analysis. Furthermore, molecular docking and ELISA validation revealed that AGXT, PAH, and NOS3 are targets of POF action, while CBS, ALDH2, and ARG1 were identified as potential targets. SignificancePOF is now commonly used in the treatment of liver disease, but its mechanism of action remains unclear. Current studies on metabolomics of liver disease primarily focuse on the interpretation of differential metabolites and related metabolic pathways. This research delves into the intricate details of metabolomics findings via network pharmacology to uncover the targets and pathways of drug action.

Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

&amp;lt;i&amp;gt;Objective&amp;lt;/i&amp;gt;: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.&amp;lt;i&amp;gt;Methods&amp;lt;/i&amp;gt;: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.&amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. &amp;lt;i&amp;gt;Conclusion&amp;lt;/i&amp;gt;: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.

Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocampal Neurogenesis.

Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone). Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment. Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.

Barriers and facilitators to perioperative smoking cessation: A scoping review.

Smoking cessation interventions are underutilized in the surgical setting. We aimed to systematically identify the barriers and facilitators to smoking cessation in the surgical setting. Following the Joanna Briggs Institute (JBI) framework for scoping reviews, we searched 5 databases (MEDLINE, Embase, Cochrane CENTRAL, CINAHL, and PsycINFO) for quantitative or qualitative studies published in English (since 2000) evaluating barriers and facilitators to perioperative smoking cessation interventions. Data were analyzed using thematic analysis and mapped to the theoretical domains framework (TDF). From 31 studies, we identified 23 unique barriers and 13 facilitators mapped to 11 of the 14 TDF domains. The barriers were within the domains of knowledge (e.g., inadequate knowledge of smoking cessation interventions) in 23 (74.2%) studies; environmental context and resources (e.g., lack of time to deliver smoking cessation interventions) in 19 (61.3%) studies; beliefs about capabilities (e.g., belief that patients are nervous about surgery/diagnosis) in 14 (45.2%) studies; and social/professional role and identity (e.g., surgeons do not believe it is their role to provide smoking cessation interventions) in 8 (25.8%) studies. Facilitators were mainly within the domains of environmental context and resources (e.g., provision of quit smoking advice as routine surgical care) in 15 (48.4%) studies, reinforcement (e.g., surgery itself as a motivator to kickstart quit attempts) in 8 (25.8%) studies, and skills (e.g., smoking cessation training and awareness of guidelines) in 5 (16.2%) studies. The identified barriers and facilitators are actionable targets for future studies aimed at translating evidence informed smoking cessation interventions into practice in perioperative settings. More research is needed to evaluate how targeting these barriers and facilitators will impact smoking outcomes.

Evaluation of an alternative process for the production of hydrocarbons from CO2: Techno-economic and environmental analysis

This study aims to evaluate and compare two integrated processes (Plant A and B) for hydrocarbon production from CO2. They involve proton exchange membrane water electrolysis for H2 production, reverse water-gas shift reaction for syngas production, pressure swing adsorption for syngas purification, Fischer-Tropsch synthesis for diesel-range hydrocarbons from CO2, and atmospheric distillation for product separation. Plant B additionally integrates a hydrocracking-based upgrading section. The simulations were performed using Aspen Plus® v10, Aspen Adsorption® v10, and Aspen Custom Modeler® v10. The evaluation covers technical, economic, environmental, and multi-criteria assessment (GREENSCOPE). The proposed processes demonstrate the potential to convert CO2 to hydrocarbons, with carbon conversion rates of 75% and 71% for Plants A and B, respectively. Process energy intensity is 155 and 170 MJ/kgLP for Plants A and B, respectively. Environmental assessment reveals CO2 reduction, resulting in negative global warming potentials of −2.20 and −0.84 kgCO2-eq/kgLP for Plants A and B, respectively. The sustainability degree indices for Plants A and B are 1.00 and 0.06, respectively, indicating Plant A as the more sustainable process alternative based on both quantitative and qualitative metrics. Economic analysis shows project unviability in the Brazilian context due to reliance on H2 production and prevailing pricing conditions. Economic viability requires a price increase of liquid products by 266% and 302% or CO2-eq abatement costs ranging from 2.05 to 3.43 US$/kgCO2-eq for Plants A and B, respectively. GREENSCOPE methodology indicates better performance for Plant A across all scores, highlighting a clear connection between the hydrocracking unit and performance indicators. The findings show that these processes align with sustainable development goals (SDGs) targets for climate action (SDG 13), clean energy (SDG 7), industry, innovation, and infrastructure (SDG 9), decent work and economic growth (SDG 8), and responsible consumption and production (SDG 12). Overall, the research moves forward SDGs by offering solutions to cut carbon emissions and promote sustainable industrial practices.

Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p=0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p=0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p=0.017). Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

Hungry for relief: Potential for neurotensin to address comorbid obesity and pain

Chronic pain and obesity frequently occur together. An ideal therapy would alleviate pain without weight gain, and most optimally, could promote weight loss. The neuropeptide neurotensin (Nts) has been separately implicated in reducing weight and pain but could it be a common actionable target for both pain and obesity? Here we review the current knowledge of Nts signaling via its receptors in modulating body weight and pain processing. Evaluating the mechanism by which Nts impacts ingestive behavior, body weight, and analgesia has potential to identify common physiologic mechanisms underlying weight and pain comorbidities, and whether Nts may be common actionable targets for both.