Target For Therapy Research Articles

Advances in research on malignant tumors and targeted agents for TOP2A (Review).

The DNA topoisomerase isoform topoisomerase IIα (TOP2A) is essential for the condensation and segregation of cellular mitotic chromosomes and the structural maintenance. It has been demonstrated that TOP2A is highly expressed in various malignancies, including lung adenocarcinoma (LUAD), hepatocellular carcinoma (HCC) and breast cancer (BC), associating with poor prognosis and aggressive tumor behavior. Additionally, TOP2A has emerged as a promising target for cancer therapy, with widespread clinical application of associated chemotherapeutic agents. The present study explored the impact of TOP2A on malignant tumor growth and the advancements in research on its targeted drugs. The fundamental mechanisms of TOP2A have been detailed, its specific roles in tumor cells are analyzed, and its potential as a biomarker for tumor prognosis and therapeutic targeting is highlighted. Additionally, the present review compiles findings from the latest clinical trials of relevant targeted agents, information on newly developed inhibitors, and discusses future research directions and clinical application strategies in cancer therapy, aiming to propose novel ideas and methods.

Influence of remnant lipoprotein particle cholesterol on non-target lesions progression in patients undergoing percutaneous coronary intervention

BackgroundLow-Density Lipoprotein Cholesterol (LDL-C) is the primary lipid therapy target for coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI). However, progression of coronary atherosclerosis occurs even LDL-C controlled well, some potentially important factors have been overlooked.ObjectiveThis study aims to elucidate the relationship between remnant lipoprotein particle cholesterol (RLP-C) and the progression of non-target lesions (NTLs) in patients with well-controlled lipid levels after PCI.MethodsThis retrospective study included 769 CAD patients who underwent PCI and followed up angiography within 6–24 months thereafter. Employing Multivariate Cox regression analysis, we assessed the correlation between RLP-C and NTLs progression. Based on the receiver operating characteristic curve analysis, we identified the optimal cutoff point for RLP-C, following which the patients were divided into two groups. Propensity score matching balanced confounding factors between groups, and Log-rank tests compared Kaplan–Meier curves for overall follow-up to assess NTLs progression.ResultsMultivariate Cox analysis revealed an independent association between RLP-C and NTLs progression when LDL-C was well-controlled. Additionally, the RLP-C level of 0.555 mmol/L was determined to be the best value for predicting NTLs progression. Following propensity score matching, Kaplan–Meier curves illustrated a significantly higher cumulative rate of NTLs progression in patients with RLP-C levels ≥0.555 mmol/L compared to the others (Log-rank P = 0.002). Elevated RLP-C levels were associated with high triglyceride concentrations, diabetes mellitus, and increased risk of revascularization.ConclusionsThis study illustrated the atherogenic impact of RLP-C in CAD patients. High RLP-C levels increased the risk of revascularization.

The Interplay Between Obesity and Aging in Breast Cancer and Regulatory Function of MicroRNAs in This Pathway.

Breast cancer (BC) is a significant contributor to cancer-related deaths in women, and it has complex connections with obesity and aging. This review explores the interaction between obesity and aging in relation to the development and progression of BC, focusing on the controlling role of microRNAs (miRNAs). Obesity, characterized by excess adipose tissue, contributes to a proinflammatory environment and metabolic dysregulation, which are important in tumor development. Aging, associated with cellular senescence and systemic changes, further exacerbates these conditions. miRNAs, small noncoding RNAs that regulate gene expression, play key roles in these processes, impacting pathways involved in cell proliferation, apoptosis, and cancer metastasis, either as tumor suppressors or oncogenes. Importantly, specific miRNAs are implicated in mediating the impact of obesity and aging on BC. Exploring the regulatory networks controlled by miRNAs provides valuable information on new targets for therapy and predictive markers, demonstrating the potential for using miRNA-based interventions to treat BC in obese and elderly individuals. This review emphasizes the importance of integrated research strategies to understand the complex connections between obesity, aging, and miRNA regulation in BC.

Regulation of AUF1 alternative splicing by hnRNPA1 and SRSF2 modulate the sensitivity of ovarian cancer cells to cisplatin.

Clarification of cisplatin resistance may provide new targets for therapy in cisplatin resistant ovarian cancer. The current study aims to explore involvement of isoforms of AU-rich element RNA-binding protein 1 (AUF1) in cisplatin resistance in ovarian cancer. The cancer stem cell-like features were analyzed using colony formation assay, tumor sphere formation assay and nude mouse xenograft experiments. AUF1 isoforms expression was analyzed using immunoblotting, qRT-PCR, and immunohistochemistry. RIP and Biotin pulldown was used to analyze the interaction of SRSF2 and hnRNPA1 with AUF1 transcript. Transcriptome regulated by AUF1 isoforms was analyzed by RNA-seq. The current study demonstrated differential expression of AUF1 isoforms in cisplatin sensitive and resistant ovarian cancer tissues and cells. P37 isoform promoted proliferation, while p45 isoform enhanced responsiveness of ovarian cancer cells to cisplatin. the clonal formation capacity of the cells, and the restoration of p45 expression reduced the capacity with cisplatin treatment. The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc-modified SRSF2 on AUF1 exon 2 and exon 7 regulated the alternative splicing of AUF1. The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc modified SRSF2 on exon 2 and exon 7 regulated the alternative splicing of AUF1 and subsequent isoform expression. P37 isoform played a "cancer promoter" role, p42 and p45, especially p45 played a "cancer suppressor" role in ovarian cancer. This study provides a new target for exploring the drug resistance mechanism of ovarian cancer.

Exploring Ion Channel Magnetic Pharmacology: Are Magnetic Cues a Viable Alternative to Ion Channel Drugs?

We explore the potential of using magnetic cues as a novel approach to modulating ion channel expression, which could provide an alternative to traditional pharmacological interventions. Ion channels are crucial targets for pharmacological therapies, and ongoing research in this field continues to introduce new methods for treating various diseases. However, the efficacy of ion channel drugs is often compromised by issues such as target selectivity, leading to side effects, toxicity, and complex drug interactions. These challenges, along with problems like drug resistance and difficulties in crossing biological barriers, highlight the need for innovative strategies. In this context, the proposed use of magnetic cues to modulate ion channel expression may offer a promising solution to address these limitations, potentially improving the safety and effectiveness of treatments, particularly for long-term use. Key developments in this area are reviewed, the relationships between changes in ion channel expression and magnetic fields are summarized, knowledge gaps are identified, and central issues relevant to future research are discussed.

Designing hypothesis of substituted naphthyridines as anti-HIV agent: A QSAR Approach

HIV-1 Integrase is a validated drug target for anti-HIV therapy. It is an essential enzyme required for replication of the AIDS-virus. 1,3,4-oxadiazole substituted naphthyridine derivatives act against HIV integrase and thus have the potential to become a part of anti-HIV drug regime. In present study, we have carried out QSAR study of 1,3,4-oxadiazole substituted naphthyridine derivatives. Stepwise multiple linear regression analysis was performed to derive QSAR models and was evaluated for statistical significance and predictive power. The best QSAR model was selected for anti-HIV activity, having correlation coefficient (R) = 0.862, standard error of estimation (SEE) = 0.271 and cross validated squared correlation coefficient (Q2) = 0.676. The QSAR model indicates that shape index, partition coefficient and solvent accessible surface area play an important role in the anti-HIV activities of 1,3,4-oxadiazole substituted naphthyridine derivatives. The results of the present study may be useful in designing more potent analogues.

TAM-Derived Exosomes Promote EMT by Upregulating lncRNA MIR4435-2HG in Head and Neck Cancer.

This study aimed to investigate the impact of tumor-associated macrophage (TAM)-derived exosomes on epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC) and the underlying mechanisms involved. Exosomes were isolated and characterized using transmission electron microscopy, nanoparticle size analysis, and western blotting. The effect on EMT in HNSCC cells was assessed using wound healing, transwell invasion, and EMT marker assays. Bioinformatics analysis was conducted to predict key TAM-related long noncoding RNAs and evaluate their relationship with EMT in HNSCC. We observed that treatment with TAM-derived conditioned medium (CM) promoted EMT in HNSCC cells. Within the CM, we observed abundant exosomes that were taken up by HNSCC cells. Furthermore, TAM-derived exosomes promoted EMT in HNSCC cells. Mechanistically, high MIR4435-2HG expression levels were observed in TAM-derived exosomes and in HNSCC cells after treatment with TAM-derived exosomes. Notably, high MIR4435-2HG expression levels may be closely related to molecules that promote EMT in HNSCC. TAM-derived exosomes promote EMT in HNSCC cells by upregulating MIR4435-2HG expression, suggesting that MIR4435-2HG is a candidate target for HNSCC therapy.

Canine Adipose-Derived Mesenchymal Stromal Cells Reduce Cell Viability and Migration of Metastatic Canine Oral Melanoma Cell Lines In Vitro

Canine oral melanoma (COM) is a promising target for immunomodulatory therapies aimed at enhancing the immune system’s antitumor response. Given that adipose-derived mesenchymal stem cells (Ad-MSCs) possess immunomodulatory properties through cytokine release, we hypothesized that co-culturing Ad-MSCs and canine peripheral blood mononuclear cells (PBMCs) could stimulate interleukin (IL) production against melanoma cell lines (MCCLs) and help identify therapeutic targets. This study evaluated IL-2, IL-8, and IL-12 expressions in co-culture with MCCL, Ad-MSCs, and PBMCs and assessed the relationship between gene expression, cell viability, and migration. Using four experimental groups in a Transwell insert system to separate cell types, we found that Ad-MSCs can reduce MCCL migration and viability, though the effect may vary depending on each cell line’s susceptibility. Furthermore, Ad-MSCs modified IL expression profiles in co-cultured cells. Our findings suggest that Ad-MSCs could have therapeutic potential for COM by inhibiting cell migration and reducing viability. However, deeper insights into Ad-MSC interactions with the tumor microenvironment and melanoma-specific factors will be essential to optimize therapeutic efficacy.

The potential of cognitive remediation therapy for improving the communication capabilities of adults with schizophrenia and other psychotic spectrum disorders.

Impairment in aspects of communication is a core diagnostic feature of schizophrenia and other psychotic spectrum disorders. These communication difficulties inhibit participation in a range of daily activities and affect relationships and quality of life. There has been little research focussed on communication outcomes in relation to cognitive remediation therapy within this population. Data collected as part of an implementation trial of the Computerised Interactive Remediation of Cognition and Thinking Skills (CIRCuiTS) program provided an opportunity to examine the potential for changes in communication capability to support activities of daily living. To survey changes in ratings of aspects of communication capability of adults with schizophrenia who completed the CIRCuiTS cognitive remediation therapy program. Thirty adults with schizophrenia and other psychotic spectrum disorders completed the CIRCuiTS therapy program as part of an implementation trial in 2018 and 2019. Most participants were male (93%) and inpatients at Bloomfield Hospital (73%) in Orange, New South Wales. Ratings on the Adaptive Behaviour Assessment System, Third Edition (ABAS3) were returned before and after completion of the CIRCuiTS program. The magnitude of changes in ABAS3 indices, the Communication scale and Functional academics scales were assessed between time points. Participants' mean adaptive functioning indices prior to the CIRCuiTS program were in the extremely low range (∼second percentile) and increased to the low range (∼seventh percentile) following this therapy, achieving large mean effect sizes (Cohen's d = 0.92-1.24). Significant improvements in functioning were observed on the ABAS3 Communication and Functional Academics scales, with large mean effect sizes on both scales (Cohen's d = 1.09 and 0.99 respectively). Improvements in ratings occurred on items including initiating conversations, talking and listening over longer periods, explaining more complex information, using lists and reminders and a schedule or diary, completing written forms and personal money management. Most participants were observed to make gains in aspects of communication. The results point to these aspects of communication as potential future targets for therapy with people with schizophrenia and other psychotic spectrum disorders. This study highlights the value and role of Speech and Language Therapists in cognitive remediation therapy. Further research seems warranted with participants with a broader range of demographic, clinical and functional capabilities, that controls for the effects of medications and other therapeutic interventions and utilises a more comprehensive assessment of communication. What is already known on the subject People with schizophrenia and other psychotic spectrum disorders experience impairment in cognitive functioning as well as communication capability that affects their daily functioning and quality of life. Cognitive remediation therapy has been shown to improve aspects of the daily functioning of people with schizophrenia and other psychotic spectrum disorders and is recommended in international treatment guidelines. However, very little research has been conducted to investigate the effectiveness of this therapy in addressing communication difficulties. What this paper adds to existing knowledge The present study found participants with schizophrenia and other psychotic spectrum disorders made significant improvements in important aspects of communication after completing the Computerised Interactive Remediation of Cognition and Thinking Skills cognitive remediation therapy program. The results point to the potential of cognitive remediation therapy as a therapeutic approach that is likely to improve communication capability. What are the potential or actual clinical implications of this work? Cognitive remediation therapy is likely to be an important treatment for improving the communication capabilities of people with severe mental illness. This relatively new area of clinical practice and research highlights the value and potential of speech and language therapy in improving the communication capabilities of people with schizophrenia and other psychotic spectrum disorders.

Vitexin mitigates oxidative stress, mitochondrial damage, pyroptosis and regulates small nucleolar RNA host gene 1/DNA methyltransferase 1/microRNA-495 axis in sepsis-associated acute lung injury.

This study examinedvitexin's effect on sepsis-induced acute lung injury. We used network pharmacology and in vivo and in vitro experiments were performed to elucidate vitexin's role in preventing pyroptosis and regulating small nucleolar RNA host gene 1 (SNHG1)/DNA methyltransferase 1 (DNMT1)/microRNA-495 (miR-495 axis. We developed an acute lung injury model using C57BL/6 mice and MLE-12 cells. Through a combination of network pharmacology and in vitro screening, vitexin was identified as the most promising anti-inflammatory compound. Multiple techniques such as western blotting, real-time PCR, Hematoxylin and eosin staining, immunohistochemistry, andTUNEL assay were used. Additionally, immunofluorescence, DCFDA and TMRE staining, flow cytometry, methylation-specific PCR, and gene transfection techniques were performed to elucidate vitexin's potential targets and underlying mechanisms. Vitexin treatment significantly reduced lung damage, neutrophil infiltration, and inflammation while improving tight junction integrity. In LPS-treated RAW264.7 macrophages and a septic mouse BALF-induced MLE-12 cell injury model, vitexin demonstrated anti-inflammatory effects, promoted M2 macrophage polarization, and enhanced regenerative markers. It also decreased oxidative stress, mitigated apoptosis and pyroptosis, and improved mitochondrial function. Our research uncovered a novel epigenetic regulatory mechanism involving lncRNA SNHG1, DNMT1, and miR-495. Vitexin's ability to reduce inflammation, counteract oxidative stress, and modulate epigenetic processes. These findings underscore the promising role of vitexin as a treatment for ALI generated by sepsis. The SNHG1/miR-495 axis, which has been identified, represents a new target for future therapies in acute lung injury.

Targeting APE1: Advancements in the Diagnosis and Treatment of Tumors.

With the emergence of the precision medicine era, targeting specific proteins has emerged as a pivotal breakthrough in tumor diagnosis and treatment. Apurinic/apyrimidinic Endonuclease 1 (APE1) is a multifunctional protein that plays a crucial role in DNA repair and cellular redox regulation. This article comprehensively explores the fundamental mechanisms of APE1 as a multifunctional enzyme in biology, with particular emphasis on its potential significance in disease diagnosis and strategies for tumor treatment. Firstly, this article meticulously analyzes the intricate biological functions of APE1 at a molecular level, establishing a solid theoretical foundation for subsequent research endeavors. In terms of diagnostic applications, the presence of APE1 can be detected in patient serum samples, biopsy tissues, and through cellular in situ testing. The precise detection methods enable changes in APE1 levels to serve as reliable biomarkers for predicting tumor occurrence, progression, and patient prognosis. Moreover, this article focuses on elucidating the potential role of APE1 in tumor treatment by exploring various inhibitors, including nucleic acid-based inhibitors and small molecule drug inhibitors categories, and revealing their unique advantages in disrupting DNA repair function and modulating oxidative-reduction activity. Finally, the article provides an outlook on future research directions for APE1 while acknowledging major technical difficulties and clinical challenges that need to be overcome despite its immense potential as a target for tumor therapy.

Transcription factors and hormone receptors: Sex‑specific targets for cancer therapy (Review)

Transcription factors and hormone receptors: Sex‑specific targets for cancer therapy (Review)

Advances towards potential cancer therapeutics targeting Hippo signaling.

Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.

Trace element zinc metabolism and its relation to tumors

Zinc is an essential trace element in the human body, playing a crucial role in cellular metabolism.Dysregulation of zinc homeostasis can lead to abnormal cellular metabolism, contributing to diseases and closely related to tumor development. Adequate zinc intake can maintain zinc homeostasis in the body and support normal cellular metabolism. This review discusses the metabolic processes of zinc in the human body and its close relationship with tumorigenesis. It briefly describes zinc absorption, transport, storage, and release, as well as its important role in gene expression, signal transduction, oxidative stress, immune response, and apoptosis. It focuses on the abnormal cellular metabolism caused by excessive or insufficient zinc, the relationship between zinc homeostasis disruption and metabolic syndrome, and the mechanisms involved in tumor development. It analyzes how changes in the expression and activity of zinc transporters may lead to disrupted zinc homeostasis in tumor tissues. It points out that zinc deficiency is associated with various cancers, including prostate cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer, ovarian cancer, esophageal squamous cell carcinoma, and breast cancer. The summary emphasizes that zinc metalloproteins could serve as potential targets for cancer therapy, and regulating the expression and activity of zinc transport proteins may offer new methods and strategies for clinical cancer treatment.

Suppression of microtubule acetylation mediates the anti-leukemic effect of CDK9 inhibition

Cyclin-dependent kinase 9 (CDK9) is a crucial component of transcription and potential target for anti-cancer therapies, particularly for hematological malignancies. However, the precise mechanisms underlying the therapeutic effects of CDK9 inhibitors remain not fully understood. Here, we found that inhibiting CDK9 either pharmacologically or through gene downregulation, significantly reduced the levels of α-tubulin protein in a time- and dose-dependent manner. We further discovered that CDK9 inhibition led to increased susceptibility of α-tubulin to proteasomal degradation due to reduced acetylation at lysine 40 (K40), an important modification for microtubule stability. An acetylation-mimicking mutant of α-tubulin mitigated the anti-tumor effects of CDK9 inhibition. Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for α-tubulin acetylation, further compromising microtubule stability. We also conducted in vivo studies in a leukemic xenograft model, where AZD4573 treatment led to significant tumor regression, decreased ATAT1 expression, and α-tubulin degradation. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.

LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis.

Gastric cancer ranks among the most prevalent malignancies globally, characterized by limited treatment efficacy and high recurrence rates. Effective management of this disease requires a comprehensive understanding of its underlying pathogenic mechanisms. Galectins have emerged as promising targets in gastric cancer therapy, with Galectin-9 (LGALS9) receiving considerable attention in recent years. However, Galectin-9B (LGALS9B) remains relatively under-explored in gastric cancer research. Our study investigates the role of LGALS9B in gastric cancer progression, demonstrating that its over-expression enhances cellular proliferation, migration, and invasion, while its knockdown inhibits these processes both in vitro and in vivo. We further elucidate that LGALS9B competes with the E3 ligase HERC5 for binding to eukaryotic translation elongation factor 1 delta (EEF1D), thereby preventing its protein degradation. This interaction results in the enrichment of EEF1D, which activates the PI3K/AKT signaling pathway and ultimately promotes gastric cancer progression. These findings highlight the regulatory role of LGALS9B in the pathogenesis of gastric cancer, offering valuable insights into potential novel therapeutic strategies for managing this challenging disease.

Aberrantly Expressed Mitochondrial Lipid Kinase, AGK Activates JAK2-Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy.

Although the B-cell receptor (BCR) signal plays a critical role in CLL cell survival and a target of current therapies (ibrutinib targets Bruton's tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the "CLL cell-survival signaling network" is largely undefined. CLL patients were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. We detected that compared to normal B-cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its non-canonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR-signal in CLL cells via LYN/BTK axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR-inhibitors or venetoclax (a BCL2-inhibitor) induced apoptosis synergistically in CLL cells. These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some CLL patients.

Preassembled complexes of hAgo2 and ssRNA delivered by nanoparticles: A novel silencing gene expression approach overcoming the absence of the canonical pathway of siRNA processing in the apicomplexan parasite Babesia microti, blood parasite of veterinary and zoonotic importance

Due to the lack of efficacy of the currently used chemical drugs, poor tick control, and lack of effective vaccines against Babesia, novel control strategies are urgently needed. In this regard, searching for anti-Babesia gene therapy may facilitate the control of this infection. Following this pattern, small interfering RNAs (siRNAs) are widely used to study gene function and hence open the way to control the parasite. However, the primary constraint of this approach is the lack of Babesia to RNA-induced silencing complex (RISC) enzymes, making siRNA impractical. In this study, we preassembled complexes with the human enzyme argonaute 2 (hAgo2) and a small interfering RNA (siRNA)/single-stranded RNA (ssRNA) against B. gibsoni and B. microti metabolite transporters. The assembled complexes were generated by developing a gene delivery system with chitosan dehydroascorbic acid nanoparticles. The delivery system effectively protected the loaded RNAi and targeted Babesia-infected RBCs with a relatively high internalization rate. The assembled complexes were successfully transfected into live parasites for specific slicing of Babesia targets. We demonstrated a reduction in the expression of target genes at the mRNA level. Furthermore, this silencing inhibited Babesia growth in vitro and in vivo. For the first time, we used this method to confirm the role of the assembled complexes in manipulating the noncanonical pathway of RNAi in Babesia parasites. This novel method provides a means of silencing Babesia genes to study their role in host-parasite interactions and as potential targets for gene therapy and control.

Radioresistance-related gene signatures identified by transcriptomics characterize the prognosis and immune landscape of pancreatic cancer patients

BackgroundRadiotherapy (RT) is an important means of local treatment of solid tumors, and radioresistance is the main reason for RT failure for tumors, especially pancreatic cancer (PC). It is urgent to distinguish key genes and mechanisms of radioresistance in PC.MethodsWe acquired the data from The Cancer Genome Atlas (TCGA), obtained the gene modules associated with radioresistance by weighted gene coexpression network analysis (WGCNA), and identified differentially expressed genes (DEGs) between normal and tumor samples. Radioresistance-related genes (RRRGs) were determined with the intersection of WGCNA and DEGs. The hub RRRGs associated with prognosis were distinguished by the least absolute shrinkage and selection operator (LASSO) regression. We established a risk score model using multivariate Cox regression. Immune cell infiltration and drug sensitivity were evaluated through the CIBERSORT algorithm and the “OncoPredict” software package, respectively. The association of the key gene RIC3 and PC clinical features was verified in public databases, and its biological behaviors were explored in vitro.ResultsThe intersection of DEGs and WGCNA confirmed 14 RRRGs, then six hub RRRGs were identified using LASSO. A key four genes (DUSP4, ADORA2B, SCGB2A1, and RIC3) risk score model was constructed and proved to be capable of independently estimating the prognosis of PC. There is no significant difference between risk score groups in various immune cell infiltration and response to immunotherapy. Although the low-risk group seemed to exhibit greater sensitivity to antitumor drugs, the four drugs (5-fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin) currently used for PC patients had no statistical difference for the low- and high- group. The overexpression of RIC3 had a synergy effect with irradiation on inhibited malignant biological properties of PC cells, which was verified by detecting the proliferation ability, apoptosis rate, cell cycle distribution, and migration ability of PANC-1 cells.ConclusionsWe herein presented signature genes correlated with radioresistance in PC and established a risk score model competent in estimating patients’ clinical outcomes and response to antitumor drugs. The above evidence could contribute to comprehending the mechanisms of radioresistance and identifying the underlying therapy targeting.

Dissecting metabolic landscape of alveolar macrophage

The highly plastic nature of Alveolar Macrophage (AM) plays a crucial role in the defense against inhaled particulates and pathogens in the lungs. Depending on the signal, AM acquires either the classically activated M1 phenotype or the alternatively activated M2 phenotype. In this study, we investigate the metabolic shift in the activated phases of AM (M1 and M2 phases) by reconstructing context specific Genome-Scale Metabolic (GSM) models. Metabolic pathways such as pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation are found to be important driving forces in the development of the M1/M2 phenotypes. Additionally, we formulated a bilevel optimization framework named MetaShiftOptimizer to identify minimal modifications that shift one activated state (M1/M2) to the other. The identified reactions involve metabolites such as glycogenin, L-carnitine, 5-hydroperoxy eicosatetraenoic acid, and leukotriene B4, which show potential to be further investigated as significant factors for developing efficient therapy targets for severe respiratory disorders in the future. Overall, our study contributes to the understanding of the metabolic capabilities of the M1 and M2 phenotype of AM and identifies pathways and reactions that can be potential targets for polarization shift and also be used as therapeutic strategies against respiratory diseases.