MedComm最新文献

{"title":"Quaking–cZFP609 Axis Remedies Aberrant Plasticity of Vascular Smooth Muscle Cells via Mediating Platelet-Derived Growth Factor Receptor β Degradation","authors":"Yong-Qing Dou,&nbsp;Xiao-Yun Zhang,&nbsp;Rui-Juan Guo,&nbsp;Xiao-Fu Huang,&nbsp;Yu Song,&nbsp;Xin-Long Liu,&nbsp;Jie Shi,&nbsp;Fan-Qin Li,&nbsp;Dan-Dan Zhang,&nbsp;Peng Kong,&nbsp;Lei Nie,&nbsp;Han Li,&nbsp;Fan Zhang,&nbsp;Mei Han","doi":"10.1002/mco2.70167","DOIUrl":"https://doi.org/10.1002/mco2.70167","url":null,"abstract":"<p>Vascular smooth muscle cell (VSMC) plasticity is crucial for the repair after vascular injury. However, the high plasticity of VSMCs may make them transform into pathogenic phenotypes. Here, we show that VSMCs overexpressing Sirtuin 1 (SIRT1) exhibit a reduced phenotypic plasticity in the context of platelet-derived growth factor (PDGF)-BB treatment. SIRT1 activated Quaking (QKI)–cZFP609 axis is involved in the plasticity regulation in the VSMCs. Mechanically, SIRT1 deacetylates K133 and K134 of QKI and mediates its activation. Activated QKI binds the QKI response elements located in the upstream and downstream of the cZFP609-forming exons in ZFP609 pre-mRNA to mediate cZFP609 production. Furthermore, the acetylation of QKI is increased by inhibiting SIRT1 with the selective and potent inhibitor EX527 or deletion of SIRT1, accompanied with parallel decrease in cZFP609 formation. Final, we identify that cZFP609 directs PDGF receptor (PDGFR)β sorting into endosomal/lysosomal pathway and degradation by bridging PDGFRβ and Rab7, resulted in attenuating Raf–MEK–ERK cascade activation downstream of PDGFRβ signaling. Overexpression of cZFP609 remedies aberrant plasticity and overproliferation of VSMCs, and ameliorates neointimal formation. Together, these results highlight that modulating the QKI–cZFP609 axis may help propel repair without stenosis as a therapeutic strategy in vascular injury.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABAB Receptor: Structure, Biological Functions, and Therapy for Diseases","authors":"Weijie Xie,&nbsp;Yuan Li,&nbsp;Xinyue Wang,&nbsp;Elena Blokhina,&nbsp;Evgeny Krupitsky,&nbsp;Marina Vetrova,&nbsp;Ji Hu,&nbsp;Ti-Fei Yuan,&nbsp;Jue Chen,&nbsp;Hua Wang,&nbsp;Xiangfang Chen","doi":"10.1002/mco2.70163","DOIUrl":"https://doi.org/10.1002/mco2.70163","url":null,"abstract":"<p>Gamma-aminobutyric acid (GABA) B receptors (GABA_BRs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABA_BRs in regulating feeding-related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding-related disorders remains underutilized. This general review summarized the physiological structure and functions of GABA_BR, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABA_BRs and its regulator-binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABA_BR1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABA_BR2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABA_BRs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABA_BR pathways in a clinical setting.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad-Spectrum Antiviral Activity of the Orally Bioavailable Antiviral ATV014 Against Multiple Coronaviruses","authors":"Sidi Yang,&nbsp;Kun Li,&nbsp;Qifan Zhou,&nbsp;Xumu Zhang,&nbsp;Deyin Guo","doi":"10.1002/mco2.70186","DOIUrl":"https://doi.org/10.1002/mco2.70186","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Coronaviruses (CoVs) frequently cross species barriers, complicating the development of targeted antiviral treatments and making it challenging to control emerging viral infections. While most CoV strains tend to be specific to particular host species, zoonotic variants have the capacity to rapidly adapt to new hosts, often resulting in severe disease outbreaks. Over the past two decades, three new human CoVs have emerged: Severe Acute Respiratory Syndrome CoV (SARS-CoV) in 2002, Middle East Respiratory Syndrome CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019, all of which caused significant health impacts in human populations. At present, no antiviral therapies have been approved that offer broad-spectrum efficacy against multiple CoV strains in humans. The development of a therapeutic agent with wide-ranging antiviral activity against CoVs would address a critical medical gap and prove invaluable in managing potential future outbreaks of novel CoV strains.&lt;/p&gt;&lt;p&gt;We recently reported the potent anti-SARS-CoV-2 efficacy of ATV014 in preclinical studies [&lt;span&gt;1&lt;/span&gt;]. ATV014 is a cyclohexane carboxylate prodrug of the parent compound 1ʹ-CN-4-aza-7,9-dideazaadenosine C-nucleoside (GS-441524) (Figure 1A), which is currently undergoing Phase III clinical trials for the treatment of both mild and severe COVID-19. Like Mindeudesivir and ATV006 (the same as Obeldesivir developed by Gilead), ATV014 is an oral analog of remdesivir (RDV), a broad-spectrum antiviral initially developed for the Ebola virus and later repurposed for COVID-19. All three compounds were developed as part of ongoing efforts to improve the pharmacokinetics, efficacy, and ease of administration of antiviral therapies for various viral infections, including those caused by CoVs [&lt;span&gt;2-4&lt;/span&gt;]. Previous studies have shown that RDV exhibits broad-spectrum antiviral activity against multiple RNA viruses, including CoVs, filoviruses, pneumoviruses, arenaviruses, and paramyxoviruses [&lt;span&gt;5&lt;/span&gt;]. In light of this, we aimed to assess the antiviral potency and breadth of activity of ATV014 against several CoVs.&lt;/p&gt;&lt;p&gt;Our previous studies demonstrated that ATV014 effectively inhibited the replication of SARS-CoV-2, including its various variants of concern (VOCs), such as Beta, Delta, and Omicron, with greater potency than RDV or GS-441524 [&lt;span&gt;1&lt;/span&gt;]. Given the evolving nature of SARS-CoV-2 variants, we initially assessed the antiviral efficacy of ATV014 in A549-hACE2 cells infected with the latest variants, including Omicron BA.5 and EG.5. As depicted in Figure 1B, ATV014 showed notably enhanced antiviral activity against BA.5 (EC50 = 0.251 µM) and EG.5 (EC50 = 0.0935 µM) compared to GS-441524, which aligns with the findings from our earlier research. CoVs are classified into several genogroups, such as alpha, beta, gamma, and delta, with human pathogenic CoVs primarily belonging to the alpha (HCoV-229E and HCoV-NL63) and beta (HCoV-OC43, HCoV-HKU1, SAR","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Multiomics Profiling of Mouse Hippocampus Reveals Transcriptional Upregulation of Interferon-Stimulated Genes Through PU.1 Regulator in Microglial Activation Induced by Chronic Cerebral Hypoperfusion","authors":"Zengyu Zhang,&nbsp;Dewen Ru,&nbsp;Zhuohang Liu,&nbsp;Zimin Guo,&nbsp;Lei Zhu,&nbsp;Yuan Zhang,&nbsp;Min Chu,&nbsp;Yong Wang,&nbsp;Jing Zhao","doi":"10.1002/mco2.70157","DOIUrl":"https://doi.org/10.1002/mco2.70157","url":null,"abstract":"<p>Chronic cerebral hypoperfusion (CCH) is a significant factor that accelerates cognitive deterioration, yet the mechanisms of hippocampal microglial activation in this context remain unclear. Using an integrative multiomics approach, we investigated the transcriptional and epigenomic landscape of microglial activation in a mouse model of CCH induced by bilateral common carotid artery stenosis. Behavioral assessments revealed cognitive impairments, while neuropathological analysis confirmed hippocampal damage. Proteomic and transcriptomic profiling uncovered significant upregulation of stress and inflammatory pathways, particularly the interferon (IFN) signaling cascade. Epigenomic analysis identified regions of open chromatin, suggesting active transcriptional regulation driven by the transcription factor (TF) PU.1. ChIP-nexus analysis further confirmed that PU.1 directly modulates the expression of IFN-stimulated genes (ISGs), which are pivotal in regulating microglial activation. Our findings demonstrate that PU.1 serves as a key regulator of the IFN-driven microglial response during CCH, mediated by enhanced chromatin accessibility and transcriptional activation of ISGs. This study highlights the critical role of PU.1 in microglial-mediated neuroinflammation and offers potential therapeutic targets for mitigating hippocampal damage associated with chronic cerebral ischemia.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Insights Into the Human Dopamine Transporter: Structure, Function, and Therapeutic Potential","authors":"Qi Weng,&nbsp;Qi Wu,&nbsp;Quan Zheng","doi":"10.1002/mco2.70187","DOIUrl":"https://doi.org/10.1002/mco2.70187","url":null,"abstract":"&lt;p&gt;Recently, three breakthrough studies on the structure and function of the human dopamine transporter (hDAT) were published consecutively in &lt;i&gt;Nature&lt;/i&gt; [&lt;span&gt;1-3&lt;/span&gt;]. Researchers used cryo-electron microscopy to resolve high-resolution structures of hDAT bound to various ligands, including dopamine (DA), methylphenidate (MPH), β-CFT, GBR12909, MRS7292, benztropine, and cocaine. The resolution of these structures revealed the detailed molecular mechanism of hDAT in DA reuptake and inhibition, providing important information to guide the development of drugs for the treatment of DA-related diseases.&lt;/p&gt;&lt;p&gt;DA is an important neurotransmitter that is involved in regulating a variety of functions in the brain, including cognition, movement, emotion, and reward [&lt;span&gt;4&lt;/span&gt;]. The dopamine transporter (DAT) is located in the presynaptic membrane of dopaminergic neurons and is responsible for the reuptake of DA in the synaptic gap, inhibition of DA signaling, and maintenance of central nervous system DA homeostasis. When hDAT malfunctions, it may lead to abnormal DA levels, which are associated with a variety of disorders such as attention deficit hyperactivity disorder (ADHD), depression, bipolar disorder, Parkinson's disease, and addictive behaviors [&lt;span&gt;5&lt;/span&gt;]. Although scientists have been studying DAT for decades, much remains unknown about the structure, conformational transitions, and specific postures of hDAT for drug binding. Therefore, an in-depth study of the structure and function of hDAT is extremely important for the development of new drugs for the treatment of DA-related diseases.&lt;/p&gt;&lt;p&gt;Li et al. [&lt;span&gt;1&lt;/span&gt;] observed three different conformational changes of hDAT during DA transport by cryo-electron microscopy, including the outward-open state, the closed state, and the inward-open state (Figure 1). It is evident that Na&lt;sup&gt;+&lt;/sup&gt; and Cl&lt;sup&gt;−&lt;/sup&gt; play key roles in the reuptake of DA, with Na&lt;sup&gt;+&lt;/sup&gt; interacting with residues N82, N353, D421, and S422, while Cl&lt;sup&gt;−&lt;/sup&gt; binds to Y102, Q317, S321, and S357. These ions form hydrogen bonds and charge interactions that stabilize DA binding in hDAT and facilitate its transport from extracellular to intracellular compartments. Notably, hDAT has fewer water molecules in the DA binding site, a phenomenon that may affect DA binding and transporter function. This creates a more hydrophobic environment, enhancing DA binding stability but reducing flexibility and binding/dissociation rates. Additionally, fewer water molecules reduce hydrogen-bonding networks, increasing reliance on direct interactions between amino acids and DA. This raises the specificity of the binding but also increases the sensitivity to structural changes.&lt;/p&gt;&lt;p&gt;Meanwhile, Srivastava et al. [&lt;span&gt;2&lt;/span&gt;] also successfully resolved the three-dimensional structure of hDAT in the binding state with the cocaine analog competitive inhibitor β-CFT, the noncompetitive inhibitor MRS7292, and Zn&lt;sup&gt;2","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM Structures Reveal Key Mechanisms of Noradrenaline Transporter","authors":"Peng Su,&nbsp;Mao Li,&nbsp;Fangfang Zhou","doi":"10.1002/mco2.70188","DOIUrl":"https://doi.org/10.1002/mco2.70188","url":null,"abstract":"&lt;p&gt;In a recent article in &lt;i&gt;Nature&lt;/i&gt;, Hu et al. [&lt;span&gt;1&lt;/span&gt;] unveiled cryo-EM (cryo-electron microscopy) structures of the human noradrenaline transporter (NET) in multiple states—unbound (&lt;i&gt;apo)&lt;/i&gt;, substrate-bound (noradrenaline), and bound with several clinically used drugs (Figure 1A). These structures, captured in inward- and outward-facing conformations, shed light on the substrate transport and inhibition mechanisms of NET.&lt;/p&gt;&lt;p&gt;The noradrenaline system, dependent on noradrenaline as its primary neurotransmitter, regulates essential physiological functions, including mood, pain perception, sleep-wake cycle, arousal, attention, feeding behavior, and fight-or-flight responses [&lt;span&gt;2&lt;/span&gt;]. Noradrenaline system dysfunction is implicated in several mental disorders. NET, located in presynaptic neurons, mediates noradrenaline reuptake, effectively terminating synaptic signaling and modulating neurotransmitter levels. Given the crucial role of NET in maintaining noradrenaline homeostasis, it has emerged as a primary target for the treatment of mental health disorders, including depression, attention deficit hyperactivity disorder, and neuropathic pain. Clinically used drugs exert their effects by targeting NET. However, the detailed molecular mechanisms underlying the effects of these inhibitors remain unclear. In addition, fundamental questions regarding the transport mechanism of NET, such as ligand and ion coupling and the conformational transition across functional states, remain elusive.&lt;/p&gt;&lt;p&gt;To elucidate the mechanisms underlying NET transport and inhibition, Hu et al. [&lt;span&gt;1&lt;/span&gt;] expressed human NET and reconstituted it into nanodiscs to comprehensively replicate the native membrane environment. Using cryo-EM, they obtained structures at 2.6 Å of NET in &lt;i&gt;apo&lt;/i&gt; and noradrenaline-bound states, capturing the transporter in inward- and outward-facing conformations. NET operates as a secondary active transporter that leverages electrochemical gradients of sodium and chloride ions. The high-resolution maps facilitated the precise localization of sodium and chloride ion-binding sites, highlighting their roles in the transport cycle of NET. In addition to the primary binding site, Hu et al. [&lt;span&gt;1&lt;/span&gt;] identified a secondary substrate-binding site within the extracellular cavity that existed only in the inward-facing conformation. Upon mutating key residues, including R301 and E382, which interact with noradrenaline at this site, they observed a partial reduction in the transport activity for the E382A mutant, whereas the R301A mutation did not appear to affect transport activity. This finding suggests that the secondary site is complementary in modulating substrate dynamics, potentially influencing the efficiency and regulation of noradrenaline transport under physiological conditions. By resolving the structure of NET in both outward- and inward-facing conformations, they mapped the structural rearrangements essenti","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70188","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Scope of Molecular Glues: TRIM21 as a Multimeric Protein Degrader","authors":"Kai Huang,&nbsp;Anqi Zhou,&nbsp;Xiangxiang Zhou","doi":"10.1002/mco2.70178","DOIUrl":"https://doi.org/10.1002/mco2.70178","url":null,"abstract":"&lt;p&gt;In a recent study published on &lt;i&gt;Cell&lt;/i&gt;, Lu et al. [&lt;span&gt;1&lt;/span&gt;] introduce a novel targeted protein degradation (TPD) strategy that employs Tripartite motif-containing protein 21 (TRIM21), an E3 ligase activated through clustering, to achieve multimeric protein degradation with remarkable selectivity.&lt;/p&gt;&lt;p&gt;The field of TPD has expanded rapidly with the development of molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs), which use E3 ubiquitin ligases to tag proteins for degradation [&lt;span&gt;2&lt;/span&gt;]. However, current TPD methods rely heavily on E3 ligases such as Cereblon and Von Hippel–Lindau tumor suppressor, which are broadly expressed and lack conditional activity, posing challenges for selective targeting, especially in complex protein assemblies [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;An additional challenge lies in selectively targeting multimeric proteins, which are often implicated in disease due to their aggregated forms, as seen in neurodegenerative disorders and certain cancers. Current TPD strategies typically lack the ability to distinguish between monomeric and multimeric forms of a protein, resulting in potential off-target effects and limited efficacy for diseases marked by aberrant multimerization. These limitations have highlighted the need for degraders that can selectively target multimeric assemblies with minimal impact on their monomeric counterparts, which may retain essential cellular functions.&lt;/p&gt;&lt;p&gt;The study focuses on (S)-ACE-OH, a metabolite derived from the antipsychotic acepromazine, which acts as a MG facilitating interaction between TRIM21 and the nuclear pore protein NUP98, leading to selective degradation of multimeric protein structures within the nuclear pore complex (NPC) (Figure 1). Specifically, the authors demonstrate that treatment with (S)-ACE-OH leads to the depletion of NPC subunits, as evidenced by proteomics analyses and transmission electron microscopy, which reveal structural disintegration of the inner NPC ring.&lt;/p&gt;&lt;p&gt;The researchers first identify (S)-ACE-OH as a MG that mediates an interaction between TRIM21 and NUP98, a protein critical to the integrity of the NPC. Using CRISPR-based screening, the authors confirmed TRIM21 as essential for the cytotoxic effects of (S)-ACE-OH, particularly under interferon-gamma conditions, which induce TRIM21 expression. Through a competitive cell growth assay in interferon-gamma-stimulated cancer cell lines, they observed that (S)-ACE-OH selectively targets multimeric NUP98-containing complexes, reducing cell viability by degrading the NPC's inner ring. Proteomic quantification demonstrated a significant reduction in NUP98 levels, underscoring the compound's potency. The work highlights how multimeric proteins, but not monomeric counterparts, induce the clustering of TRIM21, a mechanism necessary for activating TRIM21's E3 ligase function. This clustering-dependent activation serves as a unique mechanism for selectively degrading multimeric protein ass","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic and Immune Profiling of Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Therapy Versus Upfront Surgery Identifies Novel Immunogenic Cell Death-Based Signatures for Predicting Clinical Outcomes","authors":"Peidong Song,&nbsp;Wenze Tian,&nbsp;Yujia Zheng,&nbsp;Sukai Xu,&nbsp;Zihao Hu,&nbsp;Xing Jin,&nbsp;Xuejuan Zhu,&nbsp;Lijie Tan,&nbsp;Donglai Chen,&nbsp;Yongbing Chen","doi":"10.1002/mco2.70171","DOIUrl":"https://doi.org/10.1002/mco2.70171","url":null,"abstract":"<p>It remains undetermined regarding the impact of neoadjuvant therapy on immunogenic cell death (ICD) and subsequent tumor microenvironment (TME) remodeling in esophageal squamous cell carcinoma (ESCC). And it is of paramount significance to identify beneficiaries from neoadjuvant therapy in treatment-naïve ESCC. In this study, 88 ESCC samples undergoing neoadjuvant therapy plus surgery (NA+S) or surgery alone (SA) were subjected to bulk-RNA sequencing. A five-gene RINscore incorporating ICD-related signature genes with TME-based hub genes was established to predict clinical outcomes and pharmacological responses, in which SLAMF7 and IL1R1 were selected out as co-expressed genes. The regulatory mechanism of the repressive co-transcription factor BATF of SLAMF7 and IL1R1 was further demonstrated. Our data demonstrated that NA+S led to high abundance in kinds of T helper cells, nature killer T cells and M1-like macrophages with increased CD8+T cells infiltration compared with SA. ICD phenotypes were further characterized in treatment-naïve ESCC to determine their differences in TME and potential benefits from NA. Our findings not only offered novel insights into the distinct TME and ICD profiles of ESCC undergoing different therapeutic modes, but also provided the RINscore, which may aid oncologists in determining individualized (neo)adjuvant immunotherapy regimen.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic Cancer: Pathogenesis and Clinical Studies","authors":"Kexun Zhou,&nbsp;Yingping Liu,&nbsp;Chuanyun Tang,&nbsp;Hong Zhu","doi":"10.1002/mco2.70162","DOIUrl":"https://doi.org/10.1002/mco2.70162","url":null,"abstract":"<p>Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS–MAPK, PI3K–AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Posttranslational Modification in Bone Homeostasis and Osteoporosis","authors":"Yuzhe Lin,&nbsp;Shide Jiang,&nbsp;Yuming Yao,&nbsp;Hengzhen Li,&nbsp;Hongfu Jin,&nbsp;Guang Yang,&nbsp;Bingzhou Ji,&nbsp;Yusheng Li","doi":"10.1002/mco2.70159","DOIUrl":"https://doi.org/10.1002/mco2.70159","url":null,"abstract":"<p>Bone is responsible for providing mechanical protection, attachment sites for muscles, hematopoiesis micssroenvironment, and maintaining balance between calcium and phosphorate. As a highly active and dynamically regulated organ, the balance between formation and resorption of bone is crucial in bone development, damaged bone repair, and mineral homeostasis, while dysregulation in bone remodeling impairs bone structure and strength, leading to deficiency in bone function and skeletal disorder, such as osteoporosis. Osteoporosis refers to compromised bone mass and higher susceptibility of fracture, resulting from several risk factors deteriorating the balanced system between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balanced system is strictly regulated by translational modification, such as phosphorylation, methylation, acetylation, ubiquitination, sumoylation, glycosylation, ADP-ribosylation, S-palmitoylation, citrullination, and so on. This review specifically describes the updating researches concerning bone formation and bone resorption mediated by posttranslational modification. We highlight dysregulated posttranslational modification in osteoblast and osteoclast differentiation. We also emphasize involvement of posttranslational modification in osteoporosis development, so as to elucidate the underlying molecular basis of osteoporosis. Then, we point out translational potential of PTMs as therapeutic targets. This review will deepen our understanding between posttranslational modification and osteoporosis, and identify novel targets for clinical treatment and identify future directions.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}