Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

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As a pathological hallmark of type 2 diabetes mellitus (T2DM), islet amyloid is formed by the aggregation of islet amyloid polypeptide (IAPP). Endoplasmic reticulum (ER) stress interacts with IAPP aggregates and has been implicated in the pathogenesis of T2DM. To examine the role of ER stress in T2DM, we cloned the hIAPP promoter and analyzed its promoter activity in human β-cells. We found that ER stress significantly enhanced hIAPP promoter activity and expression in human β-cells via triggering X-box binding protein 1 (XBP1) splicing. We identified a binding site of XBP1 in the hIAPP promoter. Disruption of this binding site by substitution or deletion mutagenesis significantly diminished the effects of ER stress on hIAPP promoter activity. Blockade of XBP splicing by MKC3946 treatment inhibited ER stress-induced hIAPP up-regulation and improved human β-cell survival and function. Our study uncovers a link between ER stress and IAPP at the transcriptional level and may provide novel insights into the role of ER stress in IAPP cytotoxicity and the pathogenesis of T2DM.

Fibroblast activation and extracellular matrix (ECM) deposition play an important role in the tracheal abnormal repair process and fibrosis. As a transcription factor, SOX9 is involved in fibroblast activation and ECM deposition. However, the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear. We investigated the role of SOX9 in TGF-β1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast (RTF) cells. SOX9 overexpression adenovirus (Ad-SOX9) and siRNA were transfected into RTF cells. We found that SOX9 expression was up-regulated in RTF cells treated with TGF-β1. SOX9 overexpression activated fibroblasts and promoted ECM deposition. Silencing SOX9 inhibited cell proliferation, migration, and ECM deposition, induced G2 arrest, and increased apoptosis in RTF cells. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) assays identified MMP10, a matrix metalloproteinase involved in ECM deposition, as a direct target of SOX9, which promotes ECM degradation by increasing MMP10 expression through the Wnt/β-catenin signaling pathway. Furthermore, in vivo, SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis, as manifested by reduced tracheal stenosis. In conclusion, our findings indicate that SOX9 can drive fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/β-catenin signaling pathway. The SOX9–MMP10–ECM biosynthesis axis plays an important role in tracheal injury and repair. Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

Programmed cell death 2 (PDCD2) is related to cancer progression and chemotherapy sensitivity. The role of PDCD2 in solid cancers (excluding hematopoietic malignancies) and their diagnosis and prognosis remains unclear. The TCGA, CGGA, GEPIA, cBioPortal, and GTEx databases were analyzed for expression, prognostic value, and genetic modifications of PDCD2 in cancer patients. Functional enrichment analysis, CCK8, colony formation assay, transwell assay, and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma (GBMLGG). The PDCD2 gene was associated with solid cancer progression. In the functional enrichment analysis results, PDCD2 was shown to participate in several important GBMLGG biological processes. GBMLGG cells may be inhibited in their proliferation, migration, invasion, and xenograft tumor growth by knocking down PDCD2. Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.

IL-17 A is a promoter of colorectal cancer initiation and progression. Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants, which has potent anti-inflammatory and antitumor actions. The effects of narciclasine on colorectal tumors were evaluated, with a focus on IL-17 A. Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts. The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis, findings confirmed by western blotting results of reduced Bcl-2 and enhanced Bax expression, as well as accumulation of cleaved Caspase-3, Caspase-8, Caspase-9, and cytoplasmic Cytochrome-c. After narciclasine incubation, IL-17 A, Act1, and TRAF6 were down-regulated, while p-P65 (Ser536) accumulated in the cytoplasm, a finding confirmed by laser scanning confocal microscopy. IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing. Moreover, IL-17 A, Act1, and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis. This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-κB anti-apoptotic signaling pathway.

T-cell acute lymphoblastic leukemia (T-ALL), a heterogeneous hematological malignancy, is caused by the developmental arrest of normal T-cell progenitors. The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease. In this study, we performed multi-omics integration analysis, which included mRNA expression, chromatin accessibility, and gene-dependency database analyses, to identify potential stage-specific druggable targets and repositioned drugs for this disease. This multi-omics integration helped identify 29 potential pathological genes for T-ALL. These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle, hematopoietic stem cell differentiation, and the AMPK signaling pathway. Of these, four known druggable targets (CDK6, TUBA1A, TUBB, and TYMS) showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL. The TUBA1A expression level was higher in the early T cell precursor (ETP)-ALL cells, while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage. CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naïve to maturation stages. Furthermore, mebendazole and gemcitabine, which target TUBA1A and TYMS, respectively, exerted stage-specific inhibitory effects on T-ALL cell lines, indicating their potential stage-specific antileukemic role in T-ALL. Collectively, our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

Aging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H2O2. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.

Cancer stem cells (CSCs) play a crucial role in tumor initiation, recurrence, metastasis, and drug resistance. However, the current understanding of CSCs in hepatocellular carcinoma (HCC) remains incomplete. Through a comprehensive analysis of the database, it has been observed that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a critical enzyme involved in cholesterol synthesis, is up-regulated in HCC tissues and liver CSCs. Moreover, high expression of HMGCR is associated with a poor prognosis in patients with HCC. Functionally, HMGCR promotes the stemness and metastasis of HCC both in vitro and in vivo. By screening various signaling pathway inhibitors, we have determined that HMGCR regulates stemness and metastasis by activating the Hedgehog signaling in HCC. Mechanistically, HMGCR positively correlates with the expression of the Smoothened receptor and facilitates the nuclear translocation of the transcriptional activator GLI family zinc finger 1. Inhibition of the Hedgehog pathway can reverse the stimulatory effects of HMGCR on stemness and metastasis in HCC. Notably, simvastatin, an FDA-approved cholesterol-lowering drug, has been shown to inhibit stemness and metastasis of HCC by targeting HMGCR. Taken together, our findings suggest that HMGCR promotes the regeneration and metastasis of HCC through the activation of Hedgehog signaling, and simvastatin holds the potential for clinical suppression of HCC metastasis.

Transcriptional factor Forkhead box M1 (FOXM1) plays an important role in pancreatic ductal adenocarcinoma (PDAC) development and progression. The molecular mechanisms underlying its dysregulation remain unclear. We identified and functionally validated the microRNAs (miRNAs) that critically regulate FOXM1 expression in PDAC. The expression levels of miRNA-23a (miR-23a-3p and -5p) were altered in PDAC cell lines and their effects on FOXM1 signaling and cell proliferation and migration and tumorigenesis were examined in vitro and in vivo using mouse PDAC models. Compared with non-tumor pancreatic tissues, PDAC tissues and cell lines exhibited significantly reduced levels of miR-23a expression. Reduced miR-23a expression and concomitant increase in FOXM1 expression were also observed in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia, the major premalignant lesions of PDAC. Transgenic expression of miR-23a reduced the expression of FOXM1 and suppressed cell proliferation and migration in PDAC cells, whereas the inhibitors of miR-23a did the opposite. Loss or reduced levels of miR-23a increased the levels of FOXM1 expression, while increased expression of FOXM1 down-regulated miR-23a expression, suggesting that miR-23a and FOXM1 were mutual negative regulators of their expression in PDAC cells. Therefore, the miR-23a/FOXM1 signaling axis is important in PDAC initiation and progression and could serve as an interventional or therapeutic target for patients with early or late stages of PDAC.

The clearance of apoptotic cell debris, containing professional phagocytosis and non-professional phagocytosis, is essential for maintaining the homeostasis of healthy tissues. Here, we discovered that endothelial cells could engulf apoptotic cell debris in atherosclerotic plaque. Single-cell RNA sequencing (RNA-seq) has revealed a unique endothelial cell subpopulation in atherosclerosis, which was strongly associated with vascular injury-related pathways. Moreover, integrated analysis of three vascular injury-related RNA-seq datasets showed that the expression of scavenger receptor class B type 1 (SR-B1) was up-regulated and specifically enriched in the phagocytosis pathway under vascular injury circumstances. Single-cell RNA-seq and bulk RNA-seq indicate that SR-B1 was highly expressed in a unique endothelial cell subpopulation of mouse aorta and strongly associated with the reorganization of cellular adherent junctions and cytoskeleton which were necessary for phagocytosis. Furthermore, SR-B1 was strongly required for endothelial cells to engulf apoptotic cell debris in atherosclerotic plaque of both mouse and human aorta. Overall, this study demonstrated that apoptotic cell debris could be engulfed by endothelial cells through SR-B1 and associated with the reorganization of cellular adherent junctions and cytoskeleton.

Developmental defects of enamel are common due to genetic and environmental factors before and after birth. Cdc42, a Rho family small GTPase, regulates prenatal tooth development in mice. However, its role in postnatal tooth development, especially enamel formation, remains elusive. Here, we investigated Cdc42 functions in mouse enamel development and tooth repair after birth. Cdc42 showed highly dynamic temporospatial patterns in the developing incisors, with robust expression in ameloblast and odontoblast layers. Strikingly, epithelium-specific Cdc42 deletion resulted in enamel defects in incisors. Ameloblast differentiation was inhibited, and hypomineralization of enamel was observed upon epithelial Cdc42 deletion. Proteomic analysis showed that abnormal mitochondrial components, phosphotransferase activity, and ion channel regulator activity occurred in the Cdc42 mutant dental epithelium. Reactive oxygen species accumulation was detected in the mutant mice, suggesting that abnormal oxidative stress occurred after Cdc42 depletion. Moreover, Cdc42 mutant mice showed delayed tooth repair and generated less calcified enamel. Mitochondrial dysfunction and abnormal oxygen consumption were evidenced by reduced Apool and Timm8a1 expression, increased Atp5j2 levels, and reactive oxygen species overproduction in the mutant repair epithelium. Epithelium-specific Cdc42 deletion attenuated ERK1/2 signaling in the labial cervical loop. Aberrant Sox2 expression in the mutant labial cervical loop after clipping might lead to delayed tooth repair. These findings suggested that mitochondrial dysfunction, up-regulated oxidative stress, and abnormal ion channel activity may be among multiple factors responsible for the observed enamel defects in Cdc42 mutant incisors. Overall, Cdc42 exerts multidimensional and pivotal roles in enamel development and is particularly required for ameloblast differentiation and enamel matrix formation.

Vitamin D binding protein (VDBP) serves as a key transporter protein responsible for binding and delivering vitamin D and its metabolites to target organs. VDBP plays a crucial part in the inflammatory reaction following tissue damage and is engaged in actin degradation. Recent research has shed light on its potential role in various diseases, leading to a growing interest in understanding the implications of VDBP in psychiatric and neurological disorders. The purpose of this review was to provide a summary of the existing understanding regarding the involvement of VDBP in neurological and psychiatric disorders. By examining the intricate interplay between VDBP and these disorders, this review contributes to a deeper understanding of underlying mechanisms and potential therapeutic avenues. Insights gained from the study of VDBP could pave the way for novel strategies in the diagnosis, prognosis, and treatment of psychiatric and neurological disorders.

As the most prevalent and reversible internal epigenetic modification in eukaryotic mRNAs, N6-methyladenosine (m6A) post-transcriptionally regulates the processing and metabolism of mRNAs involved in diverse biological processes. m6A modification is regulated by m6A writers, erasers, and readers. Emerging evidence suggests that m6A modification plays essential roles in modulating the cell-fate transition of embryonic stem cells. Mechanistic investigation of embryonic stem cell maintenance and differentiation is critical for understanding early embryonic development, which is also the premise for the application of embryonic stem cells in regenerative medicine. This review highlights the current knowledge of m6A modification and its essential regulatory contribution to the cell fate transition of mouse and human embryonic stem cells.

Malformations of cortical development (MCD) are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors. Many kinds of MCD are caused by genetic variation. MCD is the common cause of intellectual disability and intractable epilepsy. With rapid advances in imaging and sequencing technologies, the diagnostic rate of MCD has been increasing, and many potential genes causing MCD have been successively identified. However, the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs. Thus, in this review, we outline important events of cortical development. Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway. Finally, we briefly discuss the diagnostic methods, disease models, and therapeutic strategies for MCD. The information will facilitate further research on MCD. Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.

RNA N6-methyladenosine (m6A) methylation is the most abundant and conserved RNA modification in eukaryotes. It participates in the regulation of RNA metabolism and various pathophysiological processes. Non-coding RNAs (ncRNAs) are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions. Similar to mRNAs, m6A deposition is observed in ncRNAs. Studying RNA m6A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications. In this review, we summarized the recent research findings regarding the mutual regulation between RNA m6A modification and ncRNAs (with a specific focus on microRNAs, long non-coding RNAs, and circular RNAs) and their functions. We also discussed the challenges of m6A-containing ncRNAs and RNA m6A as therapeutic targets in human diseases and their future perspective in translational roles.

Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques. Sonogenetics, a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells, is gaining prominence along with optogenetics, electrogenetics, and magnetogenetics. Upon stimulation with ultrasound, these proteins trigger a cascade of cellular activities and functions. Unlike traditional ultrasound modalities, sonogenetics offers enhanced spatial selectivity, improving precision and safety in disease treatment. This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications, including neuromodulation, oncologic treatments, stem cell therapy, and beyond. Although current literature predominantly emphasizes ultrasonic neuromodulation, this review offers a comprehensive exploration of sonogenetics. We discuss ultrasound properties, the specific ultrasound-sensitive proteins employed in sonogenetics, and the technique's potential in managing conditions such as neurological disorders, cancer, and ophthalmic diseases, and in stem cell therapies. Our objective is to stimulate fresh perspectives for further research in this promising field.

Protein lysine crotonylation (Kcr) is one conserved form of posttranslational modifications of proteins, which plays an important role in a series of cellular physiological and pathological processes. Lysine ε-amino groups are the primary sites of such modification, resulting in four-carbon planar lysine crotonylation that is structurally and functionally distinct from the acetylation of these residues. High levels of Kcr modifications have been identified on both histone and non-histone proteins. The present review offers an update on the research progression regarding protein Kcr modifications in biomedical contexts and provides a discussion of the mechanisms whereby Kcr modification governs a range of biological processes. In addition, given the importance of protein Kcr modification in disease onset and progression, the potential viability of Kcr regulators as therapeutic targets is elucidated.

Hematopoiesis represents a meticulously regulated and dynamic biological process. Genetic aberrations affecting blood cells, induced by various factors, frequently give rise to hematological tumors. These instances are often accompanied by a multitude of abnormal post-transcriptional regulatory events, including RNA alternative splicing, RNA localization, RNA degradation, and storage. Notably, post-transcriptional regulation plays a pivotal role in preserving hematopoietic homeostasis. The DEAD-Box RNA helicase genes emerge as crucial post-transcriptional regulatory factors, intricately involved in sustaining normal hematopoiesis through diverse mechanisms such as RNA alternative splicing, RNA modification, and ribosome assembly. This review consolidates the existing knowledge on the role of DEAD-box RNA helicases in regulating normal hematopoiesis and underscores the pathogenicity of mutant DEAD-Box RNA helicases in malignant hematopoiesis. Emphasis is placed on elucidating both the positive and negative contributions of DEAD-box RNA helicases within the hematopoietic system.

Mechanical stimulation is the key physical factor in cell environment. Mechanotransduction acts as a fundamental regulator of cell behavior, regulating cell proliferation, differentiation, apoptosis, and exhibiting specific signature alterations during the pathological process. As research continues, the role of epigenetic science in mechanotransduction is attracting attention. However, the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified. We focus on how histone modifications, as important components of epigenetics, are coordinated with multiple signaling pathways to control cell fate and disease progression. Specifically, we propose that histone modifications can form regulatory feedback loops with signaling pathways, that is, histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways. Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.

N6-methyladenosine (m6A) methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years. Cardiovascular diseases (CVDs) are a leading cause of death globally. Emerging evidence demonstrates that RNA modifications, such as the m6A modification, are associated with the development and progression of many diseases, including CVDs. An increasing body of studies has indicated that programmed cell death (PCD) plays a vital role in CVDs. However, the molecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood. Herein, elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs. There is great potential for clinical application.

A long noncoding RNA (lncRNA) is longer than 200 bp. It regulates various biological processes mainly by interacting with DNA, RNA, or protein in multiple kinds of biological processes. Adenosine monophosphate-activated protein kinase (AMPK) is activated during nutrient starvation, especially glucose starvation and oxygen deficiency (hypoxia), and exposure to toxins that inhibit mitochondrial respiratory chain complex function. AMPK is an energy switch in organisms that controls cell growth and multiple cellular processes, including lipid and glucose metabolism, thereby maintaining intracellular energy homeostasis by activating catabolism and inhibiting anabolism. The AMPK signalling pathway consists of AMPK and its upstream and downstream targets. AMPK upstream targets include proteins such as the transforming growth factor β-activated kinase 1 (TAK1), liver kinase B1 (LKB1), and calcium/calmodulin-dependent protein kinase β (CaMKKβ), and its downstream targets include proteins such as the mechanistic/mammalian target of rapamycin (mTOR) complex 1 (mTORC1), hepatocyte nuclear factor 4α (HNF4α), and silencing information regulatory 1 (SIRT1). In general, proteins function relatively independently and cooperate. In this article, a review of the currently known lncRNAs involved in the AMPK signalling pathway is presented and insights into the regulatory mechanisms involved in human ageing and age-related diseases are provided.

Nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) and nicotinamide adenine dinucleotide phosphate (NADP+)/reduced NADP+ (NADPH) are essential metabolites involved in multiple metabolic pathways and cellular processes. NAD+ and NADH redox couple plays a vital role in catabolic redox reactions, while NADPH is crucial for cellular anabolism and antioxidant responses. Maintaining NAD(H) and NADP(H) homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms, such as biosynthesis, consumption, recycling, and conversion between NAD(H) and NADP(H). The conversions between NAD(H) and NADP(H) are controlled by NAD kinases (NADKs) and NADP(H) phosphatases [specifically, metazoan SpoT homolog-1 (MESH1) and nocturnin (NOCT)]. NADKs facilitate the synthesis of NADP+ from NAD+, while MESH1 and NOCT convert NADP(H) into NAD(H). In this review, we summarize the physiological roles of NAD(H) and NADP(H) and discuss the regulatory mechanisms governing NAD(H) and NADP(H) homeostasis in three key aspects: the transcriptional and posttranslational regulation of NADKs, the role of MESH1 and NOCT in maintaining NAD(H) and NADP(H) homeostasis, and the influence of the circadian clock on NAD(H) and NADP(H) homeostasis. In conclusion, NADKs, MESH1, and NOCT are integral to various cellular processes, regulating NAD(H) and NADP(H) homeostasis. Dysregulation of these enzymes results in various human diseases, such as cancers and metabolic disorders. Hence, strategies aiming to restore NAD(H) and NADP(H) homeostasis hold promise as novel therapeutic approaches for these diseases.

The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance mutations. Therefore, finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system (UPS) has emerged as a focus. The UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological processes. In recent years, the study of UPS in hematological malignant tumors has resulted in effective treatments, such as bortezomib in the treatment of multiple myeloma and mantle cell lymphoma. In CML, the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL, interfering with CML-related signaling pathways, and negatively or positively affecting leukemia stem cells. Some of these molecules may help overcome TKI resistance and treat CML. In this review, the mechanism of TKI resistance is briefly described, the components of UPS are introduced, existing studies on UPS participating in TKI resistance are listed, and UPS as the therapeutic target and strategies are discussed.

Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer. Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression. Nevertheless, the mechanistic role of epigenetic dysregulation in the tumor microenvironment is not fully understood. Here, we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor microenvironment and recent research advances in cancer epigenetic drugs. In addition, we discussed the great potential of epigenetic combination therapies in the clinical treatment of cancer. However, there are still some challenges in the field of cancer epigenetics, such as epigenetic tumor heterogeneity, epigenetic drug heterogeneity, and crosstalk between epigenetics, proteomics, metabolomics, and other omics, which may be the focus and difficulty of cancer treatment in the future. In conclusion, epigenetic modifications in the tumor microenvironment are essential for future epigenetic drug development and the comprehensive treatment of cancer. Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.

Deubiquitinases (DUBs) are a class of enzymes that are able to reverse the process of ubiquitination.1 Extensive research has revealed that there are more than 100 DUBs found in humans, which are classified into seven main families: ubiquitin-specific proteases (USPs), ubiquitin carboxyl-terminal hydrolases, the Machado-Joseph disease domain superfamily, the otubain/ovarian tumor-domain containing proteins, the ZUFSP (Zinc finger with UFM1-specific peptidase domain protein) family, the JAB1/MPN/MOV34 proteases, and the novel motif interacting with ubiquitin-containing DUB family. All DUBs are cysteine proteases, except the JAB1/MPN/MOV34 proteases, which are Zn2+ metalloproteases.1 The family with the largest number is the USPs. These enzymes remove the ubiquitin molecule from the larger protein, which leads to protein stability and protection from proteasome degradation. Many USPs have been demonstrated to be closely linked with the proliferation and metastasis of tumor cells, as well as facilitating tumor immune evasion.1 More importantly, inhibitors targeting USPs have become a hot topic in tumor therapy, showing promising prospects.1

Endometriosis is a common and benign angiogenesis-dependent gynecological disorder, which refers to the proliferation and growth of endometrium-like tissues with neovasculature formation outside of the uterus.1 Available medical treatments for endometriosis containing hormonal and non-hormonal treatments had been limited for long-term usage by their side effects.2 Ideal medical treatment for endometriosis with efficacy to relieve symptoms and suppress endometriotic lesion growth and minimal side effects has been longing for decades.3 Angiogenesis is a promising therapeutic target for endometriosis.4 Chinese herbal medicines (CHM), as a mainstream medication in China and many other Asian countries, have been commonly used for women with endometriosis.5 However, there is no scientific evaluation of their anti-endometriosis and anti-angiogenic effects on endometriosis. Clinical trials can only include limited interventions for comparison and a large sample size is required to achieve statistical power for outcome measures of interest. Herewith, an experimental endometriosis mouse model was applied to investigate and compare the anti-angiogenic effect, targets, and mechanism of CHM. In this study, anti-angiogenic effects, pharmacological targets, and therapeutic mechanisms of commonly used CHM formulae, including Shaofu Zhuyu Tang (SFZY), Xuefu Zhuyu Tang (XFZY), Gexia Zhuyu Tang (GXZY), Wenjing Tang (WJD), Taohe Chengqi Tang (THCQ), and Taohong Siwu Tang (THSW) in the mouse model were studied (Table S1).

The high recurrence and low responsiveness to immunotherapy make ovarian cancer (OC) the most lethal gynecological malignancy. Tumor microenvironment is critical in risk stratification and the discovery of molecular targets. We developed a prognostic classification for OC, which could also predict the prognosis of other gynecological cancers including breast cancer, endometrial cancer, and cervical cancer. Somatic mutation, hallmark pathways, and immune landscapes were characterized. Integrative analysis of immune checkpoints and multiple immune signatures revealed the low-risk group responds better to immune checkpoint inhibitors, which was validated by an external immunotherapeutic cohort (IMvigor210). Single-cell RNA sequencing (scRNA-seq) confirmed the high expression of SERPINB1 and SERPINB9 in dendritic cells, and AlphaFold2 was used to infer their 3D protein structures. Putative molecular compounds binding to SERPINB1/SERPINB9 were predicted by virtual screening.

Endometrial cancer (EC) is one of the most prominent malignancies in gynecology. Unfortunately, despite these advancements in understanding EC pathogenesis, mortality rates have not decreased. Traction force (TF) refers to endogenous mechanical forces exerted by cells.1 These forces act on the extracellular matrix and the extracellular tumor microenvironment through focal adhesions, thereby regulating cell proliferation and migration. However, the TF characteristics of endometrial cancer cells and their heterogeneity remain unclear. SLC8A1, which encodes the Na+/Ca2+ exchanger, plays a crucial role in calcium homeostasis through calcium flux induced by cannabidiol and TRPV4 activation during mitophagy initiation. However, the regulatory mechanisms underlying SLC8A1 and its associated mechanical forces in EC remain elusive. In this study, we investigated the mechanical characteristics of different cell lines and primary EC cells. To the best of our knowledge, this is the first study to explore mechanical forces and identify a novel therapeutic target for EC.

Sarcopenia is characterized by a dramatic decline in muscle mass and function during aging, which often leads to reduced mobility, diminished quality of life, and shortened survival. Despite recent advances in sarcopenia, the mechanisms that mediate skeletal muscle dysfunction remain unclear.1 Lysosomal plays a vital role in digesting and recycling macromolecules, and several studies have shown that lysosomal acidification and autophagy decrease with age, which may impair the clearance of damaged mitochondria.2 SPNS1 (spinster homolog 1), a proton-dependent lysophosphatidylcholine and lysophosphatidylethanolamine transporter, plays a critical role in maintaining normal lysosomal function.3 However, the physiological relevance of lysosomal dysfunction in sarcopenia remains unclear. Coffey et al found that loss of SPNS1 dysregulated lysosomal pH, which impacts the expression of extracellular matrix proteins at the myotendinous junction in zebrafish.4 In this study, we demonstrate that ablation of SPNS1 in skeletal muscle results in impaired lysosomal digestion, hindering mitophagy and triggering the accumulation of abnormal mitochondria. As a result, damaged mitochondria cannot be cleared, leading to the leakage of pro-apoptotic protein and the activation of apoptosis. Our findings reveal the role of SPNS1 in maintaining mitochondrial-lysosomal homeostasis and preserving muscle mass and function.

Pulmonary hypertension (PH) due to left heart failure (HF) accounts for approximately half of PH cases worldwide. It has been demonstrated that PH is a frequent complication of HF but is difficult to recognize in its early stage because it is characterized by nonspecific symptoms including shortness of breath and decreased tolerance of activity. Moreover, nearly all multicentric clinical trials targeting pulmonary circulation in PH-HF have reported negative results.1 Thus, there are no effective methods for diagnosing early PH, and the current treatment of PH-HF is insufficient.

Dentin is a mineralized tissue with a chemical composition similar to bone but with a higher mineralized density and rigidity. It constitutes the central structure of the tooth between the internal pulp and external enamel toward the oral cavity or cementum toward the underlying roots. Inherited dentin defects occur in a variety of rare genetic diseases. They can manifest as “isolated” occurrences such as in dentinogenesis imperfecta (DI) or dentin dysplasia (DD) or can be associated with other symptoms in diseases such as osteogenesis imperfecta, Goldblatt syndrome, microcephalic osteodysplastic primordial dwarfism type II, among others.1

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and a major cause of end-stage renal disease (ESRD). The pathogenesis of DN is unknown, but it is closely related to disorders of glucolipid metabolism, abnormal hemodynamics, chronic inflammatory response, oxidative stress, and genetics. Once DN develops into ESRD, it is often more difficult to treat than ESRD caused by other kidney diseases. Therefore, a deeper knowledge of the pathophysiological mechanisms of DN and the discovery of candidate markers for early diagnosis are mandatory. Exosomes secreted by renal cells can regulate a series of pathophysiological processes such as translation and transcription by releasing miRNAs or proteins, thereby regulating the biological functions and phenotype of recipient kidney cells. It has been found that miRNA secreted by urinary exosomes in patients with DN is involved in the occurrence and development of DN and may become biological markers.1 However, studies on exosome proteins are relatively few and lack validation in humans. In the present study, we identified an altered pathway in urinary exosomes from DN patients for the first time. Notably, the altered ferroptosis-related proteins may represent novel candidate markers for early progression of disease and/or early treatment effects.

Lung cancer (LC) is a prevalent and fatal malignancy, with high incidence and mortality rates.1 ATP binding cassette (ABC) transporters, a superfamily of integral membrane proteins, use ATP hydrolysis to facilitate substrate transport across cellular membranes.2 The pivotal role of ABC transporters in tumorigenesis was initially established by Mochida,3 who demonstrated that the loss of ABCB1 suppresses intestinal polyp formation and tumor progression in mice. Recent investigations have reported correlations between ABC transporters and the tumor microenvironment and cancer immunotherapy response, suggesting their modulatory effects on tumor progression and immunotherapy.4,5 However, at present, there is a lack of comprehensive and complete analytical studies on the expression, prognosis, and immune status of all genes in the ABC transporter family. In this study, we utilized public databases, coupled with quantitative real-time PCR and immunohistochemistry verification in lung adenocarcinoma (LUAD) cell lines and tissue specimens, to identify the consistent expression of ABC transporters and PD-L1 at both mRNA and protein levels. Our findings provide novel insights into potential therapeutic targets and prognostic biomarkers for LUAD.

Cuproptosis is a newly discovered type of programmed cell death that involves the depletion of intracellular copper and is not influenced by other inhibitors of programmed cell death. This modality was first identified and named by Tsvetkov et al in the previous year.1 To further explore the relationship between cuproptosis, the tumor microenvironment, immunotherapy, and prognosis for breast cancer (BC), the expression patterns of 19 cuproptosis-related long non-coding RNAs (lncRNAs) were determined using data from the Cancer Genome Atlas (TCGA). Through Cox and Lasso regression analyses, we identified three crucial lncRNAs: AL137847.1, LRRC8C-DT, and NIFK-AS1. These lncRNAs were selected to establish a risk prediction model. Additionally, a nomogram was constructed by combining the clinical characteristics with the developed model. Differential expression analysis and functional enrichment analysis were performed based on the high- and low-risk groups derived from the risk prediction model. In addition, the mutant landscape of lncRNAs in the TCGA cohort was investigated, and the correlation between tumor mutational burden (TMB), immune activation pathways, and the prognostic model was analyzed. Real-time quantitative PCR experiments confirmed that the expression levels of AL137847.1, LRRC8C-DT, and NIFK-AS1 were significantly higher in MDA-MB-231 breast cancer cells compared with normal mammary epithelial cells. Furthermore, drug sensitivity analyses were carried out. The findings of this study may serve as a reference for individualized prognosis prediction and immunotherapy strategies for BC patients.

Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy. We previously revealed the proto-oncogenic role of neurokinin-1 receptor (NK-1R) in acute myeloid leukemia (AML),1 whereas the role of neurokinin-2 receptor (NK-2R) has not been elucidated. Herein, we found NK-2R was significantly up-regulated in AML patients in The Cancer Genome Atlas databases. This result was further confirmed in blood from AML patients and a range of human leukemia cells. Then, we verified that blocking NK-2R by SR48968 markedly promoted cell death in human myeloid leukemia without cytotoxicity to normal cells. Mechanically, we uncovered that SR48968 induced cytotoxicity through necroptosis mediated by calcium overload-driven reactive oxygen species (ROS) accumulation. In summary, our results propose that NK-2R antagonist SR48968 may be used as a new therapeutic approach for myeloid leukemia.

In aging males, benign prostatic hyperplasia (BPH) is a chronic pathological process that primarily causes lower urinary tract symptoms. According to histopathology, BPH is caused by an imbalance between cell death and proliferation.1 However, the exact pathophysiology remains unclear. Ferroptosis is a newly discovered form of programmed cell death. The cell morphology is characterized primarily by the reduction or disappearance of mitochondrial cristae and mitochondrial shrinkage.2,3 Competing endogenous RNAs (ceRNAs) are important regulators of many biological processes and have been involved in various diseases.4

The extremely poor prognosis of patients is largely due to hepatocyte growth factor (HGF)/MET signaling, which promotes migration and invasion of glioblastoma (IDH wild-type; GBM; WHO grade 4).1,2 Clinical trials targeting MET, the only receptor of HGF, have yielded unimpressive results in GBM.3,4 Here we found that HGF induced strong chemotaxis on GBM cells, but MET expression was extremely low. We, therefore, used single-cell RNA sequencing (scRNA-seq) coupled with label-free proteome profiling to identify membrane proteins associated with HGF/MET signaling amplification in GBM and to provide a novel modulator, MPZL1, for HGF/MET-targeted therapy.

Periodontitis is a chronic inflammatory disease caused by periodontopathic bacteria that affects periodontal support tissues.1 If left untreated, it results in loss of periodontal attachment and alveolar bone resorption. Approximately one-half of adults in the United States older than 30 years have periodontal disease.2 Though the disease is initiated by bacterial infection, it activates host defense systems that eventually lead to the degradation of the periodontium. During periodontitis, the disease progress involves further production of pro-inflammatory mediators such as cytokines, proteolytic enzymes like matrix metalloproteinases (MMPs), and their inhibitors.

Glioma is a common and malignant brain tumor, and molecular diagnostics for glioma have received increasing attention.1,2 Previous studies have suggested that the MAL2 gene may be involved in the transcytosis of various cancers.3 This study aimed to investigate the potential of MAL2 as a biomarker for glioma. The candidate MAL2 CpG sites were validated by pyrosequencing and used to construct a diagnostic model for glioma. Survival analysis was also conducted to determine the relationship between highly methylated MAL2-specific CpG sites and the prognosis of glioma. The findings also showed that MAL2 was more highly methylated in glioma than in other cancers. The constructed diagnostic model can distinguish glioma from other cancers with high sensitivity (93.3%) and specificity (86.5%). Additionally, a risk score model was built based on MAL2 methylation to assess the prognosis of glioma.

Tooth mineralization is a ubiquitous and tightly regulated process involving complicated interactions between dental epithelium and mesenchyme. Key molecules in tooth mineralization remain poorly identified. Microtubule actin cross-linking factor 1 (MACF1) is a spectraplakin protein that plays pivotal roles in the brain, muscle, lung, and bone developmental process.1, 2, 3 To study the specific functions of MACF1 in bone formation, we established Macf1 conditional knockout mice using the Cre-LoxP system driven by Osxterix promoter (Osx-Cre;Macf1f/f).2 Not surprisingly, Osx-Cre;Macf1f/f mice displayed the phenotypes of delayed ossification and decreased bone mass. Moreover, the Osx-Cre;Macf1f/f mice unexpectedly showed a white and opaque appearance of incisors, contrary to the normal yellow-brown and transparent incisors. Since Osxterix is expressed in dental mesenchyme during tooth development, the abnormal tooth appearance might imply a new function of MACF1 in odontoblasts, or even ameloblasts. Therefore, the present study aimed to investigate the role of MACF1 during tooth development.

Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment (TIME).1 Elegant research has indicated that cancer stem cells, a small subset of neoplastic cells confined within dedicated niches, display stem cell-like properties and interact with cells in TIME, thereby imparting an indelible impact on stemness regulation, tumor heterogeneity, and cancer cell plasticity.2 Previous taxonomies solely from the perspective of stemness or TIME may introduce some degree of bias in the comprehension of HCC carcinogenesis,3,4 and thus it is of paramount importance to systematically consider tumor stemness and TIME as a whole to truly portray the biological landscape of HCC.

Intestinal metaplasia (IM) is a key stage in the tumorigenic Correa cascade from gastritis to final intestinal-type gastric cancer (GC).1 Helicobacter pylori (H. pylori) infection is the most common trigger of IM, and it promotes GC progression through induction of gastric epithelial transition.2 Currently, the mechanism by which H. pylori infection promotes tumorigenesis in IM patients is poorly understood. Zhang et al. established a single-cell transcriptomic atlas on premalignant lesions and identified biomarkers of gastric early-malignant cells, providing an opportunity to explore the molecular mechanism of GC progression at the molecular level.3 However, the mechanism of how H. pylori causes environmental aberrations in IM is poorly understood. Here, we aimed to explore the aberrations of the cellular environment associated with tumorigenesis in IM with H. pylori infection using single-cell RNA sequencing (scRNA-seq) analysis. Notably, we found cell type-specific immune aberrations and cell-cell contact aberrations associated with carcinogenesis in IM with H. pylori infection. Ultimately, we identified a key transcription factor FOXO1 which may be functional in carcinogenesis, thus providing new insights into the carcinogenic role of H. pylori infection in IM.

Glioblastoma (GBM) is the most common primary malignant intracranial tumor with a very poor prognosis. In this study, we systematically analyzed the DNA methylation alterations of autophagy-related lncRNAs and their association with drug therapies in GBM. We identified 9 DNA methylation-dysregulated lncRNA regulators of autophagy-related genes as autophagy-related lncRNAs. A dysregulated regulatory network consisting of 9 autophagy-related lncRNAs and 237 differentially expressed autophagy-related genes was constructed. Identification of small molecule drug candidates that may affect DNA methylation dysregulated lncRNA activity, including 45 drug lncRNA pairs, involving 7 DNA methylation dysregulated lncRNAs and 43 drugs. Furthermore, we identified a DNA methylation-dysregulated autophagy-related lncRNA MIR155HG as an independent prognostic indicator for GBM. The significantly decreased methylation level of the MIR155HG promoter contributed to its up-regulated expression, which was involved in autophagy regulation through the regulation of autophagy-related genes WMP1, AP4M1, and UBQLN2. Our results showed that DNA methylation-dysregulated lncRNAs may be potential biomarkers and drug targets in GBM through regulating autophagy-related functions.

Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator that inhibits transcription primarily through trimethylation of Lys-27 in histone 3(H3K27me3), has been reported to play an important role in the regulation of cell cycle, autophagy, and apoptosis, and DNA damage repair.1 EZH2 is highly expressed in a variety of cancers including prostate cancer, breast cancer, and renal clear cell carcinoma, and is associated with adverse prognosis.1 Moreover, it has been reported that EZH2 might increase tumor stemness and metastasis capacity and inhibit antitumor immunity by affecting T cells, NK cells, macrophages, and immune checkpoints.2,3 However, the prognostic value and the mechanism of EZH2 have not been investigated in chordoma. In this study, RNA sequencing and whole genome sequencing data based on 48 skull base chordomas as well as immunohistochemistry of paraffin sections were analyzed to elucidate the role of EZH2 in skull base chordoma. We found copy number gain mediated high EZH2 expression is associated with tumor stemness, M2 macrophage infiltration, and adverse prognosis in chordoma. Moreover, we demonstrated that EZH2 promotes the proliferation, migration, and invasion of chordoma cells in in vitro cell experiments.

Hildebrandt Friedhelm，Deutsch Konstantin，Klämb t Verena，Kitzler Thomas M.，Jobst - Schwan Tilman，Schneider Ronen，Buerger Florian，Seltzsam Steve，El Desoky Sherif，Kari Jameela A.，Hafeez Farkhanda，Szczepa ńska Maria，Eid Loai A.，Awad Hazem S.，Al - Saffar Muna，Soliman Neveen A.，Tasic Velibor，Nicolas - Frank Camille，Yousef Kirollos，Schierbaum Luca M.，Schneider Sophia，Halawi Abdul，Elmubarak Izzeldin，Lemberg Katharina，Shril Shirlee，Mane Shrikant M.，Rodig Nancy

Nephronophthisis-related ciliopathies (NPHP-RC) represent one of the most common causes of chronic kidney disease in the first three decades of life and are characterized by a broad genetic and clinical heterogeneity.1 To date, more than 90 genes have been identified that cause autosomal-recessive NPHP-RC if mutated, accounting for up to 60% of cases.1 Among these, homozygous deletions of NPHP1 are the most common cause. Ciliopathy genes localize to primary cilia, basal bodies, or the centrosome and lead to a primary ciliary disruption if mutated, thereby causing a broad phenotypical spectrum.1 Patients that suffer from NPHP-RC can either have an isolated renal phenotype, such as polyuria, polydipsia, decreased urinary concentration ability, and secondary enuresis due to loss of tubular function, or present with extrarenal symptoms including retinal degeneration, cerebellar vermis hypoplasia, or hepatic fibrosis. Patients are often diagnosed in early adolescence, reaching end-stage renal disease before 25 years of age, but early onset and rapidly progressive forms of NPHP-RC also exist.1 Renal ultrasound indicates kidneys of normal or reduced renal length with increased echogenicity and corticomedullary cysts.

Antigen rapid diagnostic tests (Ag-RDTs) have been considered and implemented as an important diagnostic and screening tool to identify SARS-CoV-2 infections in community settings.1 Ag-RDTs are less sensitive, particularly in asymptomatic populations, compared with laboratory-based viral nucleic acid amplification tests (NAATs) such as reverse transcription polymerase chain reaction (RT-PCR).2 However, taking into account the facts that Ag-RDTs are effective for identifying most contagious individuals, they are faster and less expensive than RT-PCR, as well as that RT-PCR could produce positive results for weeks to months after the infection,2 WHO recommends Ag-RDTs be offered as COVID-19 self-testing for screening purposes in addition to professionally administered testing services regardless of the community transmission level.1 Although Ag-RDTs have been utilized in mass screening in Slovakia and Liverpool,2 there is a dearth of real-world evidence from prospective cohort studies on the efficacy of Ag-RDT self-testing in comparison to RT-PCR due to the challenges in performing both testing consecutively at the same time over the follow-up. The study aims to evaluate the effectiveness of rapid antigen self-testing for screening SARS-CoV-2.

Hereditary spastic paraplegia (HSP) is a group of disorders with genetic heterogeneity, lower-extremity weakness, and spasticity are the most common signs and symptoms. SPAST is the most frequently disease-causing gene. Spastin is a microtubule-severing enzyme encoded by SPAST that cleaves long microtubules into short fragments by interacting with other proteins or membranes. Hereditary spastic paraplegia type 4 (SPG4), which is autosomal dominant, is the clinical subtype associated with SPAST mutations. SPG4 accounts for up to one-third of all HSP cases and usually presents with isolated lower extremity spasticity, with or without bladder or sensory dysfunction.1 The main cause of SPG4 is believed to be spastin haploinsufficiency, which results from mutations in the SPAST gene.2 These mutations cause reduced spastin severing ability and insufficient microtubule cutting.2 However, haploinsufficiency alone cannot explain some phenomena in SPG4 models.3 Gain-of-function mutations contribute to the onsets of HSP, and truncated spastin may cause damage to the central nervous system tracts through an isoform-specific toxic effect.4

Allogeneic red blood cell (RBC) transfusion is commonly performed in medical practice because of its efficacy and low-risk level. However, pre-transfusion tests are susceptible to monoclonal antibody (mAb) interference.1 Currently, mAb therapies are being developed to treat many diseases, such as cancer. However, certain mAbs, such as anti-CD38mAb and anti-CD47mAb, can bind to RBC membranes; this binding interferes with pre-transfusion tests.2 CD47 has gained considerable attention in recent years because of its potential as a therapeutic target for hematologic malignancies and solid tumors.3 The binding of anti-CD47mAb to RBCs may lead to false-positive results in pan-agglutination tests and cause delays and risks in establishing compatible RBCs for transfusion.

Recently, immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPi) have played a pivotal role in prolonging the recurrence-free survival of patients with ovarian cancer (OC).1,2 Although PARPi have revolutionized the treatment of OC, the absence of reliable predictive biomarkers limits the broad application of ICIs for patients with homologous recombination (HR) deficiency (HRD).3 CXC-chemokine ligand 13 (CXCL13) is a cytokine constitutively secreted in the stromal cells of the B-cell region of secondary lymphoid tissue.4 It exclusively binds to the chemokine receptor CXCR5, which is abundantly expressed in subsets of mature circulating B lymphocytes, follicular helper T cells, and skin-derived dendritic cells, and governs the migration of these cells into secondary lymphoid organs in response to the CXCL13 gradient.5 In this study, we aimed to elucidate the role of CXCL13 in shaping the tumor immune microenvironment (TIME) in HR-deficient OC and to explore its relationship with the cGAS-STING signaling pathway.

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults and its unique pathology leads to limited therapeutic benefits.1,2 Mitochondrial fusion and fission play an important role in carcinogenesis; fragmented mitochondria promote tumor cell proliferation and prolonged mitochondria lead to tumor cell apoptosis.3 Therefore, profiling the function and prognostic value of mitochondrial dynamics-related genes (MDRGs) is of great interest for GBM precision treatment. Here we focused on the expression, function, and genetic alterations of MDRGs and identified new DNA methylation sites being significantly associated with the survival of GBM patients using available data in public databases. We then constructed the tumor prognostic model that accurately forecast the survival of GBM patients based on MDRGs' signature. Furthermore, it was demonstrated that the expression of MDRGs and risk factors served as independent indexes to estimate the level of immune infiltration in tumor microenvironment and response to targeted immune checkpoints in GBM patients. Notably, we filtered out acetaminophen targeting risk genes as a candidate drug for GBM treatment after clarifying risk genes' contribution to the cancer process at the single-cell level. Overall, the new biomarkers, prognostic model, and targeted drugs characterized in this study provide a novel perspective for GBM management.

Adult polyglucosan body disease (APBD) is a rare and highly heterogeneous glycogen storage disorder due to biallelic variants in GBE1.1 Typical APBD presentations include gait abnormalities with polyneuropathy, leukodystrophy, neurogenic bladder, and mild cognitive impairment. Differential diagnosis of APBD encompasses a large spectrum of conditions including axonal and demyelinating sensorimotor polyneuropathy, progressive spastic paraparesis, and leukodystrophies. The majority of APBD patients are Ashkenazi-Jewish harboring a homozygous GBE1 mutation, c.986A > C. There have been a few APBD patients reported in East Asia. In addition, the large deletion mutations of GBE1 have only been previously described in early congenital neuromuscular patients.2 In this study, we depicted the phenotypic heterogeneity in four APBD patients in China and identified five single nucleotide variants and two large deletion variants in GBE1. These findings expand the clinical and genetic spectrum of APBD patients and reaffirm the importance of a more comprehensive and cautious diagnostic approach.

Currently, the major therapy for patients with ovarian cancer includes post-cytoreductive surgery followed by chemotherapy of carboplatin or cisplatin plus paclitaxel. The rise of drug resistance is a substantial factor in cancer recurrence and mortality among ovarian cancer patients receiving cisplatin treatment. CD147 is widely expressed in a variety of cancer tissues1 and recognized as a drug target for its antibody drug Licartin which has been approved by China's National Medicines and Pharmaceutical Administration.2 Even though many studies reported that CD147 is involved in the cisplatin resistance of varieties of cancers,3 its mechanism remains unclear. In this investigation, we uncovered a distinctive mechanism by which CD147 regulates cisplatin resistance through the proteasomal degradation of the transcription factor FOXM1, which is associated with DNA damage repair, in ovarian cancer cells. Our results suggest that targeting CD147 may have therapeutic implications for increasing cisplatin efficiency in the management of ovarian cancer.

Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder that causes dementia in the aging population. One of the characteristic pathologic hallmarks of AD is the senile plaques, composed of the accumulation of β-amyloid. Neurotoxic β-amyloid results from the cleavage of transmembrane β-amyloid precursor protein (APP) by β-secretases and γ-secretases, sequentially. O-mannosylation was found essential for the normal function of APP in Saccharomyces cerevisiae.1 Protein O-linked mannose β1,2-N-acetyl-glucosaminyltransferase 1 (POMGNT1) is a glycosyltransferase crucial for the elongation of O-mannosyl glycans and catalyzes the transfer of N-acetylglucosamine from uridine 5′-diphosphate-N-acetylglucosamine to O-mannose of glycoproteins.2 Robust evidence has implicated that aberrant expression or loss of POMGNT1 had an unfavorable effect on the central nervous system, such as cognition.3 Our previous study showed that overexpression of POMGNT1 inhibited amyloid production and hyperphosphorylation of Tau in the N2a/APP cell model of AD.4 These studies demonstrated that POMGNT1 may be a potential key molecule involved in the formation of amyloid peptides associated with the pathogenesis of AD. In this study, we aimed to reveal the altered localization of POMGNT1 in the brain of APP/PS1 mice compared with wild-type (WT) mice.

Metabolic reprogramming is a key feature of tumor cells and plays a key role in the adaptation of tumor cells to increased demands of biosynthesis and rapid proliferation.1 Numerous studies have shown that some key metabolic enzymes are essential for the initiation and progression of breast cancer (BC). These metabolic enzymes are involved in the regulation of many biological processes such as gene transcription, post-translational modification, and antioxidant capacity of cells, which endow tumor cells with the ability to adapt to divergent environmental stimuli.2 Therefore, it is of great significance to identify the role of important metabolic enzymes in the occurrence and development of BC to determine promising therapeutic targets. Free fatty acids are absorbed by cells and esterified with CoA to form acyl-CoA, which can be used as substrates for fatty acid oxidation or lipid synthesis. Acyl-CoA thioesterases (ACOTs) catalyze the hydrolysis of acyl-CoA to produce fatty acids and CoA in cells, thus maintaining the ratio of activated fatty acids to free fatty acids and the content of CoA in cells. ACOT7 exhibits broad specificity; it is active towards fatty acyl-CoAs with long chain lengths and has maximal activity toward arachidonic acid-CoA.3 It has been demonstrated that ACOT7 was the only member of ACOTs to be significantly up-regulated compared with non-tumoral BC tissues based on the GEPIA database. However, the precise role of ACOT7 in BC occurrence and development is still unknown. We found that the mRNA levels of ACOT7 in BC tissues were significantly higher than that in adjacent non-tumor tissues (Fig. 1A). ACOT7 mRNA expression was associated with more advanced clinicopathological parameters, including lymph node metastasis and tumor size (Fig. 1B, C). Kaplan–Meier plotter analysis indicated that a high level of ACOT7 mRNA was correlated with shorter distant metastasis-free survival and overall survival (Fig. S1A, B). Next, we used immunohistochemistry staining to examine the protein level of ACOT7 in human BC tissues in our cohort. Evaluation of ACOT7 expression levels was according to the staining of cytoplasmic ACOT7, and the score of intensity was also shown (Fig. S1C). Combined with the clinicopathological characteristics, we found that a high protein level of ACOT7 was correlated with advanced tumor size, lymph node metastasis, and Ki-67 index (Table S1). Importantly, survival analysis of our cohort indicated that high expression of ACOT7 protein in BC tissues was associated with reduced disease-free survival (P = 0.027) and overall survival (P = 0.021) (Fig. 1D, E). Next, we tested the protein level of ACOT7 in different BC cell lines (Fig. S1D). To explore the effects of ACOT7 on the proliferation and invasion of BC cells, we first established MDA-MB-231 and MCF-7 cells stably overexpressing ACOT7 by lentiviral infection (LV). Efficiency was verified by Western blot illustrated in Figure S2A. CCK-8 experiments indicated that ACOT7 overexpression increased cell viability in MDA-MB-231 and MCF-7 cells (Fig. S2B). EdU analysis demonstrated that ACOT7 overexpression enhanced the proliferative capabilities of MDA-MB-231 and MCF-7 cells (Fig. 1F; Fig. S2C). The transwell test demonstrated that ACOT7 overexpression remarkedly increased the invasive abilities of MDA-MB-231 and MCF-7 cells (Fig. 1G; Fig. S2D). To investigate the role of ACOT7 in tumor growth in vivo, MDA-MB-231 cells stably transfected with LV-ACOT7 RNA were subcutaneously implanted into BALB/c nude mice. One week later, tumor volumes were measured every seven days. On the 28th day, the mice were euthanized and tumor weights were measured (Fig. 1H). Compared with the control groups, ACOT7 overexpression in MDA-MB-231 cells significantly increased the volume and size of subcutaneous tumors in mice (Fig. 1I, J). Tumor xenografts of the LV-ACOT7 group displayed elevated expression of ACOT7 protein level and a significant increase in the abundance of Ki-67 positive cells (Fig. S2E, F). To further validate the effects of ACOT7 on the biological properties of BC cells, we then down-regulated ACOT7 expression in MDA-MB-231 and MCF-7 cells using RNA interference. Transfection efficiency was measured by Western blot analysis shown in Figure S3A. To investigate the role of ACOT7 in BC cell proliferation, we performed CCK8 and Edu experiments to measure changes in cell proliferation after the down-regulation of ACOT7 expression levels in MDA-MB-231 and MCF-7 cells. CCK-8 experiments indicated that ACOT7 knockdown decreased cell viability in MDA-MB-231 and MCF-7 cells (Fig. S3B). Similarly, EdU experiments demonstrated that ACOT7 knockdown impaired the proliferative ability of in MDA-MB-231 and MCF-7 cells (Figure S3C, D). The transwell test indicated that the invasion abilities of MDA-MB-231 and MCF-7 cells were significantly decreased after ACOT7 knockdown (Figure S3E, F).

Stomach adenocarcinoma (STAD) is one of the most common gastric neoplasms with a high death rate. Therefore, there is an urgent need to propose an efficient therapy for STAD. Copper plays key roles in regulating the distribution of immune cells and affecting the tumor immune escape, and may be a novel indicator of immunotherapy in STAD. However, the specific impact of copper metabolism-related genes (CMRGs) on the patient's prognosis, tumor microenvironment, and immunotherapeutic response remains unelucidated.

Multiple myeloma (MM) is the second most common hematological tumor. It is characterized by high drug resistance, easy recurrence, and poor prognosis, and remains incurable. Various models or scoring modalities can be used to predict the survival prognosis of MM patients; however, these predictions are still not accurate enough. We have previously found that scorings related to bone marrow microenvironment metabolism can improve predictive efficacy.1 Given the importance of autophagy as a stress-induced self-degradation process critical for cell survival, particularly in the hypoxic bone marrow microenvironment of MM, autophagy-related genes are considered crucial.2 We constructed an Autophagy Risk Score (ARS) model using 11 survival-associated autophagy-related genes (ARGs). Multivariate analysis showed that ARS was an independent predictor of survival. Most importantly, the combination of an international staging system (ISS) and the ARS model into a new nomogram model can improve the accuracy of MM survival prediction. Additionally, targeting the autophagic gene ARNT could potentially overcome drug resistance to bortezomib in the bone marrow microenvironment of MM. The workflow is presented in Figure S1A. The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center.