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。

过刊浏览

Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome (SSNS) using genome-wide association studies (GWAS) strategy is important for understanding the disease. We conducted a multicenter cohort study (360 patients and 1835 controls) combined with a GWAS strategy to identify susceptibility variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (SNPs) in ANKRD36 and ALPG was significant between SSNSWR and healthy controls, and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls. Interestingly, rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR. No significant SNPs were observed between SSNSWR and SDNS/FRNS. Meanwhile, chromosome 2:171713702 in GAD1 was associated with a greater steroid dose (>0.75 mg/kg/d) upon relapse to first remission in patients with SDNS/FRNS (odds ratio = 3.14; 95% confidence interval, 0.97–9.87; P = 0.034). rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20% compared with the baseline in SDNS/FRNS patients (P = 0.0001). Protein–protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA. Thus, SSNSWR belongs to non-HLA region-dependent nephropathy, and the HLA-DQA/DQB region is likely strongly associated with disease relapse, especially in SDNS/FRNS. The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.

CYP3A5 is a cytochrome P450 (CYP) enzyme that metabolizes drugs and contributes to drug resistance in cancer. However, it remains unclear whether CYP3A5 directly influences cancer progression. In this report, we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma. Multi-omics analysis showed that CYP3A5 knockdown results in a decrease in various glucose-related metabolites through its effect on glucose transport. A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP, a negative regulator of GLUT1. Notably, CYP3A5-generated reactive oxygen species were proved to be responsible for attenuating the AKT–4EBP1–TXNIP signaling pathway. CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer. Taken together, our results, for the first time, reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.

The tumor suppressor p53 is the most common mutated gene in cancer, with the R175H as the most frequent p53 missense mutant. However, there are currently no approved targeted therapies or immunotherapies against mutant p53. Here, we characterized and investigated a monoclonal antibody (mAb) that recognizes the mutant p53-R175H for its affinity, specificity, and activity against tumor cells in vitro. We then delivered DNA plasmids expressing the anti-R175H mAb or a bispecific antibody (BsAb) into mice to evaluate their therapeutic effects. Our results showed that the anti-R175H mAb specifically bound to the p53-R175H antigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells, with no cross-reactivity with wild-type p53. In cultured cells, the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity. We made a recombinant MC38 mouse cell line (MC38-p53-R175H) that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles. In vivo, administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice. The administration of the anti-R175H BsAb plasmid showed no therapeutic effects, yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody. These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has decreased the efficacy of SARS-CoV-2 vaccines in containing coronavirus disease 2019 (COVID-19) over time, and booster vaccination strategies are urgently necessitated to achieve sufficient protection. Intranasal immunization can improve mucosal immunity, offering protection against the infection and sustaining the spread of SARS-CoV-2. In this study, an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum, nasal lavage fluid, and bronchoalveolar lavage fluid compared with only two doses of mRNA vaccine. After intranasal boosting with the RBD-HR vaccine, the levels of serum neutralizing antibodies against prototype and variant strains of SARS-CoV-2 pseudoviruses were markedly higher than those in mice receiving mRNA vaccine alone, and intranasal boosting with the RBD-HR vaccine also inhibited the binding of RBD to hACE2 receptors. Furthermore, the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+ dendritic cells in the respiratory mucosa, and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs, including mediastinal lymph nodes, inguinal lymph nodes, and spleen. Collectively, these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locally and systemically.

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.

Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.

Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.

Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.

Steroidogenic factor 1 (SF1/NR5A1; nuclear receptor subfamily 5 group A member 1) is an essential orphan protein involved in gonadal embryogenesis, sex determination, and reproductive endocrinology.1 Furthermore, NR5A1 is a transcription factor that regulates a number of target genes [e.g., SRY (sex determining Region Y), SOX9 (SRY-box transcription factor 9), GATA4 (GATA binding protein 4), AMH (anti-Mullerian hormone), STAR (steroidogenic acute regulatory protein), and CYP11A1 (cytochrome P450 family 11 subfamily A member 1)] crucial to reproductive biology. Several human NR5A1 gene variants have been associated with 46,XY disorders of sex development (DSD), a congenital condition in which the gonadal or anatomical sex is atypical.2 While NR5A1's role as a transcription factor essential to adrenal development is supported by several in vitro and in vivo experiments in knockout mouse models, to date, adrenal insufficiency in humans due to NR5A1 gene mutations is extremely rare.3 In this regard, next-generation sequencing approaches are a powerful tool in defining population genetics of rare diseases and allow more focused clinical genetic screening programs to be established. Therefore, the molecular etiology of this genetic steroid disorder is still unknown. Likewise, genomic analyses performed in our laboratory have revealed several non-synonymous mutations in NR3C4/AR (androgen receptor) and SRD5A2 (steroid 5 alpha-reductase 2) genes in patients with 46,XY DSD.4,5 We also showed that mutations of the NR3C4/AR protein reduced or nulled responses to androgens, testosterone, and dihydrotestosterone. Moreover, mutations in the SRD5A2 protein affect its enzymatic activity due to erroneous interactions between amino acid residues, the substrate testosterone, or nicotinamide adenine dinucleotide phosphate. Here, a novel NR5A1 gene variant is described in a Mexican patient raised as a female due to her phenotype. This female patient has a 46,XY karyotype, undescended atrophied testes, and hypergonadotropic hypogonadism. This study identiﬁed a novel heterozygous missense NR5A1 variant (c.89G > A, p.Cys30Tyr) in the first zinc finger of the DNA-binding domain that explains the 46,XY-female phenotype to a genetic condition, and adds to the variety of 46,XY DSD-causing mutations that impair the development of gonadal and phenotypic sex.

Riboflavin transporter deficiency (RTD), previously known as Brown-Vialetto–Van Laere syndrome, is a childhood-onset neurodegenerative disorder characterized by sensory and motor neuron degeneration causing ataxia, muscle weakness, optic atrophy, and respiratory failure. Mutations in SLC52A2 and SLC52A3, solute carrier family members that encode riboflavin (RF) transporters RFVT2 and RFVT3, are known to cause RTD types 2 and 3, respectively.1 RF transport activity analysis showed that SLC52A2 missense mutations caused a complete or moderate reduction in RF uptake and reduced RFVT2 protein expression in vitro,1 suggesting a loss-of-function disease mechanism.

Complement C1q was proved to be able to regulate the polarization of macrophages to the anti-inflammatory phenotype (M2 polarized), acting as an anti-inflammation molecule independent of the classical complement pathway. A high level of C1q expression has been detected in the tumor microenvironment (TME) of diverse tumors, including non-small cell lung cancer, in which C1q could be considered a predictor of poor prognosis.1 Prominently, researchers have found that C1q was positively correlated with the M2 polarization of tumor-associated macrophages (TAMs) in mouse renal clear cell carcinoma and human osteosarcoma. M2-TAMs are significantly associated with immunosuppressive TME and poor prognosis in non-small cell lung cancer. Hence, we investigated the mutual effects between C1q and TAMs in lung adenocarcinoma. The findings of this study could be extracted as below: (i) The expression of C1qA was positively correlated with M2-TAMs in lung adenocarcinoma. (ii) M2-TAMs could express abundant C1q, and C1q in lung adenocarcinoma was mainly from TAMs, especially M2-TAMs. (iii) C1qA could promote the proportion of M2-TAMs. (iv) C1qA led to the reduced phosphorylation of JAK2, STAT1, and STAT5, but augmented the levels of p52, phospho-p65, and phospho-IκBα belonging to NF-κB pathway. (v) C1q promoted the growth of LLC xenograft.

In mammals, skeletal bone development begins at hyaline cartilage formation at the early embryonic stage.1 Then osteoblasts from the periosteum, which are distributed surrounding the hyaline cartilage, build up compact bone to form diaphysis and spongy bone known as primary ossification center.1 Next, osteoclasts from the hematopoietic system destroy spongy bone to generate a medullary cavity.1 Along with this continuous establishment of the medullary cavity, after birth, there is a formation of a secondary ossification center occurring at both polar sites (epiphysis) of original hyaline cartilage in a post-axis manner.1, 2, 3, 4 After the formation of the secondary ossification center, the cartilage will be substituted by the spongy bone but leave intact articular cartilage and growth plate (epiphyseal plate) which is comprised of chondrocytes.1 This process is known as endochondral ossification.1 During endochondral ossification, the growth plate exerts a fundamental role in increasing the length of the skeletal bone.1 There are three principal layers of the structure of a growth plate: resting zone, proliferating zone, and hypertrophic zone.2 The cells with mesenchymal stem cell features in the resting zone give rise to clones of proliferating chondrocytes and control the alignment of the proliferating chondrocytes into columns parallel to the long axis of the bone via producing morphogens.2 Proliferating zone is responsible for elongating endochondral bone shape by dividing and arranging clones of chondrocytes into columnar structure.2 Chondrocytes in the hypertrophic zone generated by terminal differentiation of proliferating chondrocytes are contributing to long bone growth by attracting vascular and progenitor cell invasion from adjacent areas.2 Sustained chondrocyte proliferation and hypertrophy lead to calcification and accumulation of bone, thus lengthening the bone during skeletal development and postnatal bone growth.1,2 Unlike humans, there is no termination of proliferation and calcification of chondrocytes in the growth plate in mice. Therefore, it provides us the opportunity to investigate the mechanism of postnatal bone growth.

Tumor-associated inflammation is an important component of the tumor microenvironment, and an important factor affecting tumor progression. In the tumor microenvironment, tumor-associated macrophages (TAMs) receive different stimuli and can be polarized into classically activated M1 macrophages and alternatively activated M2 macrophages. Many studies have indicated that the polarization of TAMs is closely related to tumor progression. M2-polarized TAMs have been highly correlated with tumor metastasis, angiogenesis, and poor prognosis, whereas M1-polarized TAMs suppress tumor development. Tumors with higher densities of M2 macrophages and lower densities of M1 macrophages have poor clinical outcomes.1 In terms of molecular mechanism, M2-polarized TAMs can produce various cytokines required for tumor cell growth and angiogenesis, including TGF-β, VEGF, and EGF.2 In addition, M2-polarized TAMs can inhibit humoral and cellular immunity to cancer cells through various pathways, maintain tumor cells in an immune tolerance state, and evade clearance by the body. Tumor cells can regulate TAM polarization toward the M1 or M2 phenotype by regulating the tumor microenvironment and releasing cytokines.3 TRIM family proteins have been reported to be closely related to immune regulation, inflammation, and tumorigenesis.4 In our previously published research, we found that epinephrine (Epi) could promote the progression of colorectal cancer (CRC) by promoting the expression of TRIM2.5 However, the immunomodulatory role of TRIM2 in CRC is still unknown. In this study, we found that Epi promotes tumor proliferation, migration, and M2 polarization of TAMs by up-regulating TRIM2 expression in CRC cells. TRIM2 expression is closely related to CRC progression. TRIM2 promotes the development of CRC by promoting the ubiquitination and degradation of IκBα. TRIM2 can also promote M2 polarization of TAMs, which can further promote the progression of CRC. Collectively, targeting the Epi/TRIM2 signaling pathway might be a promising treatment option for CRC.

Osteoporosis (OP) is an aging-associated condition that significantly affects the quality of life in aging humans and has few treatment options. As an important marker, recombinant immunoglobulin superfamily containing leucine-rich repeat (ISLR) could be used as a gene therapy for OP. We herein used alkaline phosphatase (ALP) and alizarin red S (ARS) staining to evaluate osteogenic differentiation potential. Micro-computed tomography was used to determine bone formation and for image reconstruction of the trabecular distribution of the femur. ISLR knockout increased osteogenic differentiation and mineral deposition, consistent with the results in Ocn-cre:ISLRflox/flox mice and pCMV6-Islr-GFP (ISLR-overexpression, ISLR-OE) mice. ISLR negatively regulates osteogenic differentiation through the bone morphogenetic protein 4 (BMP4)-Smad-ColIα1/Ocn axis, promoting proteasomal degradation of BMP4. ISLR interacted with BMP4 to regulate osteogenic differentiation. Moreover, interference of ISLR expression was potentially therapeutic for bone loss treatment. These results demonstrated a new mechanism of osteogenic differentiation that could be used for developing effective bone therapies to treat OP.

Exome sequencing (ES) generates secondary findings (SFs) in 2 % of tested individuals if one follows the American College of Medical Genetics and Genomics (ACMG) guidelines.1,2 However, the rate of incidental and secondary findings (ISFs) is higher in routine clinical practice because of (i) the use of trio ES instead of solo sequencing and (ii) the exclusion of the incidental findings (IFs) of medical value concerning genes in the ACMG list. Hence, it is not clear how sufficient is a restricted list of genes to detect every ISF of major clinical value; and what is the amount of additional workload for the laboratory. Using 100 trio ES datasets, we determined the proportion of pathogenic or likely-pathogenic ISFs and their clinical value (See supplementary file 1 for Materials and Methods). We evaluated the accuracy of three lists of genes (see supplementary file 2) for detection of SFs: the 2021 ACMG v3 SFs list, a list of genes involved in treatable intellectual disabilities3 (treat-ID list), and a list of genes involved in the 20 most frequent diseases in general populations (CS20 list).

Prostate cancer (PCa) is considered as an age-related disease and accounts for the most prevalence of urinary malignancies in men.1 We previously analyzed the cellular landscape of tumor microenvironment in PCa patients, where we found that cancer-related fibroblasts might play an important role in tumorigenesis and the development of PCa and tumor-associated macrophage (TAM) could function synergistically with them.2 Thus, we further integrated single-cell and bulk RNA sequencing with meta-analysis to specify the prognostic effect of TAM on PCa and construct molecular subgroups and predictive index to guide clinical practice.

The COVID-19 pandemic that started in late 2019 is sweeping through the world, posing historic challenges to global health, and disrupting social and economic lives. Previous and recent studies indicate that monoclonal antibodies can be efficacious in preventing and treating SARS-CoV-1 and SARS-CoV-2 infections. Using a phage display platform, we have identified dozens of monoclonal antibodies that bind to diverse epitope groups on the SARS-CoV-2 spike protein. Many of them bound to the receptor binding domain (RBD) and inhibited ACE2-RBD interaction. Several of them were capable of inhibiting SARS-CoV-2 spike protein pseudo-typed virus (pseudovirus) entry. In addition, we isolated a dozen of S2 binding antibodies that prevented pseudovirus entry without inhibiting the ACE2-RBD interaction. A bi-epitopic antibody constructed from two non-competing, RBD binding, neutralizing antibodies displayed higher potency than either of them alone. Combinations of RBD and S2 binding antibodies displayed additive inhibitory effects against pseudovirus infection. The new antibodies and strategies reported here could expand the arsenal of anti-COVID-19 therapeutics and help understand the viral entry mechanism, the pathogenesis of the SARS-CoV-2, and anti-SARS-CoV-2 vaccine development.

Gastric cancer (GC) ranks fifth for cancer incidence and fourth for mortality globally.1 Clinical outcomes have varied among patients receiving similar treatments at the same stage, suggesting the current prognostic tools remain somewhat flawed.2,3 Single-cell analysis of GC data allowed us to dissect transcriptional programs underlying lymphocyte residency and exhaustion. Combined with tumor purity, we developed a novel classification system and data analysis following the workflow shown in Figure S1.

Preimplantation genetic testing (PGT) is a precise and effective technique for detecting inherited pathogenic mutations to prevent birth defects. However, there are few reports on PGT for pseudo-autosomal genetic diseases. In this study, both X-linked and Y-linked short stature homeobox-containing (SHOX) gene mutations were identified in the Leri-Weill dyschondrosteosis (LWD) affected family, suggesting a de novo event of X–Y pseudo-autosomal homologous recombination during sperm meiosis in the common ancestor of the affected family members. A novel PGT strategy with sequential analysis of polar bodies and embryos (PGT-Sean) was applied to the SHOX mutation carriers. Following PGT-Sean, a healthy offspring was born to the LWD-affected family. For families with pseudo-autosomal genetic diseases and other genetic disorders linked to subtelomeric regions, in case of high recombination rates and lack of multiple region-specific markers, it is recommended to perform PGT-Sean to enable a more accurate clinical genetic diagnosis.

Pancreatic cancer is one of the most lethal malignant tumors in the world. Despite advances in diagnosis and treatment, the five-year survival rate for pancreatic cancer patients remains only 9%.1 Pancreatic adenocarcinoma (PAAD) belongs to pancreatic cancer, which occupies 85% of the whole pancreatic cancer.2 Reversible modification of N6-methyladenosine (m6A) has been shown to be involved in cancer progression, resulting in up-regulation of oncogene expression or down-regulation of tumor-suppressing genes and may affect the prognosis of patients with pancreatic cancer.3 In pancreatic cancer, increasing evidence suggests that aberrant expression of lncRNA is related to tumor cell proliferation and metastasis.4,5 Although m6A can regulate lncRNA formation, the role of m6A-related lncRNAs in PAAD remains unclear.

AI-driven genetic engineering, as a burgeoning diagnostic tool, can offer predictive information on the five-year survival rate (FYSR) in the setup of a prognostic therapeutic schedule. This approach provides the individuality and accuracy of prognosis for FYSR of gastric cancer (GC). Unlike traditional neoplasm staging criteria, our technique ensures accuracy and individuality without relying on statistical data and empirical study. Here, we designed a gene mutation analysis algorithm (cumulative contribution abundance, CCA, Supplementary Material 1.1) to drive a single base substitution (SBS) signature to score GC prognosis because the algorithm can better represent the relationship between genes and mutational signatures. We found a new prognostic survival factor (SBS44) of GC and verified that SBS18 can also be utilized in this capacity. Then, a GC FYSR predictive AI model was constructed that combined the SBS44 and SBS18 (SBS44&18) signatures as characteristic variables and obtained high accuracy (AUC: 0.9194, 95% CI: 0.8357–1). Our results suggest that this technique is beneficial for accurate prognostic assessment and provide a new idea for clinical stratified treatment.

Carcinogenesis is closely associated with inflammation. Studies have shown that lipopolysaccharides (LPS) can contribute to hepatocellular carcinoma (HCC) development by inducing IL-6 and TNF-α production from the hepatic progenitor cells.1 Aquaporin 3 (AQP3), a water channel protein, has recently been found to play a critical role in cancer-associated inflammation.2,3 However, it is still unclear whether AQP3 is involved in LPS-triggered proliferation and inflammation in HCC. In this current study, we found that AQP3 expression was negatively correlated with the overall survival rate of HCC patients and positively associated with MKI67 expression in human HCC patients. In vitro study demonstrated that AQP3 promoted LPS-induced cell proliferation, colony formation, and inflammation in HCC cell lines. In vivo xenograft model further demonstrated that AQP3 could promote tumor growth induced by LPS. In summary, the present study proved that AQP3 functioned as an oncogene and might serve as a promising target for cancer therapy.

Mitochondria energize the inner ear to maintain the cochlear potential created by the stria vascularis, assist the motility of outer hair cells, perform synaptic processes, and maintain the spontaneous and sound-driven discharges of the spiral ganglion neurons (SGNs). Mitophagy deficiencies induce the accumulation of damaged organelles and mitochondria in cells and are a primary cause of drug-induced hearing loss.1 SH3GLB1, also known as endophilin B1, encoded by the SH3GLB1 gene, is a multifunctional protein that controls mitophagy, apoptosis, and autophagy. By influencing mitophagy, SH3GLB1 has been linked to the pathophysiological processes of neurodegenerative disorders, including Alzheimer's and Parkinson's disease.2 The role of SH3GLB1 in hearing is currently unclear. This study shows the localization of Sh3glb1 in the mouse inner ear, especially in SGNs and inner hair cells (IHCs), suggesting a role in auditory function. The sh3glb1a morpholino knockdown zebrafish demonstrated a considerable reduction in inner ear hair cells and neuromasts accompanied by malformation of the caudal vein plexus (CVP) and intersegmental vessels (ISV), vascular defects, pericardial edema, circulation defect, and aberrant somite. Collectively, these findings show that SH3GLB1 activity is essential in the auditory, cardiovascular, and muscular systems, where defective mitochondria play a significant role in the pathogenesis of associated diseases.

Neuroblastoma is the most common extracranial solid tumor in children, accounting for more than 10% of cancer-related deaths in this population. The standard of care for patients diagnosed with medium-to high-risk neuroblastoma, including those who present with metastatic disease, is preoperative induction chemotherapy.1 However, approximately 40% of patients experience relapse or recurrence despite treatment, and evidence suggests that certain chemotherapeutic drugs may promote metastasis through poorly-understood mechanisms.2 Recent research has highlighted the role of small extracellular vesicles (sEVs) in regulating cancer progression and metastasis through the transfer of cellular material.3 In this study, we investigated how DNA-damaging chemotherapeutic drugs affected the secretion and contents of neuroblastoma sEVs and how these sEVs impacted metastasis. We demonstrate that chemotherapy increases the secretion of neuroblastoma sEVs and alters their protein content, leading to accelerated hepatic metastasis in both immune-competent and -deficient mouse models. Additionally, we identify sEV-associated pentraxin 3 (PTX3), an acute-phase inflammatory glycoprotein, and the tissue-type plasminogen activator (PLAT), a serine protease, as critical factors involved in the formation of the pre-metastatic niche with a STAT3-associated inflammatory gene signature.

Genome-wide association studies (GWASs) have identified hundreds of loci across the human genome conferring susceptibility to autoimmune diseases (AIDs), some of which are shared between more than two diseases. However, this univariate approach has limitations in detecting complex genotype-phenotype correlations. In this work, we carried out whole-exome sequencing of Colombian Caribbean patients with type 1 diabetes (T1D), lupus nephritis (LN), and juvenile idiopathic arthritis (JIA), to evaluate functional exomic variation, i.e., single nucleotide polymorphisms (SNPs), and to outline common and rare variations underpinning the susceptibility to these autoimmune diseases. Single and multi-locus linear mixed-effects models fit the data to identify T1D-associated genomic variants and the most likely genetic architecture underpinning AID risk. Variations associated with T1D susceptibility pointed to genes related to glycoprotein oligosaccharide biosynthesis, phospholipid binding, pancreatic adenocarcinoma, systolic blood pressure, and fasting insulin metabolism, among others that highlight MGAT5 (PFDR = 1.64 × 10−22), RUNX1 (PFDR = 1.8 × 10−12), PSD3 (PFDR = 8.1 × 10−12), and HLA-DBP2 (PFDR = 2.18 × 10−9). Our study outlines oligogenic common variation underpinning the susceptibility to develop T1D. These genetic polymorphisms are also shared by patients with other AIDs such as LN and JIA, indicating that the shared genetic architecture (defined by pleiotropy and epistasis) shapes the genetic susceptibility of these disorders in this multiethnic population.

Hepatocellular carcinoma (HCC) is the major histologic type of primary liver cancer, accounting for approximately 75% of liver cancer cases.1 Despite many advancements in its treatment, the prognosis and drug response of HCC patients are dismal. Therefore, there is an unmet clinical need to explore genomic aberrations underlying early- and late-onset HCC, which might facilitate drug discovery and provide personalized biomarker-driven treatment options for these patients. This study aimed to identify biomarkers associated with early-onset (EO) and late-onset (LO) HCC with comprehensive genomic profiling.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a predominantly nuclear RNA-binding protein that can bind to DNA or RNA through three KH domains and interact with multiple proteins by interactive region. These binding activities enable hnRNPK to link the function in a wide array of diverse cellular processes, such as chromatin remodeling, gene transcription, RNA metabolism, protein translation, DNA repair, and cell signal transduction, thereby playing crucial roles in many biological processes, including development, axonal regeneration, spermatogenesis, cell cycle, apoptosis, differentiation, and carcinogenesis.1 Lack of hnRNPK in C2C12 myoblasts results in the decreased proliferation rate of myoblasts and an inhibitory effect on muscle differentiation. Homozygous Hnrnpk knockout (Hnrnpk−/−) mice are embryonic lethal, suggestive of its decisive role in development and neonatal survival.2 In addition, mutation of HNRNPK in humans causes Au-Kline syndrome which is a rare neurodevelopmental multiple congenital malformation syndrome associated with global developmental delay, characteristic facies, congenital heart defects, skeletal abnormalities, and muscle weakness.3 These findings demonstrate that hnRNPK plays a critical role in skeletal muscle development and myogenesis. However, the molecular mechanism of hnRNPK in skeletal muscle development has not been convincingly demonstrated, especially in animal models. Here, we constructed an hnRNPK-inducible skeletal muscle satellite cell-specific knockout mouse model and found that hnRNPK depletion in mice inhibited muscle regeneration, emphasizing the importance of hnRNPK in myogenesis. Further research demonstrated that hnRNPK may feature in skeletal muscle regeneration via binding Cdnk1a 3′UTR to modulate Cdnk1a mRNA stability. These findings suggested that hnRNPK is required for muscle regeneration and might be a potential novel target for the treatment of muscle disorders.

Tricho-dento-osseous (TDO) syndrome is a rare autosomal dominant disease resulting from distal-less homeobox 3 (DLX3) mutation.1,2 Accumulative bone density in alveolar bone is a clinically favorable phenotype for TDO patients. However, the limited number of bone marrow mesenchymal stem cells (BMSCs) in TDO patients restricts their application. Since TDO-specific induced pluripotent stem cells (iPSCs) can yield a large variety of patient cells as the important cell source to investigate specific tissue/organ development, establish disease models, and develop new treatment approaches, we established TDO-iPS cells with mutant DLX3 (c.533A > G, Q178R) of the host cells. Our previous research indicated that mutant DLX3 could down-regulate H19 to regulate bone formation.3 In this study, we successfully generated and verified TDO-iPSCs, and compared the osteogenic differentiation capacity from TDO-iPSCs to mesenchymal stem cells (MSCs) and from normal human iPSCs to iPS-MSCs. We also predicted that H19 could sponge miR-29c-3p and lysine demethylase 5B (KDM5B) was the target gene of miR-29c-3p. We found transfected miR-29c-3p inhibitor down-regulated miR-29c-3p and up-regulated the expression of KDM5B and osteogenic biomarker. Previous research suggested that KDM5B promoted osteo-differentiation by binding to the promoter region of alkaline phosphatase (ALP), RUNX family transcription factor 2 (RUNX2), and osteocalcin (OCN).4 We deduced that H19, miR-29c-3p, and KDM5B, together serving as a ceRNA (competing endogenous RNA) network, were regulated by DLX3 to affect osteo-differentiation, which is a novel pathway to regulate bone formation and shed light on the treatment of bone-related diseases.

COVID-19, also known as coronavirus disease 2019, is a novel coronavirus disease with high infectivity, strong heterogeneity, and long incubation period (generally 3–14 days). Its main symptoms and signs include fever, dry cough, nasal congestion, fatigue, disorientation, lymphopenia, and dyspnea.1 The short-term and long-term impacts of COVID-19 on human health, particularly its effects on human reproduction and offspring development, continue to receive significant concerns, as they may lead to potential sequelae for several decades or even centuries.

Lung cancer is the leading cause of cancer-related deaths worldwide, with an estimated 1.8 million deaths in 2020 alone.1 While several risk factors are associated with lung cancer, smoking remains the most significant environmental cause of the disease.1 One of the most potent carcinogens in tobacco smoke is 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), which is produced from nicotine through a series of metabolic reactions.1,2 NNK has been shown to cause DNA damage, activate oncogenic signaling pathways, and promote cell proliferation and survival, all of which are hallmarks of cancer development.1 Despite extensive research on the molecular mechanism of action of NNK, direct targets that mediate sensitivity to NNK and contribute to its tumorigenicity remain unknown.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma with heterogeneous clinical outcomes. Patients who are primarily refractory to the frontline therapy or relapse less than 12 months after diagnosis have an extremely dismal prognosis.1 The heterogeneous clinical outcomes of DLBCL patients result from variable genetic profiles. However, the invasiveness of tissue biopsy often hampers the clinical application of genetic analysis. Circulating tumor DNA (ctDNA) is a non-invasive source of tumor genetic material. Rossi et al reported that pretreatment plasma ctDNA from DLBCL patients have >90% sensitivity and ∼100% specificity compared with mutations that were represented in >20% of the alleles of the tumor gDNA.2 Moreover, in patients with multiregional diseases, ctDNA mutations offer a comprehensive representation of tumor genetics, regardless of anatomical biases.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell lymphoma in adult patients. Due to the clinical and molecular heterogeneity of DLBCL patients, robust biomarkers in clinical practice are still required. Clinically, the international prognostic index (IPI) was considered the most well-established predictor. Molecularly, mRNA expression and genetic subtypes were regarded as useful biomarkers. However, the prognostic potential of circRNA expression in DLBCL patients is still unclear. CircRNAs are more stable than linear mRNAs. Due to their richness, stability, and tissue specificity, circRNAs should have a potential utility as cell-free biomarkers.1,2 Notably, B-cells have specific circRNA markers compared with T-cells. Additionally, circRNA expression profiles can distinguish different B-cell malignancies.3 Besides, circRNAs are expressed in higher amounts in some diseases than their corresponding linear mRNAs. Based on these studies, we used RNA sequencing to search for circRNAs related to disease progression and identified hsa_circ_0007099 as one of the significant predictors. Furthermore, the regulatory pathway of hsa_circ_0007099 was constructed in in silico analysis and validated in in vitro cellular experiments.

Despite remarkable advances in molecular and cell biology of acute myeloid leukemia (AML), AML patients still frequently relapse and have low 5-year overall survival (OS) rates.1 It is worth noting that a recent study from the registry or clinical trial compilation has reported an improvement in the OS of adult AML patients, especially those under 60 years of age.2 There is an urgent need to unveil more accurate and sensitive biomarkers to improve the survival of AML patients. Gene expression profiling played a pivotal role in hematology and provided crucial insights into the biology of AML.3 Here, we identified TMEM217 as a promising biomarker for prognostic prediction especially for AML patients younger than 60 years of age, and as a target for developing innovative treatments for AML.

Due to the profound heterogeneity exhibited amongst patients with lung adenocarcinoma (LUAD), considerable variances in clinical efficacy emerge.1 For the aims of precision medicine, a clinical instrument to delineate distinct disease phenotypes and anticipate susceptibility to intervention is imperative. Cellular cytotoxicity mediated through T lymphocytes constitutes a pivotal mechanism of anti-tumoral immunity and the foundation for cancer immunotherapy.2 Numerous genes regulating the sensitivity of tumor cells to killing mediated by T lymphocytes (GSTKKs) are conducive to satisfying the aforesaid medical necessity.

Dysfunction of pancreatic β cells caused by zinc deficiency is related to the pathogenesis of diabetes.1 Impaired zinc homeostasis in diabetes is associated with reduced zinc transporters.2 Down-regulation of HuD, an essential factor for normal β cell function, has been shown in diabetes.3 To assess the correlation between cellular zinc level and HuD expression in diabetes, relative levels of HuD and ZIP8, a highly expressed Zrt-, Irt-like protein (ZIP) transporter protein in β cells,4 were analyzed between db/db mice and control wild-type mice. HuD and ZIP8 expressions were down-regulated in the pancreas of db/db mice compared with that in control mice (Fig. 1A, B). Cellular zinc content was also reduced in pancreatic islets of db/db mice (Fig. 1B). These results suggest a positive correlation between intracellular zinc contents and HuD expression in the islet of the pancreas.

Cancer stem cells (CSCs) are related to tumorigenesis, recurrence, metastasis, and drug resistance in hepatocellular carcinoma (HCC).1 Let-7i is a noncoding small RNA, belonging to the famous miRNA let-7 family. Recently, let-7i has been revealed as a tumor suppressor on CSCs in ovarian cancer.2 However, let-7i is overexpressed in side population cells of rat HCC.3 It is unknown about the role of let-7i on human CSCs in HCC. Wnt pathway has critical roles in tumorigenesis, including differentiation, proliferation, and drug resistance of liver cancer. Let-7i inhibits osteogenesis by targeting Wnt pathway.4 Moreover, let-7i-3p suppresses cell growth and β-catenin in hepatoblastoma.5 Nevertheless, the effect of let-7i-5p on Wnt pathway needs to be uncovered in HCC. In this study, we aimed to investigate the effect and mechanism of let-7i-5p on stemness maintenance of CSCs in HCC.

Adriamycin (ADR), also known as doxorubicin, is an anthracycline anticancer drug and a chemotherapeutic drug commonly used in breast cancer treatments.1 However, breast cancer patients can gradually become tolerant to chemotherapy. Therefore, improving the curative effect of ADR remains an urgent problem to be solved. Autophagy is a complex catabolic process; normal living cells break down damaged organelles or aggregated molecules and absorb energy to maintain homeostasis through autophagy. When autophagy dysfunction occurs, it will inevitably cause cell death. Long noncoding RNA (lncRNA) is a transcript longer than 200 nucleotides in length.2 As a human-specific gene, lncRNA human histocompatibility leukocyte antigen complex P5 (HCP5) is located in the major histocompatibility complex class Ⅰ region and can generate a transcript of approximately 2.5 kb. There is also a relationship between HCP5 and drug resistance.3

Pancreatic cancer is one of the most aggressive malignant tumors of the digestive system. Lymph node metastasis (LNM), as the main way of invasion and metastasis, can occur in the early stage of pancreatic cancer and be considered the most important factor affecting the clinical treatment and prognosis of patients with pancreatic cancer. Previous studies have found that the incidence of lymphatic invasion of cancer cells is 3–5 times higher than that of vascular invasion.1 Although LNM of pancreatic cancer has obvious clinical importance, the specific molecular mechanism is still unclear.

MicroRNAs (miRNAs) have been found to play an important role in human tumorigenesis. A study indicates that the plasma level of miR-933 was elevated in patients with dementia.1 Notably, miR-933 (RS79402775) may contribute to the reduction of gastric cancer susceptibility.2 Moreover, the study found that the miR-933 expression level in superficial diffuse melanoma was lower than in nodular melanoma.3 Furthermore, miR-933 has become a reliable prognostic tool for tumor progression.4 Strikingly, single nucleotide polymorphisms of miR-933 were found to be associated with the risk of papillary thyroid cancer.5 In this study, we demonstrate that miR-933 accelerates the growth of liver cancer cells by enhancing the expression of pyruvate kinase isoform M2 (PKM2) and increasing DNA damage repair. These results provide a basis for research on liver cancer prevention.

In recent years, the global incidence of hepatitis E virus (HEV) has been rising, leading to increased morbidity and mortality associated with hepatitis. Cas13, a CRISPR effector, shows promise as an antiviral agent against single-stranded RNA viruses. Cas13d, a type VI-D effector, exhibits higher efficiency in suppressing RNA viruses compared to other type VI variants. However, its in vivo activity against RNA viruses in mammals remains unknown. This study aimed to evaluate Cas13d′s effectiveness against HEV. By comparing HEV3 genotypes, we designed eight crRNAs targeting conserved regions, achieving a maximum interference efficiency of 94.82% using HEK293T cells. To enable in vivo targeting of HEV by Cas13d, we engineered synthetic AAV8 vectors for Cas13d delivery, along with efficient crRNAs. In gerbils, intraperitoneal injection of Cas13d and HEV3-targeting crRNAs packaged in AAV8 resulted in a 50% reduction in the detoxification rate and significantly suppressed incidence. Our study establishes an effective platform for preventing and treating HEV infection in gerbils, demonstrating the potential of CRISPR/Cas13d as an RNA-guided therapy against mammalian viruses beyond HEV.

Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes mellitus. Although functional alterations of renal infiltrating immune cells have been reported as part of the pathological mechanism of DN, the understanding of the immune response underlying peripheral blood mononuclear cells (PBMCs) in DN remains limited. Here, single-cell RNA sequencing (scRNA-seq) was used to profile the transcriptomic signatures of PBMCs from DN patients. We identified four well-known cell types of PBMCs and analyzed their respective cell subtypes. The underlying biological processes were captured from the altered cell (sub)types. A number of cell-type-specific cytokines and transcription factors driving the DN-associated transcriptomic changes were detected. Taken together, our data revealed detailed and rich single-cell transcriptomic signatures of PBMCs from DN patients and identified cell-type-specific pathways and molecules associated with the mechanisms of DN progression.

Bone undergoes continuous remodeling by tightly-coordinated actions of bone-resorbing osteoclasts and bone-forming osteoblasts.1 Recent studies document that the dysregulation of histone methylation profiles is associated with the progression of osteoclastogenesis. However, the specific epigenetic modifiers are incompletely understood. In this study, we demonstrate an inhibitory role of a variegation 3–9 homolog 1 (SUV39H1) in osteoclast formation. Public datasets find that mRNA levels of several methyltransferases are gradually decreased during osteoclastogenesis. Among them, a decrease in SUV39H1 mRNA level leads to accelerated osteoclast differentiation with the induction of several osteoclastogenic genes both in vivo and in vitro. In this regard, SUV39H1 directly binds and methylates a nuclear factor of activated T cells 1 (NFATc1) at lysine 267 of the regulatory domain (RD) motif. Of note, SUV39H1 enhances c-Cbl-dependent NFATc1 ubiquitination. Reduced NFATc1 methylation by the knockdown of SUV39H1 significantly decreases c-Cbl-dependent NFATc1 ubiquitination. Finally, SUV39H1 methylates lysine 9 of histone 3 (H3K9) at osteoclastogenic gene promoters, thereby repressing NFATc1 transcriptional activity. Taken together, our findings reveal that SUV39H1 plays both epigenetic and enzymatic roles in its action as an intrinsic suppressor of osteoclastogenesis.

Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4. Previous studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade, ATP depletion, and cell death in cancer due to high intracellular levels of lactate.1,2 The liver is the largest digestive gland in the human body and plays a crucial role in regulating energy metabolism, as well as serving as an important site for drug metabolism. Liver fibrosis is one of the most common pathological changes in the liver, which is a dynamic, highly complex molecular and cellular process leading to the excess accumulation of extracellular matrix components sustained by a heterogeneous population of hepatic myofibroblasts. Fibrosis usually follows a chronic and long-term liver injury, which may progress to hepatic cirrhosis, hepatocellular carcinoma, and liver failure.3 The major driver of liver fibrogenesis is the activated hepatic stellate cells (HSCs), which are also the major cellular sources of excessive matrix protein secretion.4 In this study, we investigated the effects of syrosingopine on HSCs in the progression of liver fibrosis.

NIBAN1 overexpression has been reported in a wide range of thyroid carcinoma subtypes, and in other cancers, while it is not expressed in thyroid benign lesions and normal thyroid.1, 2, 3 However, the mechanism associated with its expression and prognostic value remains unclear. In this study, six independent cohorts were enrolled, in which NIBAN1 expression was evaluated. A total of 583 patients with thyroid tumors, 326 patients with skin cancers, 293 patients with colorectal carcinoma, and 189 patients with lung carcinoma were analyzed. Our study demonstrates, for the first time, that NIBAN1 expression varied according to thyroid tumor subtypes, presence of BRAFV600E mutation, worse clinical features, and aggressive phenotype. Remarkably, the data suggest that BRAFV600E mutation might influence NIBAN1 expression in an MYC-dependent manner during the thyroid carcinogenic process. Furthermore, NIBAN1 expression was predicted to be associated with stress-induced transcription/translation. In summary, our findings suggested that NIBAN1 expression could be used not only to help preoperative diagnosis of a thyroid nodule but also may have prognostic implications.

Moyamoya disease (MMD, MIM 607151) is a rare vascular condition that has high recurrence, mortality, and disability rates, and an effective treatment for this disease is currently lacking. The main symptoms of affected children and adults include ischemic and hemorrhagic strokes, with an age of onset that follows a bimodal distribution trend at approximately 5 and 40 years of age. Affected individuals are at risk of intracranial hemorrhagic or ischemic stroke, seizures, cognitive impairment, and developmental delays. A strong ethnicity-related effect, combined with family aggregation, suggests a genetic basis for predisposition to MMD. Ring finger protein (RNF213) p.R4810K is only found in 20% of Chinese patients with MMD.1 Other pathogenic variants underlying MMD are yet to be identified.

With the rapid development of histological techniques and the widespread application of single-cell sequencing in eukaryotes, researchers desire to explore individual microbial genotypes and functional expression, which deepens our understanding of microorganisms. In this review, the history of the development of microbial detection technologies was revealed and the difficulties in the application of single-cell sequencing in microorganisms were dissected as well. Moreover, the characteristics of the currently emerging microbial single-cell sequencing (Microbe-seq) technology were summarized, and the prospects of the application of Microbe-seq in microorganisms were distilled based on the current development status. Despite its mature development, the Microbe-seq technology was still in the optimization stage. A retrospective study was conducted, aiming to promote the widespread application of single-cell sequencing in microorganisms and facilitate further improvement in the technology.

Tendon injuries often lead to joint dysfunction due to the limited self-regeneration capacity of tendons. Repairing tendons is a major challenge for surgeons and imposes a significant financial burden on society. Therefore, there is an urgent need to develop effective strategies for repairing injured tendons. Tendon tissue engineering using hydrogels has emerged as a promising approach that has attracted considerable interest. Hydrogels possess excellent biocompatibility and biodegradability, enabling them to create an extracellular matrix-like growth environment for cells. They can also serve as a carrier for cells or other substances to accelerate tendon repair. In the past decade, numerous studies have made significant progress in the preparation of hydrogel scaffolds for tendon healing. This review aims to provide an overview of recent research on the materials of hydrogel-based scaffolds used for tendon tissue engineering and discusses the delivery systems based on them.

Chimeric antigen receptor T (CAR-T) cell therapy represents a breakthrough in personalized cancer treatments. In this regard, synthetic receptors comprised of antigen recognition domains, signaling, and stimulatory domains are used to reprogram T-cells to target tum or cells and destroy them. Despite the success of this approach in refractory B-cell malignancies, the optimal potency of CAR T-cell therapy for many other cancers, particularly solid tumors, has not been validated. Natural killer cells are powerful cytotoxic lymphocytes specialized in recognizing and dispensing the tumor cells in coordination with other anti-tumor immunity cells. Based on these studies, many investigations are focused on the accurate designing of CAR T-cells with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system or other novel gene editing tools that can induce hereditary changes with or without the presence of a double-stranded break into the genome. These methodologies can be specifically focused on negative controllers of T-cells, induce modifications to a particular gene, and produce reproducible, safe, and powerful allogeneic CAR T-cells for on-demand cancer immunotherapy. The improvement of the CRISPR/Cas9 innovation offers an adaptable and proficient gene-editing capability in activating different pathways to help natural killer cells interact with novel CARs to particularly target tumor cells. Novel achievements and future challenges of combining next-generation CRISPR-Cas9 gene editing tools to optimize CAR T-cell and natural killer cell treatment for future clinical trials toward the foundation of modern cancer treatments have been assessed in this review.

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

Diabetic kidney disease is a leading cause of end-stage renal disease, making it a global public health concern. The molecular mechanisms underlying diabetic kidney disease have not been elucidated due to its complex pathogenesis. Thus, exploring these mechanisms from new perspectives is the current focus of research concerning diabetic kidney disease. Ion channels are important proteins that maintain the physiological functions of cells and organs. Among ion channels, potassium channels stand out, because they are the most common and important channels on eukaryotic cell surfaces and function as the basis for cell excitability. Certain potassium channel abnormalities have been found to be closely related to diabetic kidney disease progression and genetic susceptibility, such as KATP, KCa, Kir, and KV. In this review, we summarized the roles of different types of potassium channels in the occurrence and development of diabetic kidney disease to discuss whether the development of DKD is due to potassium channel dysfunction and present new ideas for the treatment of DKD.

In recent years, researchers have become focused on the relationship between lipids and bone metabolism balance. Moreover, many diseases related to lipid metabolism disorders, such as nonalcoholic fatty liver disease, atherosclerosis, obesity, and menopause, are associated with osteoporotic phenotypes. It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass. Furthermore, similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models. Abnormal lipid metabolism (such as increased oxidized lipids and elevated plasma cholesterol) affects bone microenvironment homeostasis via cross-organ communication, promoting differentiation of mesenchymal stem cells to adipocytes, and inhibiting commitment towards osteoblasts. Moreover, disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cytokines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts. Conclusively, this review addresses the possible link between lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism balance. We also summarize the possible approaches and prospects of intervening lipid metabolism for osteoporosis treatment.

Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a concentric circle structure with two α rings and two β rings overlapped. The proteasome 20S can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits (such as 19S, 11S, and 200 PA), which is performed by its active subunit β1, β2, and β5. The proteasome can degrade misfolded, excess proteins to maintain homeostasis. At the same time, it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth. Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-κB and p53, cell cycle, immune regulation, and drug resistance. Proteasome-encoding genes have been found to be overexpressed in a variety of tumors, providing a potential novel target for cancer therapy. In addition, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma. More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma, non-small cell lung cancer, glioblastoma, and neuroblastoma. However, proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors. Therefore, further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial–mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

Genetic mutations in TP53 contribute to human malignancies through various means. To date, there have been a variety of therapeutic strategies targeting p53, including gene therapy to restore normal p53 function, mutant p53 rescue, inhibiting the MDM2-p53 interaction, p53-based vaccines, and a number of other approaches. This review focuses on the functions of TP53 and discusses the aberrant roles of mutant p53 in various types of cancer. Recombinant human p53 adenovirus, trademarked as Gendicine, which is the first anti-tumor gene therapy drug, has made tremendous progress in cancer gene therapy. We herein discuss the biological mechanisms by which Gendicine exerts its effects and describe the clinical responses reported in clinical trials. Notably, the clinical studies suggest that the combination of Gendicine with chemotherapy and/or radiotherapy may produce more pronounced efficacy in slowing tumor growth and progression than gene therapy/chemotherapy alone. Finally, we summarize the methods of administration of recombinant human p53 adenovirus for different cancer types to provide a reference for future clinical trials.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 19 (COVID-19) pandemic. In viral infections like SARS-CoV-2, a robust anti-viral type 1 immune response, including up-regulation of type 1 CD4+ T helper cells (Th1), is required for effective viral clearance while minimizing end-organ pathology and collateral tissue damage. However, in severe SARS-CoV-2 infection, T cell dysregulation can occur, leading to reduced Th1 and elevated Th2 and Th17 cells, exaggerated T cell-mediated cytokine release, and extensive systemic inflammation and tissue damage known clinically as severe COVID-19.1 Despite the global impact of severe COVID-19, the molecular mechanisms of T cell dysregulation during SARS-CoV-2 infection remain largely unknown. We previously discovered that platelet-derived Dickkopf-1 (Dkk-1), a Wnt signaling inhibitor, is a critical regulatory molecule in pulmonary T cell immune responses during pulmonary infections and induces Th2 and Th17 cell differentiation and activation.2 Additionally, the Dkk-1 signaling pathway is a potential biomarker for COVID-19-induced lung injury.3 We hypothesize that platelet-derived Dkk-1 is a key regulator in SARS-CoV-2-associated T cell dysregulation leading to severe COVID-19.

Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is a unique monosaccharide modification of essential importance in physiology and pathology.1,2 As a highly dynamic process, O-GlcNAcylation is mediated by two paired enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add or remove the modification from proteins, respectively. Emerging evidence demonstrates that the aberrant O-GlcNAcylation underlies the initiation, progression, and metastasis of cancer.3,4 Remarkably, individual studies suggest that O-GlcNAc cycling enzymes and O-GlcNAcylation hold promise as biomarkers and therapeutic targets for certain types of cancers.1 However, integrated and pan-cancer analysis about the key enzymes across tumors has been lacking. In this study, we systematically explored the relationship between OGT/OGA expression with pathological status and their prognostic, immunological, and therapeutic roles in various cancers. It was revealed that OGT/OGA expression levels were significantly associated with a number of tumors, immune infiltrates and immunocytes, and cancer therapeutics (including chemotherapy and immune checkpoints). Taken together, by comprehensive pan-cancer analysis of OGT and OGA, we show that OGT/OGA can serve as valuable biomarkers for multiple types of cancers, such as colon adenocarcinoma (COAD).