ABSTRACT
Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.
Subject(s)
Prostatic Neoplasms/genetics , RNA, Long Noncoding/genetics , RNA, Untranslated/genetics , Adult , Alleles , Cell Line, Tumor , Chromosomes, Human, Pair 19/genetics , Cohort Studies , Gene Expression Regulation, Neoplastic/genetics , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Genotype , Homeodomain Proteins , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , PrognosisABSTRACT
An outstanding challenge in condensed-matter-physics research over the past three decades has been to understand the pseudogap (PG) phenomenon of the high-transition-temperature (high-Tc) copper oxides. A variety of experiments have indicated a symmetry-broken state below the characteristic temperature T* (refs. 1-8). Among them, although the optical study5 indicated the mesoscopic domains to be small, all these experiments lack nanometre-scale spatial resolution, and the microscopic order parameter has so far remained elusive. Here we report, to our knowledge, the first direct observation of topological spin texture in an underdoped cuprate, YBa2Cu3O6.5, in the PG state, using Lorentz transmission electron microscopy (LTEM). The spin texture features vortex-like magnetization density in the CuO2 sheets, with a relatively large length scale of about 100 nm. We identify the phase-diagram region in which the topological spin texture exists and demonstrate the ortho-II oxygen order and suitable sample thickness to be crucial for its observation by our technique. We also discuss an intriguing interplay observed among the topological spin texture, PG state, charge order and superconductivity.
ABSTRACT
Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
Subject(s)
Neoplasms , Pericytes , Humans , Pericytes/pathology , Pericytes/physiology , Soluble Guanylyl Cyclase , Endothelial Cells/physiology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neoplasms/genetics , Neoplasms/pathology , Guanylate Cyclase , Tumor MicroenvironmentABSTRACT
Crossovers create genetic diversity and are required for equal chromosome segregation during meiosis. Crossover number and distribution are highly regulated by different mechanisms that are not yet fully understood, including crossover interference. The chromosome axis is crucial for crossover formation. Here, we explore the function of the axis protein ASYNAPSIS3. To this end, we use the allotetraploid species Brassica napus; due to its polyploid nature, this system allows a fine-grained dissection of the dosage of meiotic regulators. The simultaneous mutation of all four ASY3 alleles results in defective synapsis and drastic reduction of crossovers, which is largely rescued by the presence of only one functional ASY3 allele. Crucially, while the number of class I crossovers in mutants with two functional ASY3 alleles is comparable to that in wild type, this number is significantly increased in mutants with only one functional ASY3 allele, indicating that reducing ASY3 dosage increases crossover formation. Moreover, the class I crossovers on each bivalent in mutants with one functional ASY3 allele follow a random distribution, indicating compromised crossover interference. These results reveal the distinct dosage-dependent effects of ASY3 on crossover formation, and provide insights into the role of the chromosome axis in patterning recombination.
ABSTRACT
Complex concentrated solutions of multiple principal elements are being widely investigated as high- or medium-entropy alloys (HEAs or MEAs)1-11, often assuming that these materials have the high configurational entropy of an ideal solution. However, enthalpic interactions among constituent elements are also expected at normal temperatures, resulting in various degrees of local chemical order12-22. Of the local chemical orders that can develop, chemical short-range order (CSRO) is arguably the most difficult to decipher and firm evidence of CSRO in these materials has been missing thus far16,22. Here we discover that, using an appropriate zone axis, micro/nanobeam diffraction, together with atomic-resolution imaging and chemical mapping via transmission electron microscopy, can explicitly reveal CSRO in a face-centred-cubic VCoNi concentrated solution. Our complementary suite of tools provides concrete information about the degree/extent of CSRO, atomic packing configuration and preferential occupancy of neighbouring lattice planes/sites by chemical species. Modelling of the CSRO order parameters and pair correlations over the nearest atomic shells indicates that the CSRO originates from the nearest-neighbour preference towards unlike (V-Co and V-Ni) pairs and avoidance of V-V pairs. Our findings offer a way of identifying CSRO in concentrated solution alloys. We also use atomic strain mapping to demonstrate the dislocation interactions enhanced by the CSROs, clarifying the effects of these CSROs on plasticity mechanisms and mechanical properties upon deformation.
ABSTRACT
Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.
Subject(s)
Adipocytes/metabolism , Energy Metabolism , Interleukin-27/metabolism , Thermogenesis , Animals , Bariatric Surgery , Disease Models, Animal , Female , Humans , Insulin Resistance , Interleukin-27/blood , Interleukin-27/therapeutic use , Male , Mice , Obesity/blood , Obesity/drug therapy , Obesity/metabolism , Obesity/prevention & control , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Receptors, Interleukin/metabolism , Signal Transduction , Uncoupling Protein 1/biosynthesis , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.
Subject(s)
Fluorescent Dyes , Precision Medicine , Cell Line, Tumor , Drug Delivery Systems , Fluorescence , Theranostic NanomedicineABSTRACT
The liquid-like feature of thermoelectric superionic conductors is a double-edged sword: the long-range migration of ions hinders the phonon transport, but their directional segregation greatly impairs the service stability. We report the synergetic enhancement in figure of merit (ZT) and stability in Cu1.99Se-based superionic conductors enabled by ion confinement effects. Guided by density functional theory and nudged elastic band simulations, we elevated the activation energy to restrict ion migrations through a cation-anion co-doping strategy. We reduced the carrier concentration without sacrificing the low thermal conductivity, obtaining a ZT of â¼3.0 at 1,050 K. Notably, the fabricated device module maintained a high conversion efficiency of up to â¼13.4% for a temperature difference of 518 K without obvious degradation after 120 cycles. Our work could be generalized to develop electrically and thermally robust functional materials with ionic migration characteristics.
ABSTRACT
B1 and B2 B cells differ in their ability to respond to T-cell-independent (TI) antigens. Here we report that the Src-family kinase (SFK) regulator CD148 has a unique and critical role in the initiation of B1 but not B2 cell antigen receptor signaling. CD148 loss-of-function mice were found to have defective B1 B-cell-mediated antibody responses against the T-cell-independent antigens NP-ficoll and Pneumovax 23 and had impaired selection of the B1 B cell receptor (BCR) repertoire. These deficiencies were associated with a decreased ability of B1 B cells to induce BCR signaling downstream of the SFK Lyn. Notably, Lyn appeared to be selectively regulated by CD148 and loss of this SFK resulted in opposite signaling phenotypes in B1 and B2 B cells. These findings reveal that the function and regulation of Lyn during B1 cell BCR signaling is distinct from other B cell subsets.
Subject(s)
B-Lymphocyte Subsets/immunology , Lymphocyte Activation/immunology , Receptors, Antigen, B-Cell/immunology , src-Family Kinases/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Enzyme-Linked Immunospot Assay , Flow Cytometry , Mice , Mice, Knockout , Receptor-Like Protein Tyrosine Phosphatases, Class 3/immunology , Signal Transduction/immunologyABSTRACT
Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.
Subject(s)
MicroRNAs , Multiple Trauma , Humans , Mice , Animals , Toll-Like Receptor 7/metabolism , Disease Models, Animal , MicroRNAs/genetics , Inflammation/genetics , Cytokines/metabolismABSTRACT
Pelvic organ prolapse (POP) is a group of diseases caused by extracellular matrix (ECM) degradation in pelvic supportive tissues. Cysteine and serine rich nuclear protein 1 (CSRNP1) is involved in cell proliferation and survival regulation, and reportedly facilitates collagen breakdown in human chondrocytes. The present study aimed to probe the effect of CSRNP1 on collagen metabolism in human-derived vaginal fibroblasts. High expression of CSRNP1 was found in POP patient-derived vaginal fibroblasts in comparison to normal-derived vaginal fibroblasts. Following functional experiments revealed that CSRNP1 overexpression led to proliferation inhibition, apoptosis and collagen degradation in normal vaginal fibroblasts. In line with this, silencing of CSRNP1 inhibited hydrogen peroxide (H2O2)-triggered apoptosis, ROS generation and collagen loss in normal vaginal fibroblasts. Silencing of CSRNP1 also reduced the expression of cell senescence markers p21 and γ-H2Ax (the histone H2Ax phosphorylated at Ser139), as well as curbed collagen breakdown in normal vaginal fibroblasts caused by a DNA damage agent etoposide. Transcriptomic analysis of vaginal fibroblasts showed that differentially expressed genes affected by CSRNP1 overexpression were mainly enriched in the Wnt signaling pathway. Treatment with a Wnt pathway inhibitor DKK1 blocked CSRNP1 knockdown-caused collagen deposition. Mechanistically, CSRNP1 was identified to be a target of Snail family transcriptional repressor 2 (SNAI2). Forced expression of CSRNP1 reversed the anti-apoptotic, anti-senescent and anti-collagen loss effects of SNAI2 in normal vaginal fibroblasts exposed to H2O2 or etoposide. Our study indicates that the SNAI2/CSRNP1 axis may be a key driver in POP progression, which provides a potential therapeutic strategy for POP.
Subject(s)
Apoptosis , Cellular Senescence , Collagen , DNA Damage , Fibroblasts , Oxidative Stress , Vagina , Female , Humans , Apoptosis/genetics , Cell Proliferation , Cells, Cultured , Cellular Senescence/genetics , Collagen/metabolism , Fibroblasts/metabolism , Gene Silencing , Hydrogen Peroxide/pharmacology , Pelvic Organ Prolapse/metabolism , Pelvic Organ Prolapse/genetics , Pelvic Organ Prolapse/pathology , Snail Family Transcription Factors/metabolism , Snail Family Transcription Factors/genetics , Vagina/metabolism , Vagina/cytology , Vagina/pathologyABSTRACT
Genetic screening based on the clustered regularly interspaced palindromic repeat (CRISPR) system has been indicated to be a powerful tool for identifying regulatory genes or cis-elements. However, when applying CRISPR screens to pinpoint functional elements at particular loci, a large number of guide RNA (gRNA) spacers may be required to achieve saturated coverage. Here, we present a controlled template-dependent elongation (CTDE) method relying on reversible terminators to synthesize gRNA libraries with genomic regions of interest. By applying this approach to H3K4me3 chromatin immunoprecipitation (ChIP)-derived DNA of mammalian cells, mega-sized gRNA libraries were synthesized in a tissue-specific manner, with which we conducted screening experiments to annotate essential sites for cell proliferation. Additionally, we confirmed that an essential site within the intron of LINC00339 regulates its own mRNA and that LINC00339 is a novel regulator of the cell cycle that maintains HepG2 proliferation. The CTDE method has the potential to be automated with high efficiency at low cost, and will be widely used to identify functional elements in mammalian genomes.
Subject(s)
Gene Library , Genome , Histones , Mammals , RNA, Guide, CRISPR-Cas Systems , Animals , Humans , Cell Proliferation , Chromatin Immunoprecipitation , Clustered Regularly Interspaced Short Palindromic Repeats , CRISPR-Cas Systems , DNA/genetics , Genome/genetics , Genomics , Hep G2 Cells , Histones/genetics , Mammals/genetics , Organ Specificity , Cell Cycle/genetics , AutomationABSTRACT
BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown. METHODS: Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed. RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1α (pyruvate dehydrogenase complex E1 subunit α) and improved abnormal pyruvate metabolism and mitochondrial dysfunction. CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.
Subject(s)
Cardiomyopathies , Mitochondrial Diseases , Protein Kinases , Sepsis , Animals , Child , Humans , Mice , Cardiomyopathies/etiology , Cardiomyopathies/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Myocardium/metabolism , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Pyruvates/metabolism , Sepsis/complications , Sepsis/metabolismABSTRACT
BACKGROUND: Drug-drug interactions (DDI) are prevalent in combination therapy, necessitating the importance of identifying and predicting potential DDI. While various artificial intelligence methods can predict and identify potential DDI, they often overlook the sequence information of drug molecules and fail to comprehensively consider the contribution of molecular substructures to DDI. RESULTS: In this paper, we proposed a novel model for DDI prediction based on sequence and substructure features (SSF-DDI) to address these issues. Our model integrates drug sequence features and structural features from the drug molecule graph, providing enhanced information for DDI prediction and enabling a more comprehensive and accurate representation of drug molecules. CONCLUSION: The results of experiments and case studies have demonstrated that SSF-DDI significantly outperforms state-of-the-art DDI prediction models across multiple real datasets and settings. SSF-DDI performs better in predicting DDI involving unknown drugs, resulting in a 5.67% improvement in accuracy compared to state-of-the-art methods.
Subject(s)
Artificial Intelligence , Deep Learning , Drug InteractionsABSTRACT
The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.
ABSTRACT
Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti-inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine-induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE-induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF-κB) activity, and the production of interleukin-1ß (IL1ß) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF-κB signaling and the production of IL1ß. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF-κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.
Subject(s)
Epilepsy , Sirtuin 3 , Status Epilepticus , Animals , Humans , Mice , Astrocytes/metabolism , Epilepsy/metabolism , Hippocampus/metabolism , NF-kappa B/metabolism , Signal Transduction , Sirtuin 3/metabolism , Status Epilepticus/chemically induced , Status Epilepticus/metabolismABSTRACT
Centromeres are no longer considered to be silent. Both centromeric and pericentric transcription have been discovered, and their RNA transcripts have been characterized and probed for functions in numerous monocentric model organisms recently. Here, we will discuss the challenges in centromere transcription studies due to the repetitive nature and sequence similarity in centromeric and pericentric regions. Various technological breakthroughs have helped to tackle these challenges and reveal unique features of the centromeres and pericentromeres. We will briefly introduce these techniques, including third-generation long-read DNA and RNA sequencing, protein-DNA and RNA-DNA interaction detection methods, and epigenomic and nucleosomal mapping techniques. Interestingly, some newly analyzed repeat-based holocentromeres also resemble the architecture and the transcription behavior of monocentromeres. We will summarize evidences that support the functions of the transcription process and stalling, and those that support the functions of the centromeric and pericentric RNAs. The processing of centromeric and pericentric RNAs into multiple variants and their diverse structures may also provide clues to their functions. How future studies may address the separation of functions of specific centromeric transcription steps, processing pathways, and the transcripts themselves will also be discussed.
Subject(s)
Centromere , Transcription, Genetic , Centromere/genetics , Nucleosomes/genetics , Base Sequence , RNAABSTRACT
Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.
ABSTRACT
Maternal poor sleep quality may increase blood pressure during pregnancy, but sound evidence is still limited and inconsistent. To evaluate whether sleep disturbances in early gestation are risk factors for the development of hypertensive disorders of pregnancy, we conducted the Early Life Plan Project from June 2016 to December 2019. Maternal sleep patterns were assessed at 12-16 weeks of gestation by using the Pittsburgh Sleep Quality Index questionnaire. For gestational hypertension and preeclampsia, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using multinomial logistic regression models adjusting for potential confounders. Among 5,532 eligible women, we observed that maternal blood pressure in early gestation was significantly higher in women with low sleep efficiency (≤85%), long sleep duration (≥9 hours/night), and snoring. Compared with nonsnorers, snoring in early gestation was independently associated with preeclampsia (OR = 1.72 (95% CI: 1.09, 2.73) for snoring once or twice per week; OR = 2.06 (95% CI: 1.01, 4.31) for snoring 3 or more times per week), particularly for term preeclampsia (OR = 1.79 (95% CI: 1.08, 2.95) and 2.26 (95% CI: 1.03, 4.95), respectively). Results suggest that snoring in early gestation may be a significant risk factor for preeclampsia, with a dose-response pattern.
Subject(s)
Hypertension, Pregnancy-Induced , Pre-Eclampsia , Sleep Wake Disorders , Pregnancy , Female , Humans , Hypertension, Pregnancy-Induced/epidemiology , Pre-Eclampsia/epidemiology , Pre-Eclampsia/etiology , Snoring/complications , Snoring/epidemiology , Prospective Studies , Sleep Wake Disorders/complications , Sleep Wake Disorders/epidemiology , SleepABSTRACT
BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.