The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.

The intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in atherosclerosis pathogenesis. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. Here, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima. Partial ligation of the left carotid artery (LCA) was performed in C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected 2 days and 2 weeks after surgery to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. The chronic effects of d-flow were decoupled from the ensuing arterial wall stiffening by administration of β-aminopropionitrile (BAPN), an inhibitor of collagen crosslinking by lysyl oxidase (LOX) enzymes. Atomic force microscopy (AFM) was used to determine stiffness of the endothelium and the denuded subendothelial matrix in carotid preparations. The stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels was also determined. Acute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. In addition, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels. We conclude that chronic d-flow results in marked stiffening of the arterial intima, which can be effectively prevented by inhibition of collagen crosslinking.

Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days ( < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.

Cerebral palsy (CP) is a prevalent motor disorder originating from early brain injury or malformation, with significant variability in its clinical presentation and etiology. Early diagnosis and personalized therapeutic interventions are hindered by the lack of reliable biomarkers. This study aims to identify potential biomarkers for cerebral palsy and develop predictive models to enhance early diagnosis and prognosis. We conducted a comprehensive bioinformatics analysis of gene expression profiles in muscle samples from CP patients to identify candidate biomarkers. Six key genes (CKMT2, TNNT2, MYH4, MYH1, GOT1, and LPL) were validated in an independent cohort, and potential biological pathways and molecular networks involved in CP pathogenesis were analyzed. The importance of processes such as functional regulation, energy metabolism, and cell signaling pathways in the muscles of CP patients was emphasized. Predictive models of muscle sample biomarkers related to CP were developed and visualized. Calibration curves and receiver operating characteristic analysis demonstrated that the predictive models exhibit high sensitivity and specificity in distinguishing individuals at risk of CP. The identified biomarkers and developed prediction models offer significant potential for early diagnosis and personalized management of CP. Future research should focus on validating these biomarkers in larger cohorts and integrating them into clinical practice to improve outcomes for individuals with CP.

Fructose and lactate are present in high concentrations in uterine luminal fluid, fetal fluids and fetal blood of ungulates and cetaceans, but their roles have been ignored and they have been considered waste products of pregnancy. This review provides evidence for key roles of both fructose and lactate in support of key metabolic pathways required for growth and development of fetal-placental tissues, implantation and placentation. The uterus and placenta of ungulates convert glucose to fructose via the polyol pathway. Fructose is sequestered within the uterus and cannot be transported back into the maternal circulation. Fructose is phosphorylated by ketohexokinase to fructose-1-PO4 (F1P) by that is metabolized via the fructolysis pathway to yield dihydoxyacetone phosphate and glyceraldehyde-3-PO4 that are downstream of phosphofructokinase. Thus, there is no inhibition of the fructolysis pathway by low pH, citrate or ATP which allows F1P to continuously generate substrates for the pentose cycle, hexosamine biosynthesis pathway, one-carbon metabolism and tricarboxylic acid cycle, as well as lactate. Lactate sustains the activity of hypoxia-inducible factor alpha and its downstream targets such as vascular endothelial growth factor to increase utero-placental blood flow critical to growth and development of the fetal-placental tissues and a successful outcome of pregnancy. Pregnancy has been referred to as a controlled cancer and this review addresses similarities regarding metabolic aspects of tumors and the placenta.

Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating immune cells remains largely unknown. This study aimed to investigate the role of SE-controlled genes in regulating the interactions between DLBCL cells and tumor-infiltrating immune cells. Single-cell RNA-seq, bulk RNA-seq and H3K27ac ChIP-seq data were downloaded from the Heidelberg Open Research Data database and Gene Expression Omnibus database. HOMER algorithm and Seurat package in R were used for bioinformatics analysis. Cell proliferation and lactate dehydrogenase (LDH) release was detected by MTS and LDH release assays, respectively. Interaction between B cell cluster and CD8 T cell and NK cell cluster was most obviously enhanced in DLBCL, with CD70-CD27, MIF-CD74/CXCR2 complex, MIF-CD74/CD44 complex and CCL3-CCR5 interactions were significantly increased. NK cell sub-cluster showed the strongest interaction with B cell cluster. ZZZ3 upregulated the transcription of by binding to its SE. Silencing CD70 in DOHH2 cells significantly promoted the proliferation of co-cultured NK92 cells and LDH release from DOHH2 cells, which was counteracted by ZZZ3 overexpression in DOHH2 cells. CD70 silencing combined with PD-L1 blockade promoted LDH release from DOHH2 cells co-cultured with NK92 cells. In conclusion, DLBCL cells inhibited the proliferation and killing of infiltrating NK cells by regulating ZZZ3/CD70 axis. Targeting ZZZ3/CD70 axis combined with PD-L1 blockade is expected to be a promising strategy for DLBCL treatment.

Observational studies have linked autoimmune diseases (ADs) with rhinosinusitis (RS) manifestations. To establish a causal relationship between ADs and RS, and to explore the potential mediating role of inflammatory mediators between ADs and RS, we utilized Mendelian randomization (MR) analysis. Using a two-sample MR methodology, we examined the causality between multiple sclerosis (MS), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (PsO), type 1 diabetes (T1D), Sjogren's syndrome (SS), celiac disease (CeD), Crohn's disease (CD), hypothyroidism (HT), Graves' disease (GD), and Hashimoto's thyroiditis and their association with chronic and acute rhinosinusitis (CRS and ARS, respectively).To achieve this, we employed three distinct MR techniques: inverse variance weighting (IVW), MR-Egger, and the weighted median method. Our analysis also included a variety of sensitivity assessments, such as Cochran's Q test, leave-one-out analysis, MR-Egger intercept, and MR-PRESSO, to ensure the robustness of our findings. Additionally, the study explored the role of inflammation proteins as a mediator in these relationships through a comprehensive two-step MR analysis. Among the ADs, MS, RA, T1D, CeD, and HT were determined as risk factors for CRS. Only CeD exhibited a causal relationship with ARS. Subsequent analyses identified interleukin-10 (IL-10) as a potential mediator for the association of MS, RA and HT with CRS, respectively., while C-X-C motif chemokine 10 levels (CXCL10) and T-cell surface glycoprotein CD6 isoform levels (CD6) were found to influence HT's effect on CRS. Our findings demonstrate a causative link between specific autoimmune diseases and rhinosinusitis, highlighting IL-10, CXCL10, and CD6 as potential mediators in this association.

Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but the recurrence rate remains high due to angiogenesis in residual cancer cells. We used thermal stimulation to simulate the post-RFA microenvironment. The expression profile of circRNAs between normal control HCC cell-derived exosomes and exosomes after heat stimulation were analyzed by RNA sequencing. Quantitative real-time PCR was applied to evaluate the expression of circPTPRK in exosomes and human umbilical vein endothelial cells (HUVECs). Then, the functions of heat-stimulated HCC cell-derived exosomes and exosomal circPTPRK on HUVECs were unveiled. Transcriptome sequencing was utilized to determine targeted genes of circPTPRK. Heat-stimulated HCC cell-derived exosomes augmented cell proliferation, migration, and angiogenesis of HUVECs. In total, 229 differentially expressed circRNAs were obtained, including 211 upregulated circRNAs and 18 downregulated circRNAs in heat-stimulated HCC cell-derived exosomes. The expression of circPTPRK was remarkably increased in heat-stimulated HCC cell-derived exosomes and the HUVECs incubated with them. Heat-stimulated HCC cell-derived exosomes with circPTPRK knockdown significantly inhibited cell proliferation, migration, and angiogenesis of HUVECs. Mechanistic studies indicated that PLA2G4E is a downstream target of circPTPRK, and PLA2G4E overexpression reversed the inhibitory effect of circPTPRK knockdown on HUVEC angiogenesis. Our results indicated that exosomal circPTPRK activated HUVEC angiogenesis by upregulating PLA2G4E expression.

Traumatic spinal cord injury (SCI) is a devastating and complex condition to treat with no curative options. In the past few decades, rapid advancements in our understanding of SCI pathophysiology as well as the mergence of new treatments has created more optimism. Focusing on clinical translation, this paper provides a comprehensive overview of SCI through its epidemiology, pathophysiology, currently employed management strategies, and emerging therapeutic approaches. Additionally, it emphasizes the importance of addressing the heavy quality of life (QoL) challenges faced by SCI patients and their desires, providing a basis to tailor patient-centric forms of care. Furthermore, this paper discusses the frequently encountered barriers in translation from preclinical models to clinical settings. It also seeks to summarize significant completed and ongoing SCI clinical trials focused on neuroprotective and neuroregenerative strategies. While developing a cohesive regenerative treatment strategy remains challenging, even modest improvements in sensory and motor function can offer meaningful benefits and motivation for patients coping with this highly debilitating condition.

Current pneumococcal vaccines, including the pneumococcal polysaccharide (PPV23) and conjugate (PCV13) vaccines, offer protection against specific serotypes but pose risks of serotype replacement that can alter the composition of the nasopharyngeal microbiota. To address this challenge, a novel strategy has been proposed to provide effective protection without disrupting the colonization of other bacterial populations. In our study, we found that subcutaneous immunization with recombinant peptidoglycan N-acetylglucosamine deacetylase A (rPgdA) elicited robust humoral and cellular immune responses, significantly reducing the invasion of pneumoniae in the lungs without affecting nasopharyngeal carriage. Furthermore, rPgdA antisera were shown to diminish bacterial invasion of lung epithelial cells . Notably, sera from patients with invasive pneumococcal infections exhibited higher levels of antibodies against the PgdA protein compared to sera from healthy adults, suggesting that a natural immune response to this protein occurs during infection. These results suggest a promising new target for the development of pneumococcal vaccines.

This study explores the feasibility of quantitative Optical Coherence Tomography Angiography (OCTA) features translated from OCT using generative machine learning (ML) for characterizing vascular changes in retina. A generative adversarial network framework was employed alongside a 2D vascular segmentation and a 2D OCTA image translation model, trained on the OCT-500 public dataset and validated with data from the University of Illinois at Chicago (UIC) retina clinic. Datasets are categorized by scanning range (Field of view) and disease status. Validation involved quality and quantitative metrics, comparing translated OCTA (TR-OCTA) with ground truth OCTAs (GT-OCTA) to assess the feasibility for objective disease diagnosis. In our study, TR-OCTAs showed high image quality in both 3 and 6 mm datasets (high-resolution and contrast quality, moderate structural similarity compared to GT-OCTAs). Vascular features like tortuosity and vessel perimeter index exhibits more consistent trends compared to density features which are affected by local vascular distortions. For the validation dataset (UIC), the metrics show similar trend with a slightly decreased performance since the model training was blind on UIC data, to evaluate inference performance. Overall, this study presents a promising solution to the limitations of OCTA adoption in clinical practice by using vascular features from TR-OCTA for disease detection. By making detailed vascular imaging more widely accessible and reducing reliance on expensive OCTA equipment, this research has the potential to significantly enhance the diagnostic process for retinal diseases.

Prolonged exposure to volatile anesthetics may raise the risk of developing cognitive impairment by acting on gamma-a Aminobutyric acid A receptors (GABAAR). The dentate gyrus plays an important role in the hippocampus and has a high potential for neural plasticity. However, it is unknown whether prolonged anesthesia induces a change in acute phasic or tonic inhibition in dentate gyrus granule cells (DGGCs) by acting on GABAAR. In order to verify the effects of volatile anesthetics on the current in DGGCs, a whole-cell patch was applied to record acute brain slices, and this study indicated that 4 h but not 2 h of isoflurane (ISO) exposure induced significantly larger tonic currents in DGGCs other than hippocampal CA1 pyramidal and thalamic relay neurons. Furthermore, this study demonstrated that the increased tonic current in DGGCs was dependent on the δ subunit-containing GABAARs by using transgenic δ subunit knockout mice. In conclusion, the δ subunit specific GABAAR is the key element that increased acute tonic inhibition in DGGCs of mice after prolonged ISO exposure, which may be one of the mechanisms of ISO neurotoxicity to the developing brain.

Antiretroviral drugs have made significant progress in treating HIV-1 and improving the quality of HIV-1-infected individuals. However, due to their limited permeability into the brain HIV-1 replication persists in brain reservoirs such as perivascular macrophages and microglia, which cause HIV-1-associated neurocognitive disorders. Therefore, it is highly desirable to find a novel therapy that can cross the blood-brain barrier (BBB) and target HIV-1 pathogenesis in brain reservoirs. A recently developed 2-amino-3-methylpentanoic acid [2-morpholin-4-yl-ethyl]-amide (LM11A-31), which is a p75 neutrotrophin receptor (p75) modulator, can cross the BBB. In this study, we examined whether LM11A-31 treatment can suppress HIV-1 replication, oxidative stress, cytotoxicity, and inflammatory response in macrophages. Our results showed that LM11A-31 (100 nM) alone and/or in combination with positive control darunavir (5.5 µM) significantly suppresses viral replication and reduces cytotoxicity. Moreover, the HIV-1 suppression by LM11A-31 was comparable to the HIV-1 suppression by darunavir. Although p75 was upregulated in HIV-1-infected macrophages compared to uninfected macrophages, LM11A-31 did not significantly reduce the p75 expression in macrophages. Furthermore, our study illustrated that LM11A-31 alone and/or in combination with darunavir significantly suppress pro-inflammatory cytokines including IL-1β, IL-8, IL-18, and TNF-α and chemokines MCP-1 in HIV-induced macrophages. The suppression of these cytokines and chemokines by LM11A-31 was comparable to darunavir. In contrast, LM11A-31 did not significantly alter oxidative stress, expression of antioxidant enzymes, or autophagy marker proteins in U1 macrophages. The results suggest that LM11A-31, which can cross the BBB, has therapeutic potential in suppressing HIV-1 and inflammatory response in brain reservoirs, especially in macrophages.

[This corrects the article DOI: 10.1177/15353702231198068.].

HbSC disease, a less severe form of sickle cell disease, affects the retina more frequently and patients have higher rates of proliferative retinopathy that can progress to vision loss. This study aimed to identify differences in the expression of endothelial cell-derived molecules associated with the pathophysiology of proliferative sickle cell retinopathy (PSCR). RNAseq was used to compare the gene expression profile of circulating endothelial colony-forming cells from patients with SC hemoglobinopathy and proliferative retinopathy (n = 5), versus SC patients without retinopathy (n = 3). Real-time polymerase chain reaction (qRT-PCR) was used to validate the RNAseq results. A total of 134 differentially expressed genes (DEGs) were found. DEGs were mainly associated with vasodilatation, type I interferon signaling, innate immunity and angiogenesis. Among the DEGs identified, we highlight the most up-regulated genes (log2FoldChange = 4.32, FDR = 1.35E-11) and (log2FoldChange = 3.36 FDR = 1.59E-07). , an axon-guided receptor, promotes endothelial cell migration and contributes to the development of retinal angiogenesis and pathological ocular neovascularization. Endothelial an amino acid (AA) transporter, regulates developmental and pathological retinal angiogenesis by controlling the uptake of AA nutrient, which may serve as metabolic fuel for the proliferation of endothelial cells (ECs) and consequent promotion of angiogenesis. Our data provide an important step towards elucidating the molecular pathophysiology of PSCR that may explain the differences in ocular manifestations between individuals with hemoglobinopathies and afford insights for new alternative strategies to inhibit pathological angiogenesis.

The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen receptor (AR) is a critical component of the endocrine system, playing a pivotal role in mediating the biological effects of androgens, which are male sex hormones. Exposure to androgen-disrupting chemicals during critical periods of development, such as fetal development or puberty, may result in adverse effects on reproductive health, including altered sexual differentiation, impaired fertility, and an increased risk of reproductive disorders. Therefore, androgenic activity data is critical for chemical risk assessment. A large amount of androgenic data has been generated using various experimental protocols. Moreover, the data are reported in different formats and in diverse sources. To facilitate utilization of androgenic activity data in chemical risk assessment, the Molecules with Androgenic Activity Resource (MAAR) was developed. MAAR is the first open-access platform designed to streamline and enhance the risk assessment of chemicals with androgenic activity. MAAR's development involved the integration of diverse data sources, including data from public databases and mining literature, to establish a reliable and versatile repository. The platform employs a user-friendly interface, enabling efficient navigation and extraction of pertinent information. MAAR is poised to advance chemical risk assessment by offering unprecedented access to information crucial for evaluating the androgenic potential of a wide array of chemicals. The open-access nature of MAAR promotes transparency and collaboration, fostering a collective effort to address the challenges posed by androgenic EDCs.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, having become a global public health problem, so the pathophysiological mechanisms and therapeutic strategies of CVDs need further study. Legumain is a powerful enzyme that is widely distributed in mammals and plays an important role in a variety of biological processes. Recent research suggests that legumain is associated with the occurrence and progression of CVDs. In this review, we provide a comprehensive overview of legumain in the pathogenesis of CVDs. The role of legumain in CVDs, such as carotid atherosclerosis, pulmonary hypertension, coronary artery disease, peripheral arterial disease, aortic aneurysms and dissection, is discussed. The potential applications of legumain as a biomarker of these diseases are also explored. By understanding the role of legumain in the pathogenesis of CVDs, we aim to support new therapeutic strategies to prevent or treat these diseases.

Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by in mice and in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysiology remains to be fully defined. In this review, we mined single-cell and single-nucleus RNA sequencing databases of mouse and human kidneys and found that glomerular parietal epithelial cells (PECs) express a full set of genes encoding proteins needed for cellular vitamin A uptake, intracellular transport, and metabolism into retinoic acid. In particular, mRNAs are selectively enriched in mouse and human PECs. expression in PECs is greatly increased in a mouse model of anti-glomerular basement membrane glomerulonephritis and moderately induced in a mouse model of ischemia-reperfusion acute kidney injury. expression in PECs is substantially repressed in a chronic kidney disease mouse model combining diabetes, hypertension, and partial nephrectomy and is moderately repressed in mouse models of focal segmental glomerulosclerosis and diabetic nephropathy. Single-nucleus RNA sequencing data show that mRNA expression in PECs is diminished in patients with chronic kidney disease associated with diabetes, hypertension and polycystic kidney disease. In addition to data mining, we also performed Spearman's rank correlation coefficient analyses and identified gene transcripts correlated with transcripts in mouse PECs and PEC subtypes, and in human PECs of healthy subjects and patients with AKI or CKD. Furthermore, we conducted Gene Ontology pathway analyses and identified the biological pathways enriched among these -correlated genes. Our data mining and analyses led us to hypothesize that ALDH1A2mediated retinoic acid synthesis in PECs plays a yet-undefined role in the kidney and that its dysregulation mediates injury. Conditional, PEC-selective knockout, RNA silencing and transgenic mouse models will be useful tools to test this hypothesis. Clinical studies on genetics, epigenetics, expression and functions of and other genes needed for retinoic acid biosynthesis and signaling are also warranted.

Cyclin-dependent kinase-like 3 (CDKL3) has been identified as an oncogene in certain types of tumors. Nonetheless, its function in hepatocellular carcinoma (HCC) is poorly understood. In this study, we conducted a comprehensive analysis of CDKL3 based on data from the HCC cohort of The Cancer Genome Atlas (TCGA). Our analysis included gene expression, diagnosis, prognosis, functional enrichment, tumor microenvironment and metabolic characteristics, tumor burden, mRNA expression-based stemness, alternative splicing, and prediction of therapy response. Additionally, we performed a cell counting kit-8 assay, TdT-mediated dUTP nick-end Labeling staining, migration assay, wound healing assay, colony formation assay, and nude mouse experiments to confirm the functional relevance of CDKL3 in HCC. Our findings showed that CDKL3 was significantly upregulated in HCC patients compared to controls. Various bioinformatic analyses suggested that CDKL3 could serve as a potential marker for HCC diagnosis and prognosis. Furthermore, CDKL3 was found to be involved in various mechanisms linked to the development of HCC, including copy number variation, tumor burden, genomic heterogeneity, cancer stemness, and alternative splicing of CDKL3. Notably, CDKL3 was also closely correlated with tumor immune cell infiltration and the expression of immune checkpoint markers. Additionally, CDKL3 was shown to independently function as a risk predictor for overall survival in HCC patients by multivariate Cox regression analysis. Furthermore, the knockdown of CDKL3 significantly inhibited cell proliferation and , indicating its role as an oncogene in HCC. Taken together, our findings suggest that CDKL3 shows promise as a biomarker for the detection and treatment outcome prediction of HCC patients.

This review outlines some of the many approaches taken over a decade or more to repair damaged hearts. We showcase the recent breakthroughs in organ regeneration elicited by reprogramming factors OCT3/4, SOX2, KLF4, and C-MYC (OKSM). Transient OKSM transgene expression rejuvenated senescent organs in mice. OKSM transgenes also caused murine heart cell regeneration. A triplet alanine mutation of the N-terminus of Serum Response Factor's MADS box SRF153(A3), termed STEMIN, and the YAP mutant, YAP5SA synergized and activated OKSM and NANOG in adult rat cardiac myocytes; thus, causing rapid nuclear proliferation and blocked myocyte differentiation. In addition, ATAC seq showed induced expression of growth factor genes , , , and non-canonical Injected STEMIN and YAP5SA synthetic modifying mRNA (mmRNA) into infarcted adult mouse hearts, brought damaged hearts back to near normal contractility without severe fibrosis. Thus, STEMIN and YAP5SA mmRNA may exert additional regenerative potential than OKSM alone for treating heart diseases.