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Current Medical Science Jun 2024Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular...
OBJECTIVE
Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition.
METHODS
Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets.
RESULTS
Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells.
CONCLUSION
Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.
Topics: Humans; Leukemia, Myeloid, Acute; MicroRNAs; SOXC Transcription Factors; RNA, Circular; Male; Female; Middle Aged; Apoptosis; Prognosis; Cell Proliferation; Cell Line, Tumor; Disease Progression; Adult; Gene Expression Regulation, Leukemic; Up-Regulation
PubMed: 38842772
DOI: 10.1007/s11596-024-2878-y -
Cureus May 2024Epithelial-myoepithelial carcinoma (EMC) is a rare tumor, characterized by two different cell populations and both demonstrate a malignant nature microscopically. It...
Epithelial-myoepithelial carcinoma (EMC) is a rare tumor, characterized by two different cell populations and both demonstrate a malignant nature microscopically. It constitutes less than 2% of all salivary gland malignancies. The World Health Organization (WHO) has classified this disease as a separate pathological category. The diagnosis of this tumor is arrived by biopsy. It shows slow growth and is small in size; it appears in ulcerative form of mucosa in some cases. Gland cells consist of two layers of outer myoepithelium cells and inner epithelial cells. Vimentin staining is positive. It shows calponin, muscle-specific actin, S100, smooth muscle actin, p63, and smooth muscle myosin heavy chain I. Examining different sets of data reveals that tumors exhibiting a solid growth pattern, nuclear atypia, DNA aneuploidy, and increased proliferative activity typically display a more aggressive nature, accompanied by a heightened likelihood of local recurrences and metastases. The clinical and radiological observations frequently resemble those of a benign tumor. Due to the uncommon nature of EMC, there is currently no established standard treatment protocol. It is considered a low-grade tumor where good resection holds better results. Individuals displaying histopathological indicators of aggressive disease should be evaluated for potential adjuvant radiotherapy. We present a case of a patient who had recurrence twice in a period of seven years despite surgical management, chemotherapy, and radiotherapy.
PubMed: 38841034
DOI: 10.7759/cureus.59701 -
Drug Metabolism and Disposition: the... Jun 2024This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450...
This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450 1B1 (CYP1B1) and arachidonic acid (AA) metabolites. Currently there is no evidence to suggest that cannflavin-C; a prenylated flavonoid, has any significant effects on the heart or cardiac hypertrophy. The metabolism of arachidonic acid (AA) into midchain hydroxyeicosatetraenoic acids (HETEs), facilitated by CYP1B1 enzyme, plays a role in the development of cardiac hypertrophy which is marked by enlarged cardiac cells. Adult human ventricular cardiomyocytes cell line (AC16) were cultured and exposed to cannflavin-C in the presence and absence of Ang II. The assessment of mRNA expression pertaining to cardiac hypertrophic markers and CYPs was conducted via real-time polymerase chain reaction (PCR) while the quantification of CYPs protein levels was carried out through western blot analysis. Ang II induced hypertrophic markers myosin heavy chain (β/α-MHC), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) and increased cell surface area, while cannflavin-C mitigated these effects. Gene and protein expression analysis revealed that cannflavin-C downregulated CYP1B1 gene expression, protein level as well as the enzyme activity assessed by 7-methoxyresorufin O-deethylase (MROD). Arachidonic acid metabolites analysis, using LC-MS/MS, demonstrated that Ang II increased midchain (R/S)-HETEs concentrations, which were attenuated by cannflavin-C. This study provides novel insights into the potential of cannflavin-C in modulating arachidonic acid metabolites and attenuating Ang II-induced cardiac hypertrophy, highlighting the importance of this compound as potential therapeutic agents for cardiac hypertrophy. This study demonstrates that cannflavin-C offers protection against cellular hypertrophy induced by Ang II. The significance of this research lies in its novel discovery, which elucidates a mechanistic pathway involving the inhibition of CYP 1B1 by cannflavin-C. This discovery opens up new avenues for leveraging this compound in the treatment of heart failure.
PubMed: 38839111
DOI: 10.1124/dmd.124.001705 -
Frontiers in Immunology 2024Infectious diseases continue to pose significant global health challenges. In addition to the enduring burdens of ailments like malaria and HIV, the emergence of... (Review)
Review
Infectious diseases continue to pose significant global health challenges. In addition to the enduring burdens of ailments like malaria and HIV, the emergence of nosocomial outbreaks driven by antibiotic-resistant pathogens underscores the ongoing threats. Furthermore, recent infectious disease crises, exemplified by the Ebola and SARS-CoV-2 outbreaks, have intensified the pursuit of more effective and efficient diagnostic and therapeutic solutions. Among the promising options, antibodies have garnered significant attention due to their favorable structural characteristics and versatile applications. Notably, nanobodies (Nbs), the smallest functional single-domain antibodies of heavy-chain only antibodies produced by camelids, exhibit remarkable capabilities in stable antigen binding. They offer unique advantages such as ease of expression and modification and enhanced stability, as well as improved hydrophilicity compared to conventional antibody fragments (antigen-binding fragments (Fab) or single-chain variable fragments (scFv)) that can aggregate due to their low solubility. Nanobodies directly target antigen epitopes or can be engineered into multivalent Nbs and Nb-fusion proteins, expanding their therapeutic potential. This review is dedicated to charting the progress in Nb research, particularly those derived from camelids, and highlighting their diverse applications in treating infectious diseases, spanning both human and animal contexts.
Topics: Animals; Single-Domain Antibodies; Humans; Camelidae; Communicable Diseases; Camelids, New World; COVID-19
PubMed: 38827746
DOI: 10.3389/fimmu.2024.1334829 -
BioRxiv : the Preprint Server For... May 2024We sought to examine how resistance exercise (RE), cycling exercise, and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation in humans. In the first...
We sought to examine how resistance exercise (RE), cycling exercise, and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation in humans. In the first study (1boutRE), younger adult men (n=8; 5±2 years of RE experience) performed a lower body RE bout with vastus lateralis (VL) biopsies obtained immediately before, 3-, and 6-hours post-exercise. In the second study (10weekRT), VL biopsies were obtained in untrained younger adults (n=36, 18 men and 18 women) before and 24 hours (24h) after their first/naïve RE bout. These participants also engaged in 10 weeks (24 sessions) of resistance training and donated VL biopsies before and 24h after their last RE bout. VL biopsies were also examined from a third acute cycling study (n=7) and a fourth study involving two weeks of leg immobilization (n=20, 15 men and 5 women) to determine how MyHC fragmentation was affected. In the 1boutRE study, the fragmentation of all MyHC isoforms (MyHC) increased 3 hours post-RE (~ +200%, p=0.018) and returned to pre-exercise levels by 6 hours post-RE. Immunoprecipitation of MyHC revealed ubiquitination levels remained unaffected at the 3- and 6-hour post-RE time points. Interestingly, a greater increase in magnitude for MyHC type IIa versus I isoform fragmentation occurred 3-hours post-RE (8.6±6.3-fold versus 2.1±0.7-fold, p=0.018). In all 10weekRT participants, the first/naïve and last RE bouts increased MyHC fragmentation 24h post-RE (+65% and +36%, respectively; p<0.001); however, the last RE bout response was attenuated compared to the first bout (p=0.045). The first/naïve bout response was significantly elevated in females only (p<0.001), albeit females also demonstrated a last bout attenuation response (p=0.002). Although an acute cycling bout did not alter MyHC fragmentation, ~8% VL atrophy with two weeks of leg immobilization led to robust MyHC fragmentation (+108%, p<0.001), and no sex-based differences were observed. In summary, RE and disuse atrophy increase MyHC protein fragmentation. A dampened response with 10 weeks of resistance training, and more refined responses in well-trained men, suggest this is an adaptive process. Given the null polyubiquitination IP findings, more research is needed to determine how MyHC fragments are processed. Moreover, further research is needed to determine how aging and disease-associated muscle atrophy affect these outcomes, and whether MyHC fragmentation is a viable surrogate for muscle protein turnover rates.
PubMed: 38826385
DOI: 10.1101/2024.05.24.595789 -
American Journal of Physiology. Cell... Jun 2024In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA...
In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA Polymerase Mu (POLM) , especially G312R mutation, in propelling oncogenesis through dual pathways. POLM markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. Additionally, our research reveals that POLM perturbs Collagen alpha-1 (XI) chain (COL11A1) expression-a gene plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression.
PubMed: 38826139
DOI: 10.1152/ajpcell.00025.2024 -
Biochemical Pharmacology Jul 2024Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40...
Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40 neutralizing antibody and characterize its potentially therapeutic signature. We utilized in silico CDR-grafting bioinformatics to replace the complementarity determining regions (CDRs) of human IgG1 with mouse CDRs of our previously established anti-YKL-40 antibody (mAY). In fifteen candidates (VL1-3/VH1-5) of heavy and light chain variable region combination, one antibody L3H4 named Rosazumab demonstrated strong binding affinity with YKL-40 (K = 4.645 × 10 M) and high homology with human IgG (80 %). In addition, we established different overlapping amino acid peptides of YKL-40 and found that Rosazumab specifically bound to residues K337, K342, and R344, the KR-rich functional domain of YKL-40. Rosazumab inhibited migration and tube formation of YKL-40-expressing tumor cells and induced tumor cell apoptosis. Mechanistically, Rosazumab induced interaction of N-cadherin with β-catenin and activation of downstream MST1/RASSF1/Histone H2B axis, leading to chromosomal DNA breakage and cell apoptosis. Treatment of xenografted tumor mice with Rosazumab twice a week for 4 weeks inhibited tumor growth and angiogenesis, but induced tumor apoptosis. Rosazumab injected in mice distributed to blood, tumor, and other multiple organs, but did not impact in function or structure of liver and kidney, indicating non-detectable toxicity in vivo. Collectively, the study is the first one to demonstrate that a humanized YKL-40 neutralizing antibody offers a valuable means to block tumor development.
Topics: Animals; Humans; Chitinase-3-Like Protein 1; Mice; Female; Xenograft Model Antitumor Assays; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Mice, Nude; Neoplasms; Antibodies, Neutralizing
PubMed: 38824968
DOI: 10.1016/j.bcp.2024.116335 -
Molecular Therapy : the Journal of the... May 2024Single monoclonal antibodies (mAbs) can be expressed in vivo through gene delivery of their mRNA formulated with lipid nanoparticles (LNPs). However, delivery of a mAb...
Single monoclonal antibodies (mAbs) can be expressed in vivo through gene delivery of their mRNA formulated with lipid nanoparticles (LNPs). However, delivery of a mAb combination could be challenging due to the risk of heavy and light variable chain mispairing. We evaluated the pharmacokinetics of a three mAb combination against Staphylococcus aureus first in single chain variable fragment scFv-Fc and then in immunoglobulin G 1 (IgG1) format in mice. Intravenous delivery of each mRNA/LNP or the trio (1 mg/kg each) induced functional antibody expression after 24 h (10-100 μg/mL) with 64%-78% cognate-chain paired IgG expression after 3 days, and an absence of non-cognate chain pairing for scFv-Fc. We did not observe reduced neutralizing activity for each mAb compared with the level of expression of chain-paired mAbs. Delivery of the trio mRNA protected mice in an S. aureus-induced dermonecrosis model. Intravenous administration of the three mRNA in non-human primates achieved peak serum IgG levels ranging between 2.9 and 13.7 μg/mL with a half-life of 11.8-15.4 days. These results suggest nucleic acid delivery of mAb combinations holds promise and may be a viable option to streamline the development of therapeutic antibodies.
PubMed: 38822525
DOI: 10.1016/j.ymthe.2024.05.036 -
European Journal of Ophthalmology May 2024To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal...
PURPOSE
To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD).
OBSERVATIONS
Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss.
CONCLUSIONS AND IMPORTANCE
Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.
PubMed: 38815990
DOI: 10.1177/11206721241257553 -
Cureus May 2024A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was...
A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was less than 10%. Transthoracic echocardiography and cardiovascular magnetic resonance (CMR) imaging also revealed severe bicuspid aortic valve stenosis, dilated cardiomyopathy with LV hypertrophy, prominent LV trabeculations, and features suggestive of mild myocarditis with active inflammation. While myocarditis was suspected on CMR imaging, his mild degree of myocardial involvement did not explain the entirety of his clinical presentation, degree of LV dysfunction, or other structural abnormalities. An extensive work-up for his LV dysfunction was unremarkable for ischemic, metabolic, infiltrative, infectious, toxic, oncologic, connective tissue, and autoimmune etiologies. Genetic testing was positive for a () variant, which was deemed likely to be a unifying etiology underlying his presentation. The sarcomere gene allows beta-myosin expression in heart ventricles, with variants associated with hypertrophic and dilated cardiomyopathies, congenital heart diseases, myocarditis, and excessive trabeculation (formerly known as left ventricular noncompaction). This case highlights the diverse array of cardiac pathologies that can present with gene variants and reviews an extensive work-up for this unusual presentation of heart failure in a young patient.
PubMed: 38813076
DOI: 10.7759/cureus.61252