Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Resolution of anti-LGI1-associated autoimmune encephalitis in a patient after treatment with efgartigimod.

BACKGROUND: Anti leucine-rich, glioma inactivated 1 (LGI1) antibody-associated autoimmune encephalitis (AE) is the second most common AE, where the trafficking and recycling of the pathogenic immunoglobulin (IgG) can be controlled by the neonatal crystallizable fragment receptor (FcRn), making the latter as a candidate therapeutic target. Efgartigimod is an antagonist of FcRn, its ability to increase the degradation of IgGs and improve the health and quality of life of patients. ADAPT trail indicated its rapid efficacy and safety on myasthenia gravis. However, there is currently no case reported using efgartigimod for the treatment of anti-LGI1-associated AE. CASE DESCRIPTION: The patient presented with five episodes of generalized tonic-clonic seizures in the past 2 weeks. The patient had no abnormal signs on magnetic resonance imaging. Electroencephalogram examinations showed an increase in bilateral symmetric or asymmetric slow activity, without any clear epileptic waves. The cerebrospinal fluid (CSF) examination results indicated a slight increase in protein (47 mg/dL). The anti-LGI1 antibody titer in serum was 1:100 and that in CSF was 1:3.2. The treatment with intravenous methylprednisolone 1000 mg once a day combined with levetiracetam tablets failed to completely control the patient's seizures. Thus, 10 mg/kg efgartigimod was administered intravenously once a week for 2 weeks. After 2 weeks of treatment, serum levels of anti-LGI1 antibody and IgG decreased and the patient's epilepsy did not recur in the next 3 months. CONCLUSIONS: This is the first case report of using efgartigimod to treat anti-LGI1-associated AE. The combination of efgartigimod and methylprednisolone resulted in favorable outcomes, indicating that this is an optional treatment plan.

Caspase-12 is Expressed in Purkinje Neurons and Prevents Psychiatric-Like Behavior in Mice.

Caspase-12 is a caspase family member for which functions in regulating cell death and inflammation have previously been suggested. In this study, we used caspase-12 lacZ reporter mice to elucidate the expression pattern of caspase-12 in order to obtain an idea about its possible in vivo function. Strikingly, these reporter mice showed that caspase-12 is expressed explicitly in Purkinje neurons of the cerebellum. As this observation suggested a function for caspase-12 in Purkinje neurons, we analyzed the brain and behavior of caspase-12 deficient mice in detail. Extensive histological analyses showed that caspase-12 was not crucial for establishing cerebellum structure or for maintaining Purkinje cell numbers. We then performed behavioral tests to investigate whether caspase-12 deficiency affects memory, motor, and psychiatric functions in mice. Interestingly, while the absence of caspase-12 did not affect memory and motor function, caspase-12 deficient mice showed depression and hyperactivity tendencies, together resembling manic behavior. Next, suggesting a possible molecular mechanistic explanation, we showed that caspase-12 deficient cerebella harbored diminished signaling through the brain-derived neurotrophic factor/tyrosine kinase receptor B/cyclic-AMP response binding protein axis, as well as strongly enhanced expression of the neuronal activity marker c-Fos. Thus, our study establishes caspase-12 expression in mouse Purkinje neurons and opens novel avenues of research to investigate the role of caspase-12 in regulating psychiatric behavior.

Long non-coding RNA SIX1-1 promotes proliferation of cervical cancer cells via negative transcriptional regulation of RASD1.

Cervical cancer poses a significant health burden for women globally, and the rapid proliferation of cervical cancer cells greatly worsens patient prognosis. Long non-coding RNAs (lncRNAs) play a crucial role in regulating tumor cell proliferation. However, the involvement of lncRNAs in cervical cancer cell proliferation remains unclear. In this study, we investigated the lncRNA SIX1-1, which was found to be upregulated in cervical cancer tissues and cell lines. Functional assays revealed that knockdown of SIX1-1 inhibited cell proliferation in vitro and reduced tumor growth in vivo. Mechanistically, SIX1-1 was predominantly localized in the nucleus and could bind with DNMT1 protein. The expression of SIX1-1 enhanced the interaction of DNMT1 with RASD1 promoter, leading to the methylation of the promoter and decreased mRNA transcription. Then RASD1 downregulation activated the cAMP/PKA/CREB signaling pathway, promoting cell proliferation. Rescue experiments showed that knockdown of RASD1 restored the inhibited cell proliferation caused by decreased expression of SIX1-1, indicating that RASD1 acted as the functional mediator of SIX1-1. In conclusion, SIX1-1 promoted cervical cancer cell proliferation by modulating RASD1 expression. This suggests that targeting the SIX1-1/RASD1 axis could be a potential antitumor strategy for cervical cancer.

Disintegration of Cav-1/ß-catenin complex attenuates neuronal death after ischemia-reperfusion injury by promoting ß-catenin nuclear translocation.

BACKGROUND: The roles of Caveolin-1 (Cav-1) and the Wnt/ß-catenin signaling pathways in cerebral ischemia-reperfusion (I/R) injury are well established. The translocation of ß-catenin into the nucleus is critical for regulating neuronal apoptosis, repair, and neurogenesis within the ischemic brain. It has been reported that the scaffold domain of Caveolin-1 (Cav-1) (residues 95-98) interacts with ß-catenin (residues 330-337). However, the specific contribution of the Cav-1/ß-catenin complex to I/R injury remains unknown. METHODS AND RESULTS: To investigate the mechanism underlying the involvement of the Cav-1/ß-catenin complex in the subcellular translocation of ß-catenin and its subsequent effects on cerebral I/R injury, we treated ischemic brains with ASON (Cav-1 antisense oligodeoxynucleotides) or FTVT (a competitive peptide antagonist of the Cav-1 and ß-catenin interaction). Our study demonstrated that the binding of Cav-1 to ß-catenin following I/R injury prevented the nuclear accumulation of ß-catenin. Treatment with ASON or FTVT after I/R injury significantly increased the levels of nuclear ß-catenin. Furthermore, ASON reduced the phosphorylation of ß-catenin at Ser33, Ser37, and Thr41, which contributes to its proteasomal degradation, while FTVT increased phosphorylation at Tyr333, which is associated with its nuclear translocation. CONCLUSIONS: The above results indicate that the formation of the Cav-1/ß-catenin complex anchors ß-catenin in the cytoplasm following I/R injury. Additionally, both ASON and FTVT treatments attenuated neuronal death in ischemic brains. Our study suggests that targeting the interaction between Cav-1 and ß-catenin serve as a novel therapeutic strategy to protect against neuronal damage during cerebral injury.

Relationship between preoperative psychological stress and short-term prognosis in elderly patients with femoral neck fracture.

BACKGROUND: Older adults are at high risk of femoral neck fractures (FNFs). Elderly patients face and adapt to significant psychological burdens, resulting in different degrees of psychological stress response. Total hip replacement is the preferred treatment for FNF in elderly patients; however, some patients have poor postoperative prognoses, and the underlying mechanism is unknown. We speculated that the postoperative prognosis of elderly patients with FNF may be related to preoperative psychological stress. AIM: To explore the relationship between preoperative psychological stress and the short-term prognosis of elderly patients with FNF. METHODS: In this retrospective analysis, the baseline data, preoperative 90-item Symptom Checklist score, and Harris score within 6 months of surgery of 120 elderly patients with FNF who underwent total hip arthroplasty were collected. We analyzed the indicators of poor short-term postoperative prognosis and the ability of the indicators to predict poor prognosis and compared the correlation between the indicators and the Harris score. RESULTS: Anxiety, depression, garden classification of FNF, cause of fracture, FNF reduction quality, and length of hospital stay were independent influencing factors for poor short-term postoperative prognoses in elderly patients with FNF (P < 0.05). The areas under the curve for anxiety, depression, and length of hospital stay were 0.742, 0.854, and 0.749, respectively. The sensitivities of anxiety, depression, garden classification of FNF, and prediction of the cause of fracture were 0.857, 0.786, 0.821, and 0.821, respectively. The specificities of depression, FNF quality reduction, and length of hospital stay were the highest at 0.880, 0.783, and 0.761, respectively. Anxiety, depression, and somatization scores correlated moderately with Harris scores (r = -0.523, -0.625, and -0.554; all P < 0.001). CONCLUSION: Preoperative anxiety, depression, and somatization are correlated with poor short-term prognosis in elderly patients with FNF and warrant consideration.

Mutant NOTCH3ECD Triggers Defects in Mitochondrial Function and Mitophagy in CADASIL Cell Models.

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy.

18F-FDG PET/CT for early prediction of pathological complete response in breast cancer neoadjuvant therapy: a retrospective analysis.

BACKGROUND: Neoadjuvant treatment has been developed as a systematic approach for patients with early breast cancer and has resulted in improved breast-conserving rate and survival. However, identifying treatment-sensitive patients at the early phase of therapy remains a problem, hampering disease management and raising the possibility of disease progression during treatment. METHODS: In this retrospective analysis, we collected 2-deoxy-2-[F-18] fluoro-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) images of primary tumor sites and axillary areas and reciprocal clinical pathological data from 121 patients who underwent neoadjuvant treatment and surgery in our center. The univariate and multivariate logistic regression analyses were performed to investigate features associated with pathological complete response (pCR). An 18F-FDG PET/CT-based prediction model was trained, and the performance was evaluated by receiver operating characteristic curves (ROC). RESULTS: The maximum standard uptake values (SUVmax) of 18F-FDG PET/CT were a powerful indicator of tumor status. The SUVmax values of axillary areas were closely related to metastatic lymph node counts (R = 0.62). Moreover, the early SUVmax reduction rates (between baseline and second cycle of neoadjuvant treatment) were statistically different between pCR and non-pCR patients. The early SUVmax reduction rates-based model showed great ability to predict pCR (AUC = 0.89), with all molecular subtypes (HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2-) considered. CONCLUSION: Our research proved that the SUVmax reduction rate of 18F-FDG PET/CT contributed to the early prediction of pCR, providing rationales for utilizing PET/CT in NAT in the future.

Management of Idiopathic Intracranial Hypertension: A Case Report.

ABSTRACT: BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure, affecting predominantly obese women of childbearing age. Early recognition and comprehensive management are vital for preventing severe complications, particularly vision loss. METHODS: This study reports a case of a 27-year-old woman who presented with chronic headaches and blurred vision. Notable findings included headaches that were intensified upon waking and exacerbated by activities that elevated intracranial pressure. The patient also reported nausea, vomiting, transient visual obscurations, and pulsatile tinnitus. After a clinical examination, she was given a diagnosis of IIH. RESULTS: The patient underwent a lumbar-peritoneal shunt procedure to alleviate her symptoms in conjunction with medication treatment. This case study highlights the importance of a multidisciplinary approach in diagnosing and treating IIH. In particular, weight management emerged as a crucial preventive measure against IIH recurrence. CONCLUSION: A multidisciplinary team strategy can enhance outcomes and quality of life, accentuating the need for continued research into IIH recurrence, treatments, and wider implications.

Identification of two novel B cell epitopes on E184L protein of African swine fever virus using monoclonal antibodies.

African swine fever virus (ASFV) is a large double-stranded DNA virus with a complex structural architecture and encodes more than 150 proteins, where many are with unknown functions. E184L has been reported as one of the immunogenic ASFV proteins that may contribute to ASFV pathogenesis and immune evasion. However, the antigenic epitopes of E184L are not yet characterized. In this study, recombinant E184L protein was expressed in prokaryotic expression system and four monoclonal antibodies (mAbs), designated as 1A10, 2D2, 3H6, and 4C10 were generated. All four mAbs reacted specifically with ASFV infected cells. To identify the epitopes of the mAbs, a series of overlapped peptides of E184L were designed and expressed as maltose binding fusion proteins. Accordingly, the expressed fusion proteins were probed with each E184L mAb separately by using Western blot. Following a fine mapping, the minimal linear epitope recognized by mAb 1A10 was identified as 119IQRQGFL125, and mAbs 2D2, 3H6, and 4C10 recognized a region located between 153DPTEFF158. Alignment of amino acids of E184L revealed that the two linear epitopes are highly conserved among different ASFV isolates. Furthermore, the potential application of the two epitopes in ASFV diagnosis was assessed through epitope-based ELISA using 24 ASFV positive and 18 negative pig serum and the method were able to distinguish positive and negative samples, indicating the two epitopes are dominant antigenic sites. To our knowledge, this is the first study to characterize the B cell epitopes of the antigenic E184L protein of ASFV, offering valuable tools for future research, as well as laying a foundation for serological diagnosis and epitope-based marker vaccine development.

Effects of Different Farming Modes on Salmo trutta fario Growth and Intestinal Microbial Community.

The gut microbiota plays a pivotal role in upholding intestinal health, fostering intestinal development, fortifying organisms against pathogen intrusion, regulating nutrient absorption, and managing the body's lipid metabolism. However, the influence of different cultivation modes on the growth indices and intestinal microbes of Salmo trutta fario remains underexplored. In this study, we employed high-throughput sequencing and bioinformatics techniques to scrutinize the intestinal microbiota in three farming modes: traditional pond aquaculture (TPA), recirculating aquaculture (RA), and flow-through aquaculture (FTA). We aimed to assess the impact of different farming methods on the water environment and Salmo trutta fario's growth performance. Our findings revealed that the final weight and weight gain rate in the FTA model surpassed those in the other two. Substantial disparities were observed in the composition, relative abundance, and diversity of Salmo trutta fario gut microbiota under different aquaculture modes. Notably, the dominant genera of Salmo trutta fario gut microbiota varied across farming modes: for instance, in the FTA model, the most prevalent genera were SC-I-84 (7.34%), Subgroup_6 (9.93%), and UTCFX1 (6.71%), while, under RA farming, they were Bacteroidetes_vadinHA17 (10.61%), MBNT15 (7.09%), and Anaeromyxoactor (6.62%). In the TPA model, dominant genera in the gut microbiota included Anaeromyxobacter (8.72%), Bacteroidetes_vadinHA17 (8.30%), and Geobacter (12.54%). From a comparative standpoint, the genus-level composition of the gut microbiota in the RA and TPA models exhibited relative similarity. The gut microbiota in the FTA model showcased the most intricate functional diversity, while TPA farming displayed a more intricate interaction pattern with the gut microbiota. Transparency, pH, dissolved oxygen, conductivity, total dissolved solids, and temperature emerged as pivotal factors influencing Salmo trutta fario gut microbiota under diverse farming conditions. These research findings offer valuable scientific insights for fostering healthy aquaculture practices and disease prevention and control measures for Salmo trutta fario, holding substantial significance for the sustainable development of the cold-water fish industry in the Qinghai-Tibet Plateau.

A Molecular Dynamics Study on the Defect Formation and Mechanical Behavior of Molybdenum Disulfide under Irradiation.

Due to its appealing characteristics, molybdenum disulfide (MoS2) presents a promising avenue for the exploration of lubrication protection materials in high-energy irradiation scenarios. Herein, we present a comprehensive investigation into the defect behavior of multilayer MoS2 under argon (Ar) atom irradiation leveraging molecular dynamics simulations. We have demonstrated the energy shifts and structural evolution in MoS2 upon irradiation, including the emergence of Frenkel defects and intricate defect clusters. The structural damage exhibits an initial increase followed by a subsequent decrease as the incident kinetic energy increases, ultimately peaking at 2.5 keV. Moreover, we investigated the effect of postannealing on defect recovery and conducted the uniaxial tensile and interlayer shearing simulation in order to provide valuable insights for the defect evolution and its impact on mechanical and tribological properties. Furthermore, we have proposed the optimal annealing temperature. The current study reveals the atomic mechanisms underlying irradiation-induced damage on the structural integrity and mechanical performance of MoS2, thereby providing crucial guidance for its vital application in nuclear reactors and aerospace industries.

Epitope mapping and establishment of a blocking ELISA for mAb targeting the p72 protein of African swine fever virus.

The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20-39 aa, 8A9 and 5E10 are recognized at 263-282 aa, which is consistent with the reported 265-280 aa epitopes. Conserved analysis revealed 20-39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. KEY POINTS: • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.

A novel radiomics-based technique for identifying vulnerable coronary plaques: a follow-up study.

BACKGROUND: Previous reports have suggested that coronary computed tomography angiography (CCTA)-based radiomics analysis is a potentially helpful tool for assessing vulnerable plaques. We aimed to investigate whether coronary radiomic analysis of CCTA images could identify vulnerable plaques in patients with stable angina pectoris. METHODS: This retrospective study included patients initially diagnosed with stable angina pectoris. Patients were randomly divided into either the training or test dataset at an 8 : 2 ratio. Radiomics features were extracted from CCTA images. Radiomics models for predicting vulnerable plaques were developed using the support vector machine (SVM) algorithm. The model performance was assessed using the area under the curve (AUC); the accuracy, sensitivity, and specificity were calculated to compare the diagnostic performance using the two cohorts. RESULTS: A total of 158 patients were included in the analysis. The SVM radiomics model performed well in predicting vulnerable plaques, with AUC values of 0.977 and 0.875 for the training and test cohorts, respectively. With optimal cutoff values, the radiomics model showed accuracies of 0.91 and 0.882 in the training and test cohorts, respectively. CONCLUSION: Although further larger population studies are necessary, this novel CCTA radiomics model may identify vulnerable plaques in patients with stable angina pectoris.

Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis.

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO-). We recently developed a new ONOO--triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO-. ONOO- scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO- reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke.

Correlation Between Messenger RNA Expression and Clinicopathological Features of Breast Cancer: A systematic review.

BACKGROUND: Meta analysis was adopted to investigate the correlation between messenger ribonucleic acid (mRNA) expression and clinicopathological features of breast cancer (BC). METHODS: English databases, PubMed, Web of Science, Embase, and The Cochrane Library, etc., were searched using a computer. The time range of retrieval was set to be from the establishment of the database to December 2023. The search terms were set as "mRNA", "Breast cancer", "Pathology", "Clinicopathological characteristics", etc. The literatures were screened in line with the inclusion and exclusion criteria, and the data was extracted for analysis by Revman5.3. RESULTS: Finally, 5 suitable included literatures were selected, including 969 patients. The analysis results were found to reveal a significant association between mRNA expression and BC grading (OR = 0.11, 95% CI = 0.04-0.30, Z = 4.26, P<0.0001); a significant correlation was observed between mRNA expression and BC staging (OR = 0.19, 95% CI = 0.05-0.65, Z = 2.65, P = 0.008<0.05); no correlation was found between mRNA expression and menstrual status of BC patients (OR = 0.63, 95% CI = 0.22-1.78, Z = 0.88, P = 0.38>0.05); a correlation was identified between mRNA expression and tumor size in BC (OR = 0.48, 95% CI = 0.24-0.99, Z = 2.00, P = 0.05). In the Discussion section, this study, comprising 10 research studies, aimed to explore the correlation between messenger ribonucleic acid and the clinical pathological features of BC. staging and grading of BC, a certain correlation with tumor size, and no correlation with the menstrual status of BC patients.

Discovery of a Long Half-Life AURKA Inhibitor to Treat MYC-Amplified Solid Tumors as a Monotherapy and in Combination with Everolimus.

Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors, that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC-overexpressing xenografts including SCLC, triple-negative breast cancer, hepatocellular carcinoma, and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC-driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC and/or N-MYC.

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition.

Neuronal death resulting from ischemic stroke is the primary cause of adult mortality and disability, and effective neuroprotective agents for poststroke intervention are still lacking. Remote ischemic postconditioning (RIPostC) has demonstrated significant protective effects against ischemia in various organs; however, the specific mechanisms are not fully understood. This study investigated the potential neuroprotective mechanisms of RIPostC in the context of ischemic stroke. Using a rat model of middle cerebral artery occlusion, we found that RIPostC mitigated neurological damage, improved movement in the open-field test, and protected against neuronal apoptosis. In terms of energy metabolism, RIPostC enhanced ATP levels, suppressed lactate content, and increased the production of ketone bodies (KBs). In the ferroptosis assay, RIPostC protected against lipoperoxidation, reversed the reduction of glutathione peroxidase 4 (GPX4), and mitigated the excessive expression of long-chain acyl-CoA synthetase family member 4 (ACSL4). In oxygen-glucose deprivation/reoxygenation-treated HT22 cells, KBs maintained GPX4 levels, suppressed ACSL4 expression, and preserved the mitochondrial cristae number. However, the effect of KBs on the expression of GPX4, ACSL4, and the number of mitochondrial cristae was blocked by erastin. Moreover, both RIPostC and KBs reduced total iron and ferrous ion content by repressing iron transporters both in vitro and in vivo. In conclusion, KBs-induced mitigation of ferroptosis could represent a new therapeutic mechanism for RIPostC in treating stroke.