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Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.
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Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.
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Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
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Apolipoproteína A-V , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Mutación , Oxaliplatino , Especies Reactivas de Oxígeno , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Apolipoproteína A-V/genética , Apolipoproteína A-V/metabolismo , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Animales , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones , Masculino , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2⯵g/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.
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Toxinas Marinas , Microcistinas , Sirtuinas , Espermatogonias , Animales , Masculino , Ratones , Apoptosis , Proliferación Celular , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN , Toxinas Marinas/metabolismo , Toxinas Marinas/toxicidad , Ratones Endogámicos ICR , Microcistinas/metabolismo , Microcistinas/toxicidad , Semen , Sirtuinas/efectos de los fármacos , Sirtuinas/metabolismo , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismoRESUMEN
BACKGROUND: Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies. CASE SUMMARY: We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated. CONCLUSION: In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.
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This study aimed to investigate the role of the long non-coding RNA (lncRNA) LINC00342-207 (LINC00342) in the development and progression of primary hepatocellular carcinoma (HCC). Forty-two surgically resected HCC tissues and corresponding paracancerous tissues were collected from October 2019 to December 2020 and examined for lncRNA LINC00342, microRNA (miR)-19a-3p, miR-545-5p, miR-203a-3p, cell cycle protein D1 (CyclinD1/CCND1), murine double minute 2 (MDM2), and fibroblast growth factor 2 (FGF2) expression. The disease-free survival and overall survival of patients with HCC were followed up. HCC cell lines and the normal hepatocyte cell line HL-7702 were cultured and the expression level of LINC00342 was measured. HepG2 cells were transfected with LINC00342 siRNA, LINC00342 overexpression plasmid, miR-19a-3p mimics and their corresponding suppressors, miR-545-5p mimics and their corresponding suppressors, and miR-203a-3p mimics and their corresponding suppressors. The proliferation, apoptosis, migration, and invasion of HepG2 cells were detected. Stably transfected HepG2 cells were inoculated into the left axilla of male BALB/c nude mice, and the volume and quality of transplanted tumors as well as the expression levels of LINC00342, miR-19a-3p, miR-545-5p, miR-203a-3p, CCND1, MDM2, and FGF2 were examined. LINC00342 played an oncogenic role in HCC and exhibited inhibitory effects on proliferation, migration, and invasion, and promoted the apoptosis of HepG2 cells. Moreover, it inhibited the growth of transplanted tumors in vivo in mice. Mechanistically, the oncogenic effect of LINC00342 was associated with the targeted regulation of the miR-19a-3p/CCND1, miR-545-5p/MDM2, and miR-203a-3p/FGF2 axes.
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OBJECTIVE: To evaluate the effects of platelet-rich plasma (PRP) supernatants with different activation methods and storage time on human monocyte-derived macrophages phenotype and explore the possible mechanism. METHODS: Human monocyte-derived macrophages were cultured in vitro with PRP or activated PRP supernatants activated with different activators. The expression of marker molecules on the surface of macrophages was detected by flow cytometry, and the concentration of growth factors in PRP supernatants was detected by ELISA. RESULTS: After 24 h of coculture, the expression level of CD86 in macrophages stimulated by PRP supernatant (thrombin and Cacl2 activated) was significantly higher than that by PRP group (P<0.05), and the expression of CD163 in macrophages was increased by Cacl2 activated PRP supernatant. Compared with different activator groups, the expression of CD163 in macrophages of Cacl2 activated group was significantly higher than that of thrombin and ADP groups (P<0.05). ELISA results showed that the concentrations of FGF (P<0.001) and EGF (P<0.05) in the supernatant of PRP stored at -80 â for more than 20 months and 10-20 months were significantly higher than those in the group stored at less than 10 months after Cacl2 activation, and the expressions of CD86 (P<0.01), CD163 (P<0.001) and CD206 (P<0.001) in macrophages cocultured with the supernatant of the two groups were significantly increased. CONCLUSION: PRP activated by different activators has different effects on the phenotype of macrophages. Meanwhile, the storage time will also affect the growth factor concentration and effect of PRP.
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Furcation defects pose a significant challenge in the diagnosis and treatment planning of periodontal diseases. The accurate detection of furcation involvements (FI) on periapical radiographs (PAs) is crucial for the success of periodontal therapy. This research proposes a deep learning-based approach to furcation defect detection using convolutional neural networks (CNN) with an accuracy rate of 95%. This research has undergone a rigorous review by the Institutional Review Board (IRB) and has received accreditation under number 202002030B0C505. A dataset of 300 periapical radiographs of teeth with and without FI were collected and preprocessed to enhance the quality of the images. The efficient and innovative image masking technique used in this research better enhances the contrast between FI symptoms and other areas. Moreover, this technology highlights the region of interest (ROI) for the subsequent CNN models training with a combination of transfer learning and fine-tuning techniques. The proposed segmentation algorithm demonstrates exceptional performance with an overall accuracy up to 94.97%, surpassing other conventional methods. Moreover, in comparison with existing CNN technology for identifying dental problems, this research proposes an improved adaptive threshold preprocessing technique that produces clearer distinctions between teeth and interdental molars. The proposed model achieves impressive results in detecting FI with identification rates ranging from 92.96% to a remarkable 94.97%. These findings suggest that our deep learning approach holds significant potential for improving the accuracy and efficiency of dental diagnosis. Such AI-assisted dental diagnosis has the potential to improve periodontal diagnosis, treatment planning, and patient outcomes. This research demonstrates the feasibility and effectiveness of using deep learning algorithms for furcation defect detection on periapical radiographs and highlights the potential for AI-assisted dental diagnosis. With the improvement of dental abnormality detection, earlier intervention could be enabled and could ultimately lead to improved patient outcomes.
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As the popularity of dental implants continues to grow at a rate of about 14% per year, so do the risks associated with the procedure. Complications such as sinusitis and nerve damage are not uncommon, and inadequate cleaning can lead to peri-implantitis around the implant, jeopardizing its stability and potentially necessitating retreatment. To address this issue, this research proposes a new system for evaluating the degree of periodontal damage around implants using Periapical film (PA). The system utilizes two Convolutional Neural Networks (CNN) models to accurately detect the location of the implant and assess the extent of damage caused by peri-implantitis. One of the CNN models is designed to determine the location of the implant in the PA with an accuracy of up to 89.31%, while the other model is responsible for assessing the degree of Peri-implantitis damage around the implant, achieving an accuracy of 90.45%. The system combines image cropping based on position information obtained from the first CNN with image enhancement techniques such as Histogram Equalization and Adaptive Histogram Equalization (AHE) to improve the visibility of the implant and gums. The result is a more accurate assessment of whether peri-implantitis has eroded to the first thread, a critical indicator of implant stability. To ensure the ethical and regulatory standards of our research, this proposal has been certified by the Institutional Review Board (IRB) under number 202102023B0C503. With no existing technology to evaluate Peri-implantitis damage around dental implants, this CNN-based system has the potential to revolutionize implant dentistry and improve patient outcomes.
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Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.
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Antioxidantes , Testículo , Masculino , Ratones , Animales , Testículo/metabolismo , Antioxidantes/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Testosterona/metabolismo , Estrés Oxidativo , Acetilcisteína/farmacología , Acetilcisteína/metabolismoRESUMEN
Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.
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Neoplasias de la Mama , Receptores Quiméricos de Antígenos , Humanos , Femenino , Receptores Quiméricos de Antígenos/metabolismo , Neoplasias de la Mama/metabolismo , Linfocitos T , Recurrencia Local de Neoplasia/metabolismo , Inmunoterapia Adoptiva , Microambiente TumoralRESUMEN
@#Objective To evaluate the pharmacodynamics of human interferon(IFN)α1b against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron strain in vitro.Methods Total four drugs human IFNα1b bulk,human IFNα1b eye drops,human IFNα1b spray and Remdesivir were detected for cytotoxicity by CCK-8 assay.The inhibitory effect of human IFNα1b on SARS-CoV-2 Omicron strains(BA.5/BA.2/BA.1)was determined by qPCR.Results Human IFNα1b bulk of the maximum concentration(1 × 107IU/mL)and Remdesivir of the maximum concentration(150 μmol/L)did not achieve half cytotoxicity to Vero cells;The median cytotoxicity concentrations(CC_(50))of human IFNα1b eye drops and human IFNα1b sprays were 29 958 and 37 550 IU/mL,respectively,showing toxicity to Vero cells.The median effective concentrations(EC_(50))of human IFNα1b against virus strains BA.1,BA.2 and BA.5 after incubation for 2 h in advance were 9.30,13.38 and 12.33 IU/mL and those of Remdesivir were 0.314 7,0.291 0 and0.300 3 μmol/L.When incubation with virus simultaneously,the EC_(50)of human IFNα1b to BA.1,BA.2 and BA.5 were19.68,10.91 and 18.84 IU/mL and those of the control drug Remdesivir were 0.320 5,0.274 4 and 0.304 1 μmol/L,respectively.Conclusion At the cell level in vitro,human IFNα1b of very low activity showed a good inhibitory effect on SARS-CoV-2 Omicron strain,which was expected to be a clinical specific drug for the treatment of SARS-CoV-2 Omicron strain infection.
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Brain-inspired neuromorphic computing has become one of the critical technologies to overcome the bottleneck of von Neumann architecture. It is a vital step to construct a brain-like neuromorphic computing system at the hardware level by utilizing artificial synaptic devices. Compared with electronic synaptic devices, optoelectronic synaptic devices have the advantages of low power consumption, low crosstalk, and high bandwidth. Artificial optoelectronic synapses, analogous to retinal structure, can directly respond to and process light signal information to mimic the neuromorphic visual system. As high-level nerve impulses, both generated and regulated, emotions affect the strength and persistence of memory. Ambient illumination can provide visual perception to distinguish the size, color, and other characteristics of objects as well as affect the nonvisual functions of individuals, such as emotional states, thereby affecting learning and memory function. Herein, an artificial optoelectronic synapse composed of ITO/TiO2-x /p-Si was proposed. A variety of biologically dependent synaptic plasticity relating to learning and memory, including short-term synaptic plasticity, long-term synaptic plasticity, and learning-forgetting-relearning multifunctional advanced synaptic activity, was successfully simulated. A 3 × 3 artificial optoelectronic synapse array based on 9 devices was constructed to mimic the functions of visual learning and memory affected by internal emotion and ambient illumination. The proposed artificial optoelectronic synapse will exhibit great potential in visual and image information perception and memory.
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Background: The risk and prognosis of pancreatic cancer with lung metastasis (PCLM) are not well-defined. Thus, this study aimed to identify the risk and prognostic factors for these patients, and establish predictive nomogram models. Methods: Patients diagnosed with PCLM between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Independent risk factors and prognostic factors were identified using logistic regression and Cox regression analyses. Nomograms were constructed to predict the risk and survival of PCLM, and the area under the curve (AUC), C-index, and calibration curve were used to determine the predictive accuracy and discriminability of the established nomogram, while the decision curve analysis was used to confirm the clinical effectiveness. Results: A total of 11287 cases with complete information were included; 601 (5.3%) patients with PC had lung metastases. Multivariable logistic analysis demonstrated that primary site, histological subtype, and brain, bone, and liver metastases were independent risk factors for lung metastases. We constructed a risk prediction nomogram model for the development of lung metastases among PC patients. The c-index of the established diagnostic nomogram was 0.786 (95%CI 0.726-0.846). Multivariable Cox regression analysis demonstrated that primary site, liver metastases, surgery, and chemotherapy were independent prognostic factors for both overall survival (OS) and cancer-specific survival (CSS), while bone metastases were independent prognostic factors for CSS. The C-indices for the OS and CSS prediction nomograms were 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.78), respectively. Based on the AUC of the receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analysis (DCA), we concluded that the risk and prognosis model of PCBM exhibits excellent performance. Conclusions: The present study identified the risk and prognostic factors of PCLM and further established nomograms, which can help clinicians effectively identify high-risk patients and predict their clinical outcomes.
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During an investigation of freshwater fungi in Jiangxi province, China, a new hyphomycetous fungus, Aquapteridospora jiangxiensis, was collected and isolated. Aquapteridospora jiangxiensis is characterized by its unbranched and guttulate conidiophores with multi-septa swollen at the base, polyblastic conidiogenous cells with sympodial proliferations, and denticles, and guttulate conidia with a sheath. A photo plate of the macro- and micro-morphology and a muti-loci (ITS, LSU, SSU, TEF1 and RPB2) phylogenetic tree are provided. A key to the species of Aquapteridospora is also presented in this paper.
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Ascomicetos , Hongos Mitospóricos , ADN de Hongos/genética , ADN Ribosómico , Ecosistema , Agua Dulce , Filogenia , Análisis de Secuencia de ADNRESUMEN
Previous study found 1-NP disrupted steroidogenesis in mouse testis, but the underlying mechanism remained elusive. The current work aims to explore the roles of ROS-promoted AKAP1 degradation and excessive mitochondrial fission in 1-NP-induced steroidogenesis disruption in MLTC-1 cells. Transmission electron microscope analysis found 1-NP promoted excessive mitochondrial fission. Further data showed 1-NP disrupted mitochondrial function. pDRP1 (Ser637), a negative regulator of mitochondrial fission, was reduced in 1-NP-treated MLTC-1 cells. Mechanistically, 1-NP caused degradation of AKAP1, an upstream regulator of pDRP1 (Ser637). MG132, a proteasome inhibitor, attenuated 1-NP-induced AKAP1 degradation and downstream pDRP1 (Ser637) reduction, thereby ameliorating 1-NP-downregulated steroidogenesis. Further analysis found that cellular ROS was elevated and NOX4, HO-1 and SOD2 were upregulated in 1-NP-exposed MLTC-1 cells. NAC, a well-known commercial antioxidant, alleviated 1-NP-induced excessive ROS and oxidative stress. 1-NP-induced AKAP1 degradation and subsequent downregulation of pDRP1 (Ser637) were prevented by NAC pretreatment. Moreover, NAC attenuated 1-NP-resulted T synthesis disturbance in MLTC-1 cells. The present study indicates that ROS mediated AKAP1 degradation and subsequent pDRP1 (Ser637) dependent mitochondrial fission is indispensable in 1-NP caused T synthesis disruption. This study provides a new insight into 1-NP-induced endocrine disruption, and offers theoretical basis in public health prevention.
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Células Intersticiales del Testículo , Dinámicas Mitocondriales , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Pirenos , Especies Reactivas de Oxígeno/metabolismo , Testosterona/metabolismoRESUMEN
OBJECTIVES: To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction. METHODS: In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3+, CD4+, and CD8+ T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55). RESULTS: iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759-0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647-0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206-0.546, p < 0.001), Resec4 (0.199, 0.040-1.000, p < 0.001), and TCIA (0.303, 0.098-0.944, p = 0.001). CONCLUSIONS: iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection. KEY POINTS: ⢠Decoding tumour immune microenvironment enables advanced biomarkers identification. ⢠Immune ecosystem diversity index characterises intratumoural immune status noninvasively. ⢠Immune ecosystem diversity index is prognostic for NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Linfocitos T CD8-positivos/patología , Estudios Retrospectivos , Ecosistema , Estadificación de Neoplasias , Pronóstico , Tomografía Computarizada por Rayos X , Biomarcadores , Microambiente TumoralRESUMEN
OBJECTIVE: This study aimed to identify microRNAs (miRNAs) involved in the development of perioperative neurocognitive disorders (PND). METHODS: Plasma exosomal miRNA expression was examined in patients before and after cardiopulmonary bypass (CPB) using microarray and qRT-PCR and these patients were diagnosed as PND later. Elderly rats were subjected to CPB, and the cognitive functions were examined. Bioinformatics analysis was conducted to predict the targets of miR-214-3p. Rats were administered rno-miR-214-3p agomir before or after CPB to investigate the role of miR-214-3p in PND development. RESULTS: We identified 76 differentially expressed plasma exosomal miRNAs in PND patients after surgery (P<0.05, â£log2FCâ£>0.58), including the upregulated hsa-miR-214-3p (P=0.002399392). Prostaglandin-endoperoxide synthase 2 (PTGS2) was predicted as a miR-214-3p target. In rats, CPB reduced the platform crossing numbers and target quadrant stay time, accompanied with hippocampal neuronal necrosis. The rno-miR-214-3p level was significantly increased in plasma exosomes but decreased in rat hippocampus after surgery, exhibiting a negative correlation (P<0.001, r=-0.762). A negative correlation between miR-214-3p and PTGS2 protein expression was also observed in the hippocampus after surgery. Importantly, rno-miR-214-3p agomir treatment, before or after surgery, significantly increased the platform crossing numbers (P=0.035) and target quadrant stay time (P=0.029) compared with negative control. Hippocampal PTGS2 protein level was increased in the untreated surgery group and decreased in response to rno-miR-214-3p agomir treatment before or after surgery (both P<0.05 vs. negative control). CONCLUSION: These data suggest that miR-214-3p/PTGS2 signaling contributes to the development of PND, serving as a potential therapeutic target for PND.
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Puente Cardiopulmonar , Exosomas , MicroARNs , Trastornos Neurocognitivos , Animales , Puente Cardiopulmonar/efectos adversos , Biología Computacional , Ciclooxigenasa 2/genética , Exosomas/genética , Humanos , MicroARNs/genética , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/genética , RatasRESUMEN
BACKGROUND: Freshwater fungi, growing on submerged wood, can promote the degradation of organisms and the reuse of rotten wood energy and play key roles in freshwater ecosystems. Here, a new hyphomycetous fungus, Sporidesmiellalignicola, was isolated and identified from submerged wood samples collected in a small stream in Jiangxi Province, south-eastern China. NEW INFORMATION: The new taxon was studied, based on morphological characters and phylogenetic analyses combined with LSU, ITS, TEF1α and RPB2 sequences data. Sporidesmiellalignicola was morphologically characterised by its pink colonies on PDA medium in prophase, macronematous, mononematous, solitary, brown, septate, unbranched, straight or slightly flexuous conidiophores with holoblastic, polyblastic, integrated, terminal, pale brown conidiogenous cells and cylindrical, narrowly clavate, broadly obovoid to cuneiform, 3-4-distoseptate, olivaceous brown or brown conidia with rounded apex. A phylogenetic tree was constructed, based on the combination of LSU, ITS, TEF1α and RPB2 sequences data.
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Apical lesions, the general term for chronic infectious diseases, are very common dental diseases in modern life, and are caused by various factors. The current prevailing endodontic treatment makes use of X-ray photography taken from patients where the lesion area is marked manually, which is therefore time consuming. Additionally, for some images the significant details might not be recognizable due to the different shooting angles or doses. To make the diagnosis process shorter and efficient, repetitive tasks should be performed automatically to allow the dentists to focus more on the technical and medical diagnosis, such as treatment, tooth cleaning, or medical communication. To realize the automatic diagnosis, this article proposes and establishes a lesion area analysis model based on convolutional neural networks (CNN). For establishing a standardized database for clinical application, the Institutional Review Board (IRB) with application number 202002030B0 has been approved with the database established by dentists who provided the practical clinical data. In this study, the image data is preprocessed by a Gaussian high-pass filter. Then, an iterative thresholding is applied to slice the X-ray image into several individual tooth sample images. The collection of individual tooth images that comprises the image database are used as input into the CNN migration learning model for training. Seventy percent (70%) of the image database is used for training and validating the model while the remaining 30% is used for testing and estimating the accuracy of the model. The practical diagnosis accuracy of the proposed CNN model is 92.5%. The proposed model successfully facilitated the automatic diagnosis of the apical lesion.