DMXL2 Is Required for Endocytosis and Recycling of Synaptic Vesicles in Auditory Hair Cells.

Ribbon synapses of inner hair cells (IHCs) are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles (SVs), however, remains elusive. This study showed that hair cell knock-out of murine Dmxl2, whose human homolog is responsible for nonsyndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave I amplitude of the auditory brainstem response. Membrane capacitance measurements of the IHCs revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of SVs and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the SVs.

SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage.

BACKGROUND: Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated TH2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive. OBJECTIVE: We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP. METHODS: Real-time reverse transcription-quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with TH2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages. RESULTS: Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis. CONCLUSIONS: SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.

Gut microbiota and chronic rhinosinusitis: a two-sample Mendelian randomization study.

BACKGROUND: The nasal cavity and gut are interconnected, both housing a rich natural microbiome. Gut microbiota may interact with nasal microbiota and contribute to the development of chronic rhinosinusitis (CRS). However, the specific role of gut microbiota in CRS has not been fully investigated. Therefore, we conducted a two-sample Mendelian randomization study to reveal the potential genetic causal effect of gut microbiota on CRS. METHODS: We performed a two-sample Mendelian Randomization (MR) analysis using aggregated data from genome-wide association studies (GWAS) on gut microbiota and CRS. The primary method used to assess the causal relationship between gut microbiota and CRS was the inverse variance weighting (IVW) method. In addition, sensitivity analyses were conducted to evaluate the robustness of the MR results, including heterogeneity, pleiotropy, and leave-one-out tests. RESULTS: Genetically predicted twelve gut microbiota, including class Coriobacteriia, class Methanobacteria, family Coriobacteriaceae, family Methanobacteriaceae, family Pasteurellaceae, genus Haemophilus, genus Ruminococcus torques group, genus Subdoligranulum, order Coriobacteriales, order Methanobacteriales, order Pasteurellales, and phylum Proteobacteria, demonstrated a potential inhibitory effect on CRS risk (P < 0.05). In addition, four gut microbiota, including family Streptococcaceae, genus Clostridium innocuum group, genus Oscillospira, and genus Ruminococcaceae NK4A214 group, exhibited a causal role in increasing CRS risk (P < 0.05). Sensitivity analyses showed no evidence of heterogeneity or pleiotropy (P > 0.05). CONCLUSIONS: This study reveals the causal relationship between specific gut microbiota and CRS, which provides a new direction and theoretical foundation for the future development of interventions and prevention and treatment strategies for CRS.

Infratemporal Fossa Schwannoma Surgery via a Combined Prelacrimal Recess, Caldwell-Luc, and Distal Intraoral Approach.

BACKGROUND: The deep location of infratemporal fossa (ITF) combined with the abundant vascular plexus in it increased the difficulty of removing the mass in ITF through endoscope surgery approach. However, under appropriate circumstances, the excision of ITF tumors through a combined prelacrimal recess, Caldwell-Luc, and distal intraoral approach can be safely performed with minimal impact on the surrounding tissues. CASE PRESENTATION: The Department of Neurology received a 69-year-old male patient who had been experiencing headache, dizziness, and numbness from the mastoid region of his left ear to the corner of his mouth for a duration of 22 days. Cranial magnetic resonance imaging revealed the presence of a tumor located in the ITF. Following transfer to our department, surgical intervention was performed using a combined approach involving the prelacrimal recess, the anterior wall of maxillary sinus, and lateral ITF to successfully remove the tumor. Postoperative pathologic examination confirmed schwannoma as its nature. The patient was discharged in excellent condition without any functional impairment. CONCLUSIONS: On the basis of this case, the authors believe that this combined approach can offer a distinct endoscopic perspective and adequate surgical workspace, which is crucial for tumor removal while preserving the integrity of surrounding normal tissues. Moreover, the utilization of multiple small incisions has minimal impact on postoperative recovery.

Analysis of Diagnosis and Treatment Strategies for Primary Juvenile Psammomatoid Ossifying Fibroma Complicated With Primary Aneurysmal Bone Cyst.

BACKGROUND: Juvenile Psammomatoid Ossifying Fibroma (JPOF) is a type of noncancerous bone tumor that usually affects adolescents in the craniomaxillofacial area. Clinical manifestations are usually symptoms caused by the tumor's invasive compression of surrounding tissues. Aneurysmal Bone Cyst (ABC) is also a benign bone tumor, and it typically occurs in long bones and the spine. Only 2% to 3% of cases occur in the head and neck. Due to the rarity of this combination of clinical cases, clinicians face difficulties in comprehensively understanding this complex lesion. Therefore, a comprehensive review of the clinical manifestations and characteristic imaging findings is necessary for surgeons. CASE PRESENTATIONS: On April 6, 2019, a 13-year-old boy presented with left maxillofacial bulge and pain for 1 month. Magnetic resonance imaging of the paranasal sinuses showed an irregular hive-like mass signal in the left maxillary sinus, and cystic changes with fluid levels were seen in the lesion. After the initial diagnosis of JPOF with primary ABC, we decided to perform a facial mid-facial resection of maxillary sinus tumor to remove the tumor tissue. Finally, after 3 recurrences and 4 operations, there was no tumor recurrence for 20 months after the last operation, and the patient was still under continuous follow-up. CONCLUSIONS: This case provided a reference for the diagnosis and treatment of JPOF combined with ABC. In particular, a new understanding of the association between the two diseases and the management of recurrence were proposed, which had the potential to improve clinical understanding of this complicated condition.

Profiling of the chemical space on the phenyl group of substituted benzothiazole RIPK3 inhibitors.

Necroptosis is confirmed as a precisely programmed cell death that is activated in caspase-deficient conditions. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase (MLKL) are the key regulators involved in the signaling pathway. However, accumulating evidence suggests that RIPK1 also works in apoptosis and inflammation pathways independent of necroptosis. Differently, RIPK3 signals necroptosis independent of RIPK1. Thus, identification of specific RIPK3 inhibitors is of great importance for the drug development associated with necroptosis. The benzothiazole carboxamide is a privileged scaffold as RIPK3 inhibitors developed by our group recently. In this study, we work on the phenyl group in-between of benzothiazole and carboxamide to profile the chemical space. Finally, a chlorinated derivative XY-1-127 was found to specifically inhibit necroptosis rather than apoptosis with an EC50 value of 676.8 nM and target RIPK3 with a Kd of 420 nM rather than RIPK1 (Kd = 4300 nM). It was also confirmed to block the formation of necrosome by inhibiting RIPK3 phosphorylation at 1 µM in necroptosis cells. This work discovers the chemical space insights on the phenyl group of the substituted benzothiazole RIPK3 inhibitors and provides a new lead compound for further development.

Identification and analysis of lipid metabolism-related genes in allergic rhinitis.

BACKGROUND: Studies have shown that the lipid metabolism mediator leukotriene and prostaglandins are associated with the pathogenesis of allergic rhinitis (AR). The aim of this study was to identify key lipid metabolism-related genes (LMRGs) related to the diagnosis and treatment of AR. MATERIALS AND METHODS: AR-related expression datasets (GSE75011, GSE46171) were downloaded through the Gene Expression Omnibus (GEO) database. First, weighted gene co-expression network analysis (WGCNA) was used to get AR-related genes (ARRGs). Next, between control and AR groups in GSE75011, differentially expressed genes (DEGs) were screened, and DEGs were intersected with LMRGs to obtain lipid metabolism-related differentially expressed genes (LMR DEGs). Protein-protein interaction (PPI) networks were constructed for these LMR DEGs. Hub genes were then identified through stress, radiality, closeness and edge percolated component (EPC) analysis and intersected with the ARRGs to obtain candidate genes. Biomarkers with diagnostic value were screened via receiver operating characteristic (ROC) curves. Differential immune cells screened between control and AR groups were then assessed for correlation with the diagnostic genes, and clinical correlation analysis and enrichment analysis were performed. Finally, real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was made on blood samples from control and AR patients to validate these identified diagnostic genes. RESULTS: 73 LMR DEGs were obtained, which were involved in biological processes such as metabolism of lipids and lipid biosynthetic processes. 66 ARRGs and 22 hub genes were intersected to obtain four candidate genes. Three diagnostic genes (LPCAT1, SGPP1, SMARCD3) with diagnostic value were screened according to the AUC > 0.7, with markedly variant between control and AR groups. In addition, two immune cells, regulatory T cells (Treg) and T follicular helper cells (TFH), were marked variations between control and AR groups, and SMARCD3 was significantly associated with TFH. Moreover, SMARCD3 was relevant to immune-related pathways, and correlated significantly with clinical characteristics (age and sex). Finally, RT-qPCR results indicated that changes in the expression of LPCAT1 and SMARCD3 between control and AR groups were consistent with the GSE75011 and GSE46171. CONCLUSION: LPCAT1, SGPP1 and SMARCD3 might be used as biomarkers for AR.

Multidisciplinary Team in Severe Infectious Complications Caused by Pharyngeal Foreign Body.

BACKGROUND: Pharyngeal foreign body is not only a common emergency in people's daily life, but also a common simple disease in otorhinolaryngology. However, the disease is easy to be ignored due to its common occurrence, which may lead to a series of serious complications including sepsis and local abscess. CASE PRESENTATION: In this case, a patient with sepsis, piriform fistula, deep neck abscess, and mediastinal abscess caused by a fishbone was reported. After reviewing the international literature on severe infectious complications caused by foreign bodies in pharynx, the authors emphasize the important role of multidisciplinary team in dealing with complex complications. RESULT: The whole process of patient from onset to recovery was summarized in a timeline. During hospitalization, the value of leukocyte counts and C-reactive protein in routine blood test was record dynamically. The electronic laryngoscopy, neck computed tomography and chest computed tomography were used to judge treatment efficacy. After about 2 months of hospitalization, the patient was recovered without sequelae. No adverse reactions were found during the follow-up. CONCLUSION: The incorrect method of removing foreign body after mis-swallowing may develop serious complications. Therefore, It is important to strengthen medical preaching for general population of correct treatments after foreign body ingestion. In addition, the case reminds clinicians to pay more attention to patients' medical history and details of all medical examinations, which may provide significant clues for making the correct diagnosis and treatment quickly.

A Review of Microsurgical Resection of Recurrent Laryngeal Neurilemmoma Under Nerve Monitoring.

BACKGROUND: Laryngeal neurilemmoma, especially recurrent laryngeal neurilemmoma, is a rare neural sheath tumor in head and neck. The most common symptom of laryngeal neurilemmoma is hoarseness or dysphonia, followed by dysphagia, dyspnea, and foreign body sensation. At present, surgical resection is the most effective treatment for this kind of tumor, thus making how to remove it become the most concerned problem of surgeons. CASE PRESENTATION: On February 18, 2021, a 64-year-old male presented to our clinic with recurrent sore throat and intermittent hoarseness for 3 years. The results of electronic laryngoscope and magnetic resonance imaging showed a 25×10×21 mm well-defined tumor in the left pyriform sinus without laryngeal cartilage destruction and enlarged lymph nodes. After the initial diagnosis of recurrent laryngeal neurilemmoma, to preserve the continuity of recurrent laryngeal nerve as much as possible, the authors determine to perform anatomical resection of recurrent laryngeal neurilemmoma with operating microscope under the monitoring of recurrent laryngeal nerve function. Finally, the patient recovered completely from hoarseness during postoperative follow-up. CONCLUSION: A complete diagnosis and treatment process of recurrent laryngeal neurilemmoma was presented by the case. Particularly, it shows the application of recurrent laryngeal nerve monitoring in the operation helps to protect the continuity of the recurrent laryngeal nerve, which lays a anatomical bases for the follow-up nerve repair.

Retropharyngeal Abscess in an Adult With Pneumonia During COVID-19 Outbreak.

BACKGROUND: Retropharyngeal abscesses are rarely reported in adults and occur mostly in patients with immunocompromised or as a foreign body complication. Admittedly, the treatment of retropharyngeal abscesses frequently involves surgical drainage to achieve the best results. However, when retropharyngeal abscesses occurred in a highly suspected patient with COVID-19, the managements and treatments should be caution to prevent the spread of the virus. CLINICAL PRESENTATION: On February 13, a 40-year-old male with retropharyngeal abscesses turned to our department complaining dyspnea and dysphagia. In addition, his chest CT scan shows a suspected COVID-19 infection, thus making out Multiple Disciplinary Team determine to perform percutaneous drainage and catheterization through left anterior cervical approach under the guidance of B-ultrasound. Finally, the patient recovered and was discharged from the hospital on February 27 after 14 days of isolation. There was no recurrence after half a year follow-up. CONCLUSIONS: By presenting this case, we aim at raising awareness of different surgical drainage methods and summarizing our experience in the management of retropharyngeal abscesses during the outbreak of COVID-19.

RASSF10 regulates bone invasion of growth hormone-secreting adenomas via exosomes.

BACKGROUND: Invasion of pituitary growth hormone-secreting adenoma into surrounding tissues poses a challenge for complete resection in surgery, which is the main reason for recurrence of this type of cancer. Studies have shown that abnormal methylation of RASSF10 can promote the expression of MDM2 and regulate the tumor microenvironment by affecting the secretion of exosomes. In the present study, we aim to uncover the specific underlying mechanism of this effect. METHOD: Transwell co-culture assays was performed using GT1.1 cells or exosomes and RAW264.7 cells. RAW264.7 cells were collected for invasion, proliferation and apoptosis assays, RT-qPCR and western blotting. RNA-seq was performed and used to assess the potential molecular pathways of the effect of GT1.1 cell-exosomes on RAW264.7 cells. RESULTS: GT1.1 cells with reduced RASSF10 expression could promote the proliferation and migration of RAW264.7 cells, and promote their expression of osteoclast markers TRAP and CK. The effect of GT1.1 cell exosomes on the RAW264.7-cell phenotype was shown to be achieved through the RASSF10-MDM2 pathway. RNA-seq allowed the identification of PI3K-AKT, MAPK, and calcium signaling as important in this regulation system of RASSF10-MDM2. CONCLUSION: Our results indicate that GT1.1 cells activate PI3K-AKT, MAPK and calcium signaling via the RASSF10-MDM2 pathway, and promote the differentiation of RAW264.7 cells into osteoclasts through exosomes. This study may provide new ideas to aid in early diagnosis, prognostic assessment and treatment of aggressive pituitary adenomas.

NLRP3 inflammasome activation promotes the development of allergic rhinitis via epithelium pyroptosis.

Allergic rhinitis (AR) is a worldwide highly prevalent nasal inflammatory disease with elusive mechanisms about the regulation of innate immune response. The roles and mechanisms of NLRP3, a typical inflammasome, in AR development remain unclear. Here we investigate the roles of NLRP3 inflammasome activation in the development and progression of AR and try to uncover its potential mechanisms underlying. Wildtype and NLRP3 knockout mice were applied to construct the ovalbumin (OVA)-induced AR model. Caspase-1 specific inhibitor Belnacasan and inflammasome activator ATP were used for adjuvant stimulation of AR-model mice respectively. We found that the production of IL-1ß and the activation of inflammasome were increased in both patients and mice with AR. NLRP3 deficiency markedly suppressed AR progression with reduced inflammatory response and epithelium pyroptosis in mice with AR. Furthermore, Caspase-1 inhibitor treatment in vivo ameliorated the development and progression of AR with favorable outcomes. Mechanistically, inflammation augments and nasal mucosa injury during AR were partially due to ASC-specks accumulation and subsequent cell pyroptosis. Our study reveals the previously unknown roles of NLRP3 inflammasome in promoting the development and progression of AR via enhancing inflammatory response and epithelium pyroptosis and thus provides a potential clue for allergic disease interventions.

Construction of an irreversible allergic rhinitis-induced olfactory loss mouse model.

Clinical data show that part of patients with sinonasal diseases suffered from olfactory dysfunction, especially with allergic rhinitis (AR) and chronic rhinosinusitis (CRS). However, the mechanisms responsible for AR-induced olfactory loss are still largely unknown. Because of the difficulty to obtain human olfactory mucosa, an AR-induced olfactory loss animal model needs to be constructed to clarify the mechanism. The AR mouse model was induced by intraperitoneal sensitizing with ovalbumin (OVA) followed by intranasal challenge lasted from 1 to 12 weeks. For groups with recovery, mice were housed for another 4-week long without any treatment after the last intranasal challenge. Olfactory function, olfactory receptor neurons (ORNs) density and leukocytes infiltration were examined at different time points. Olfactory loss occurs immediately after 1-week intranasal challenge and deteriorates almost to anosmia after 8th week, and after that olfactory loss become irreversible. Nasal inflammation induces significant infiltration of leukocytes into olfactory epithelium (OE), which negatively correlated with the density of ORNs and mouse olfaction in a time dependent manner. The neutrophilic subtype dominates in number amongst the total infiltrated leukocytes, indicating its pivotal role in nasal inflammation-induced olfactory dysfunction. In this study, we constructed a persistent AR-induced olfactory loss mouse model, losing the ability to recover from dysfunction if the disease duration more than eight weeks, which implies that timely treatments are necessary. Meanwhile, this mouse model could provide an easy and reliable system to clarify the mechanisms of AR-induced irreversible olfactory dysfunction.

Olfactory-ensheathing cells promote physiological repair of injured recurrent laryngeal nerves and functional recovery of glottises in dogs.

The aim of this study was to investigate whether the transplantation of olfactory-ensheathing cells (OECs) could physiologically repair severely injured recurrent laryngeal nerve (RLN) in dogs. Adult Beagle dogs were surgically introduced with a 10-mm defect in the left RLN and transplanted with a nerve guide (NEUROLAC) containing dog olfactory mucosa-olfactory-ensheathing cells (OM-OECs) in matrigel. The effects of OM-OECs on the morphology, histology, and electrophysiology of the injured RLNs, glottis movement, and voice acoustics were comparatively studied. Two months after transplantation, the normal dogs (group N) had intact left RLNs that contained axons well organized as bundles, transmitted action potentials of high amplitudes without latent phases, and modulated glottis movement to produce normal voices. The RLN-damaged dogs transplanted with OM-OECs (group CTT) had pieces of nerves regenerated in the place of the defects, which contained fewer axons scattered in the internal nerve membrane and wrapped peripherally by the connective tissue, prevented the distal trunk of the defected RLN from shrinking, transmitted action potentials of lower amplitudes with latent phases, and modulated a slightly impaired glottis movement to produce voices with slight differences compared to the N dogs. The RLN-damaged dogs without OM-OECs (group NC) had no nerves generated at the defective or the damaged area, leading to a shrinkage in the enervated distal nerve trunks; a blockage in nerve pulse transit; a paralysis of the left vocal cords; an impaired glottis movement; and abnormal voices. Transplantation of OM-OECs promoted nerve regeneration, and the recoveries of glottises and voices in dogs with RLN injury.

Deprivation of asparagine triggers cytoprotective autophagy in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC), one of the most common malignancies in the head and neck, has poor prognosis and high mortality. The need of novel and effective treatment for LSCC is urgent. Asparaginase, an enzyme-depriving asparagine, has been employed for the treatment of various cancers. In this study, we reported for the first time that asparaginase could induce remarkable cytotoxicity and caspase-dependent apoptosis in human LSCC Tu212 and Tu686 cells. Meanwhile, autophagy was triggered by asparaginase in LSCC cells, which was confirmed by accumulation of autophagosomes and the conversion of light chain 3-I (LC3-I) to LC3-II. Importantly, inhibition of autophagy by chloroquine (CQ) significantly enhanced asparaginase-induced cytotoxicity, indicating that autophagy has a cytoprotective role in asparaginase-treated LSCC cells. Meanwhile, we found that mitochondrial-originated reactive oxygen species (ROS) participated in asparaginase-induced autophagy and cytotoxicity. N-acetyl-L-cysteine (NAC), a common antioxidant, was employed to scavenge ROS, and our results demonstrated that NAC could significantly block asparaginase-induced autophagy and attenuate asparaginase-induced cytotoxicity, indicating that intracellular ROS played a crucial role in asparagine deprivation therapy. Furthermore, western blot analysis showed that asparaginase-induced autophagy was mediated by inactivation of Akt/mTOR and activation of the Erk signaling pathway in Tu212 and Tu686 cells. Therefore, these results indicated the protective role of autophagy in asparaginase-treated LSCC cells and provided a new attractive therapeutic strategy for LSCC by asparaginase alone or in combination with autophagic inhibitors.

Pectolinarigenin Suppresses the Tumor Growth in Nasopharyngeal Carcinoma.

BACKGROUND/AIMS: Nasopharyngeal cancer (NPC) is one of the common human malignant diseases all over the world, and chemotherapy remains the main therapy for NPC. However, the survival and life quality of NPC patients are still very poor. Thus, novel and selective anti-tumor agents are pressingly needed. Our previous study identified pectolinarigenin as a novel effective anti-tumor drug candidate for NPC. In this study, we further investigated its anti-tumor activities and explored the potential molecular mechanism. METHODS: NPC C666-1 cells were cultured and treated by pectolinarigenin. Cell proliferation assay, colony formation assay, Transwell assay and wound healing assay were conducted and cell apoptosis was detected by flow cytometry. Mitochondrial transmembrane potential and ROS were also observed. NPC subcutaneous xenograft mice model was established to evaluate the anti-tumor effect of pectolinarigenin in vivo. RESULTS: We observed that treatment of pectolinarigenin inhibited cell viability and cell migration of NPC C666-1 cells in concentration- and time-dependent manner. Pectolinarigenin induced cell apoptosis in C666-1 cells detected by flow cytometry analysis, which was associated with the activation of mitochondrial-related apoptosis and the accumulation of reactive oxygen species (ROS). Pectolinarigenin also activated caspase signaling pathway. The in vivo experiment of subcutaneous xenograft mice model also indicated that the administration of pectolinarigenin could decrease the tumor growth of NPC and no severe toxicity was observed. CONCLUSIONS: Based on our findings, we conclude that pectolinarigenin could suppress the tumor growth of NPC, which verifies it as a new therapeutic agent for treating this devastating disease.

Structure-Activity Relationship Study of (E)-3-(6-Fluoro-1H-indol-3-Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) Against Metastatic Colorectal Cancers Resistant to Oxaliplatin.

Advanced metastatic colorectal cancer (mCRC) and the development of drug resistance to chemotherapy pose significant challenges in clinical settings. In previous studies, we have demonstrated the potent cytotoxic activity of (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) and related 30 derivatives against mCRC by targeting microtubules. In this study, we aimed to evaluate the efficacy of the 31 compounds and explore the structure-activity relationship (SAR) against oxaliplatin-resistant mCRC. We found that most of the derivatives showed high sensitivity toward the oxaliplatin-resistant HCT-116/L cells. Particularly, FC116 exhibited a better GI50 value against the resistant mCRC cell line, HCT-116/L, compared to standard therapies. We also observed a safer therapeutic window for FC116 and a synergistic effect when it was used in combination with oxaliplatin. Mechanistically, FC116 induced the G2/M phase arrest by downregulating cyclin B1 expression through its interaction with microtubules in resistant colorectal cancer cells. Furthermore, in vivo experiments demonstrated that FC116 significantly suppressed tumor growth, achieving a 78% reduction at a dose of 3 mg/kg, which was superior to the 40% reduction achieved by oxaliplatin treatment. Overall, our findings suggest that the indole-chalcone compound FC116 represents a promising lead for chemotherapy in oxaliplatin-resistant mCRC.

Eosinophil extracellular traps in respiratory ailment: Pathogenic mechanisms and clinical translation.

Background: Eosinophilic extracellular traps (EETs) are reticular complexes comprising deoxyribonucleic-Acid (DNA) fibers and granule proteins. Aims: EETs play a crucial role in antimicrobial host responses and are pathogenic when overproduced or under degraded. EETs created by eosinophils appear to enable vital immune responses against extra-cellular pathogens, nevertheless, trap overproduction is evident in pathology. Materials & Methods: As considerably research is performed, new data affirmed that EETs can alter the outcome of respiratory ailment. Results: We probe into the disclosure and specificity of EETs produced in reaction to various stimuli and propose a role for those frameworks in ailment pathogenesis and the establishment of chronic, unresolved inflammation. Discussion: Whether EETs can be used as a prospective brand-new target for the diagnosis, treatment and prognosis of respiratory ailments is a scientific theme worth studying. Conclusion: We probe into the disclosure and specificity of EETs produced in reaction to various stimuli and propose a role for those frameworks in ailment pathogenesis and the establishment of chronic, unresolved inflammation.

Blood Eosinophil Percentage and Improved Sinus CT Score as Diagnostic Tools for ECRS.

Objective: Differentiating 2 types of chronic rhinosinusitis with nasal polyps (CRSwNP) is important for the treatment. The current diagnostic methods using single indicators, including peripheral blood eosinophils and traditional sinus computed tomography (CT) scores, are not accurate. In this study, we aimed to investigate the diagnostic value of combining peripheral blood eosinophils and improved sinus CT scores for eosinophic chronic rhinosinusitis (ECRS). Study Design: Retrospective cohort. Setting: Tertiary medical center. Methods: We conducted a study involving 81 patients with CRSwNP. Peripheral blood samples were collected from the non-ECRS and ECRS groups. Improved three-dimensional volume image analysis and Lund-Mackay scoring system were performed to quantify the thickening of sinus mucosa. Multivariate binary logistic regression analysis was carried out to detect the predictive value of the scoring indicators. For significant indexes, receiver operating characteristic (ROC) curve analysis was applied. Results: The ECRS group had higher levels of blood eosinophil percentage and count, ethmoid sinus score, total sinus score, the ratio of ethmoid sinus score and maxillary sinus score, and the difference between ethmoid and maxillary score, compared to the non-ECRS group (P < 0.05). Binary logistic regression analysis demonstrated that both blood eosinophil percentage and the improved E - M score (subtraction of ethmoid and maxillary sinus scores) were significant predictors of ECRS diagnosis (P < .01). ROC curve analysis indicated that the combination of improved E - M score and blood eosinophil percentage had a higher diagnostic value compared to either factor alone (area under the curve = 0.874). Conclusion: Our study suggested the combination of improved total ethmoid sinus-maxillary score and blood eosinophil percentage is more accurate in predicting the diagnosis of ECRS.