Application of modified spiral tracheoplasty in thyroid carcinoma with trachea invasion: a retrospective analysis of 15 cases.

BACKGROUND: To describe the indications, techniques and preliminary experience of modified spiral tracheoplasty in the reconstruction of large tracheal defect after thyroidectomy. METHODS: The medical records of patients who underwent tracheal torsion to repair large tracheal defects after thyroid carcinoma surgery from January 2019 to January 2022 were retrospectively reviewed. The extent of tracheal defect, duration of tracheal reconstruction, postoperative complications and surgery results were analyzed. RESULTS: The duration of tracheal reconstruction was 30-60 min. No postoperative bleeding, incision infection, tracheostomy stenosis occurred. Recurrent laryngeal nerve palsy occurred in 5 patients. All patients were followed up for 24 to 60 months. The 2-year overall survival rate was 100%, the 2-year local control rate of trachea was 100%, and the 2-year tumor-free survival rate was 81.8%. CONCLUSION: The modified spiral tracheoplasty is a safe and effective method to repair the large defect of trachea after thyroid carcinoma invading the trachea.

Investigation of differentially expressed genes related to cellular senescence between high-risk and non-high-risk groups in neuroblastoma.

Object: This study aims to identify differentially expressed genes (DEGs) between high-risk and non-high-risk groups in neuroblastoma (NB), construct a prognostic model, and establish a risk score formula. Materials and methods: The NB dataset GSE49710 (n = 498) from the GEO database served as the training cohort to select DEGs between high-risk and non-high-risk NB groups. Cellular senescence-related genes were obtained from the Aging Atlas database. Intersection genes from both datasets were identified as key genes of cellular senescence-related genes (SRGs). A prognostic model was constructed using Univariate Cox regression analysis and the Lasso algorithm with SRGs. Validation was performed using the E-MTAB-8248 cohort (n = 223). The expression levels of AURKA and CENPA were evaluated via RT-qPCR in two clinical NB sample groups. Results: Eight SRGs were identified, and a prognostic model comprising five genes related to cellular senescence was constructed. AURKA and CENPA showed significant expression in clinical samples and were closely associated with cellular senescence. Conclusion: The prognostic model consisted with five cellular senescence related genes effectively predicts the prognosis of NB patients. AURKA and CENPA represent promising targets in NB for predicting cellular senescence, offering potential insights for NB therapy.

Leveraging oncovirus-derived antigen against the viral malignancies in adoptive cell therapies.

Adoptive cell therapies (ACTs) have revolutionized cancer immunotherapy, prompting exploration into their application against oncoviruses. Oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV) contribute significantly (12-25%) to human malignancies through direct or indirect oncogenic mechanisms. These viruses persistently or latently infect cells, disrupt cellular homeostasis and pathways, challenging current antiviral treatment paradigms. Moreover, viral infections pose additional risks in the setting of long-term cancer therapy and lead to morbidity and mortality. Virally encoded oncoproteins, which are tumor-restricted, immunologically foreign, and even uniformly expressed, represent promising targets for patient-tailored ACTs. This review elucidates the rationale for leveraging viral antigen-specific ACTs in combating viral-associated malignancies. On this basis, ongoing preclinical studies consolidate our understanding of harnessing ACTs against viral malignancies, underscoring their potential to eradicate viruses implicated in cancer progression. Furthermore, we scrutinize the current landscape of clinical trials focusing on virus-specific ACTs and discuss their implications for therapeutic advancement.

Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

Curcumin inhibits the growth and invasion of gastric cancer by regulating long noncoding RNA AC022424.2.

BACKGROUND: Gastric cancer, characterized by a multifactorial etiology and high heterogeneity, continues to confound researchers in terms of its pathogenesis. Curcumin, a natural anticancer agent, exhibits therapeutic promise in gastric cancer. Its effects include promoting cell apoptosis, curtailing tumor angiogenesis, and enhancing sensitivity to radiation and chemotherapy. Long noncoding RNAs (lncRNAs) have garnered significant attention as biomarkers for early screening, diagnosis, treatment, and drug response because of their remarkable specificity and sensitivity. Recent investigations have revealed an association between aberrant lncRNA expression and early diagnosis, clinical staging, metastasis, drug sensitivity, and prognosis in gastric cancer. A profound understanding of the intricate mechanisms through which lncRNAs influence gastric cancer development can provide novel insights for precision treatment and tailored management of patients with gastric cancer. This study aimed to unravel the potential of curcumin in suppressing the malignant behavior of gastric cancer cells by upregulating specific lncRNAs and modulating gastric cancer onset and progression. AIM: To identify lncRNAs associated with curcumin treatment and investigate the role of lncRNA AC022424.2 in the effects of curcumin on gastric cancer cell apoptosis, proliferation, and invasion. Furthermore, these findings were validated in clinical samples. METHODS: The study employed CCK-8 assays to assess the impact of curcumin on gastric cancer cell proliferation, flow cytometry to investigate its effects on apoptosis, and scratch and Transwell assays to evaluate its influence on the migration and invasion of BGC-823 and MGC-803 cells. Western blotting was used to gauge changes in the protein expression levels of CDK6, CDK4, Bax, Bcl-2, caspase-3, P65, and the PI3K/Akt/mTOR pathway in gastric cancer cell lines after curcumin treatment. Differential expression of lncRNAs before and after curcumin treatment was assessed using lncRNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in BGC-823 and MGC-803 cells. AC022424.2-1 knockdown BGC-823 and MGC-803 cells were generated to scrutinize the impact of lncRNA AC022424.2 on apoptosis, proliferation, migration, and invasion of gastric cancer cells. Western blotting was performed to ascertain changes in the expression of proteins implicated in the PI3K/Akt/mTOR and NF-κB signaling pathways. RT-PCR was employed to measure lncRNA AC022424.2 expression in clinical gastric cancer tissues and to correlate its expression with clinical pathological characteristics. RESULTS: Curcumin induced apoptosis and hindered proliferation, migration, and invasion of gastric cancer cells in a dose- and time-dependent manner. LncRNA AC022424.2 was upregulated after curcumin treatment, and its knockdown enhanced cancer cell aggressiveness. LncRNA AC022424.2 may have affected cancer cells via the PI3K/Akt/mTOR and NF-κB signaling pathways. LncRNA AC022424.2 downregulation was correlated with lymph node metastasis, making it a potential diagnostic and prognostic marker. CONCLUSION: Curcumin has potential anticancer effects on gastric cancer cells by regulating lncRNA AC022424.2. This lncRNA plays a significant role in cancer cell behavior and may have clinical implications in diagnosis and prognosis evaluation. The results of this study enhance our understanding of gastric cancer development and precision treatment.

Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner.

Recombinant adenovirus (rAd) regimens, including replication-competent oncolytic adenovirus (OAV) and replication-deficient adenovirus, have been identified as potential cancer therapeutics. OAV presents advantages such as selective replication, oncolytic efficacy, and tumor microenvironment (TME) remodeling. In this perspective, the principles and advancements in developing OAV toolkits are reviewed. The burgeoning rAd may dictate efficacy of conventional cancer therapies as well as cancer immunotherapies, including cancer vaccines, synergy with adoptive cell therapy (ACT), and TME reshaping. Concurrently, we explored the potential of rAd hitchhiking to adoptive immune cells or stem cells, highlighting how this approach facilitates synergistic interactions between rAd and cellular therapeutics at tumor sites. Results from preclinical and clinical trials in which immune and stem cells were infected with rAd have been used to address significant oncological challenges, such as postsurgical residual tumor tissue and metastatic tissue. Briefly, rAd can eradicate tumors through various mechanisms, resulting from tumor immunogenicity, reprogramming of the TME, enhancement of cellular immunity, and effective tumor targeting. In this context, we argue that rAd holds immense potential for enhancing cellular immunity and synergistically improving antitumor effects in combination with novel cancer immunotherapies.

Association Between ALDH2 Polymorphisms and the Risk of Diabetes Mellitus in Hypertensive Patients.

Background: Aldehyde dehydrogenase 2 (ALDH2) polymorphisms have been extensively studied in patients with hypertension (HTN) and diabetes mellitus (DM) in recent years. However, it is unclear whether ALDH2 polymorphisms are correlated with the risk of developing DM in patients with HTN. This study was designed to examine the association between ALDH2 single nucleotide polymorphism (SNP) rs671 and the risks of DM in patients with HTN. Methods: This study retrospectively analyzed the patients with HTN who were treated in Meizhou People's Hospital from August 2016 to December 2020, 788 HTN patients with DM as case patients, and 1632 HTN patients without DM history as controls. ALDH2 polymorphisms were analyzed using a polymerase chain reaction (PCR)-gene chip. Differences in ALDH2 genotypes between subjects and controls were compared. To analyze the relationship between ALDH2 genotype and DM risk, multiple logistic regression analysis was performed after adjusting for gender, age, smoking history, and drinking history. Results: The proportion of the G/A plus A/A genotype was significantly higher in patients with DM than in controls (52.8% vs 48.2%, P=0.033). DM patients with G/A genotype had lower LDL-C (P<0.017) than those with G/G genotype. The results of logistic regression analysis indicated that the G/A genotype increased the risk of DM in HTN patients, with an adjusted odds ratio (OR) of 1.209 (95% confidence interval (CI) 1.010-1.446) (P=0.038), whereas the G/A plus A/A genotype in the dominant model increased the risk of DM significantly, with an adjusted OR of 1.203 (95% CI 1.013-1.428) (P=0.035). Conclusion: ALDH2 A allele (G/A + A/A genotype) increased the risk of DM in patients with HTN.

Does an apple a day keep away diseases? Evidence and mechanism of action.

Apples and their products exemplify the recently reemphasized link between dietary fruit intake and the alleviation of human disease. Their consumption does indeed improve human health due to their high phytochemical content. To identify potentially relevant articles from clinical trials, some epidemiological studies and meta-analyses, and in vitro and in vivo studies (cell cultures and animal models), PubMed was searched from January 1, 2012, to May 15, 2022. This review summarized the potential effects of apple and apple products (juices, puree, pomace, dried apples, extracts rich in apple bioactives and single apple bioactives) on health. Apples and apple products have protective effects against cardiovascular diseases, cancer, as well as mild cognitive impairment and promote hair growth, healing of burn wounds, improve the oral environment, prevent niacin-induced skin flushing, promote the relief of UV-induced skin pigmentation, and improve the symptoms of atopic dermatitis as well as cedar hay fever among others. These effects are associated with various mechanisms, such as vascular endothelial protection, blood lipids lowering, anti-inflammatory, antioxidant, antiapoptotic, anti-invasion, and antimetastatic effects. Meanwhile, it has provided an important reference for the application and development of medicine, nutrition, and other fields.

Sodium Danshensu stabilizes atherosclerotic vulnerable plaques by targeting IKKß mediated inflammation in macrophages.

BACKGROUND: The primary cause of acute cardiovascular events with high mortality is the rupture of atherosclerotic plaque followed by thrombosis. Sodium Danshensu (SDSS) has shown potential in inhibiting the inflammatory response in macrophages and preventing early plaque formation in atherosclerotic mice. However, the specific targets and detailed mechanism of action of SDSS are still unclear. OBJECTIVE: This study aims to investigate the efficacy and mechanism of SDSS in inhibiting inflammation in macrophages and stabilizing vulnerable plaques in atherosclerosis (AS). MATERIALS AND METHODS: The efficacy of SDSS in stabilizing vulnerable plaques was demonstrated using various techniques such as ultrasound, Oil Red O staining, HE staining, Masson staining, immunohistochemistry, and lipid analysis in ApoE-/- mice. Subsequently, IKKß was identified as a potential target of SDSS through protein microarray, network pharmacology analysis, and molecular docking. Additionally, ELISA, RT-qPCR, Western blotting, and immunofluorescence were employed to measure the levels of inflammatory cytokines, IKKß, and NF-κB pathway-related targets, thereby confirming the mechanism of SDSS in treating AS both in vivo and in vitro. Finally, the impact of SDSS was observed in the presence of an IKKß-specific inhibitor. RESULTS: Initially, the administration of SDSS led to a decrease in the formation and area of aortic plaque, while also stabilizing vulnerable plaques in ApoE-/- mice. Furthermore, it was identified that IKKß serves as the primary binding target of SDSS. Additionally, both in vivo and in vitro experiments demonstrated that SDSS effectively inhibits the NF-κB pathway by targeting IKKß. Lastly, the combined use of the IKKß-specific inhibitor IMD-0354 further enhanced the beneficial effects of SDSS. CONCLUSIONS: SDSS stabilized vulnerable plaques and suppressed inflammatory responses by inhibiting the NF-κB pathway through its targeting of IKKß.

A newborn with convulsions 12 days after birth was misdiagnosed as neonatal intracranial hemorrhage: Case report.

INTRODUCTION: Cases with early diagnosis of neonatal tuberous sclerosis syndrome (TSC) are relatively seldom seen, and misdiagnosis of intracranial hemorrhage is even more rare. We retrospectively analyzed the clinical data of a case of neonatal tuberous sclerosis with atypical early symptoms and misdiagnosed as more common intracranial hemorrhage of the newborn. PATIENT CONCERNS: The child was female and had no obvious cause of convulsion 12 days after birth. The local hospital was initially diagnosed as "neonatal intracranial hemorrhage, congenital heart disease," and still had convulsions after 5 days of treatment, so it was transferred to neonatal intensive care unit of our hospital. DIAGNOSIS: After admission, cardiac color ultrasound, magnetic resonance imaging, and electroencephalogram were performed, and TSC was diagnosed in combination with clinical symptoms. However, no known pathogenic mutations such as TSC1 and TSC2 were detected by peripheral blood whole exon sequencing. INTERVENTION: After a clear diagnosis, sirolimus, and vigabatrin were given. But there were still convulsions. Topiramate, valproic acid, and oxcarbazepine were successively added to the outpatient department for antiepileptic treatment, and vigabatrin gradually decreased. OUTCOME: Up to now, although the seizures have decreased, they have not been completely controlled. CONCLUSIONS: The TSC of neonatal tuberous sclerosis is different from that of older children. It is usually characterized by respiratory distress and arrhythmia, and may be accompanied by convulsions, but the activity between attacks is normal. However, neonatal intracranial hemorrhage can be caused by premature delivery, birth injury, hypoxia, etc. Its characteristics are acute onset, severe illness, and rapid progression. Consequently, the diagnosis of these 2 diseases should not only be based on medical imaging, but also be combined with their clinical characteristics. When the imaging features are inconsistent with the clinical diagnosis, a comprehensive evaluation should be made again. The timing and pattern of onset of neonatal convulsions can help in differential diagnosis. If there is cardiac rhabdomyoma, subependymal or cortical nodule, skin low melanoma, etc, the possibility of neonatal TSC should be considered, and the diagnosis should be made according to its diagnostic criteria to avoid or reduce misdiagnosis.

COMBINATION OF VITRECTOMY AND INTENTIONAL MACULAR DETACHMENT IS ASSOCIATED WITH A FASTER EDEMATOUS REGRESSION THAN VITRECTOMY ALONE IN THE TREATMENT OF REFRACTORY DIABETIC MACULAR EDEMA.

PURPOSE: To compare clinical outcomes in eyes with refractory diabetic macular edema managed by vitrectomy combined with and without intentional macular detachment (IMD). METHODS: This is a retrospective cohort study. Forty-one eyes with diabetic macular edema that were previously poorly responsive to at least 5 monthly anti-vascular endothelial growth factor and at least twice switch therapy previously were included in this study. All eyes underwent pars plana vitrectomy with internal limiting membrane peeling, 21 of which were combined with an IMD procedure (assigned to an IMD group) and 20 of which did not have IMD performed (nMD group). Macular morphologic and visual acuity changes were analyzed from baseline through the endpoint (24 weeks) postprocedure, and were compared between groups. RESULTS: All patients completed at least six months of follow-up, with a mean of 29.7 weeks (24-56 weeks). The mean central retinal thickness reduction was greater in the IMD group than that in the nMD group at 1 week (P = 0.001), 2 weeks (P = 0.008), and 4 weeks (P = 0.004), but there was no statistically significant difference at 12 weeks (P = 0.051) or 24 weeks (P = 0.056). There were no significant differences in the mean changes of best-corrected visual acuity from baseline to the 24 weeks endpoint in either group (P = 0.83). CONCLUSION: Vitrectomy can release macular edema in the eyes with refractory diabetic macular edema. Combined with IMD technical, patients seemed to achieve a faster central retinal thickness decrease but neither the final morphologic outcome nor the visual acuity was affected.

Serum Trimethylamine N-oxide and the Diversity of the Intestinal Microbial Flora in Type 2 Diabetes Complicated by Diabetic Kidney Disease.

BACKGROUND: Trimethylamine N-oxide (TMAO) serves as a metabolite of intestinal bacteria as well as a urotoxin influencing the prognosis of chronic kidney disease (CKD), which has become a research hotspot in the field of kidney disease. This study preliminarily explored the alternations of the microbial flora and serum TMAO in patients with type 2 diabetes mellitus (T2DM) complicated with diabetic kidney disease (DKD). METHODS: Seventeen T2DM patients at the Affiliated Hospital of Zunyi Medical University between September 2018 and February 2019 were included. Among these patients, 8 patients had T2DM complicated with DKD. Eight healthy volunteers constituted the control group. Fresh stool was collected for Illumina sequencing. Based on the sequencing outcomes, the flora diversity and species differences were analyzed. Serum TMAO, cystatin C, urinary albumin/urine creatinine ratios (ACRs), and routine biochemical outcomes were also compared. RESULTS: The DKD group exhibited a significantly higher TMAO level than the remaining groups. The high-TMAO group had a significantly increased ACR level compared with the low-TMAO group. TMAO positively correlated with the ACR. Compared with the control group, the DKD group exhibited a decreased flora diversity. At the genus level, both the T2DM group and the DKD group showed decreased numbers of Alloprevotella and Megasphaera compared with the control group. The difference in Megasphaera between the DKD group and the control group was significant. CONCLUSIONS: The alternation of the intestinal microbial flora may participate in the development of DKD, and TMAO and chronic inflammation might be important factors for DKD development.

Two birds with one stone: YQSSF regulates both proliferation and apoptosis of bone marrow cells to relieve chemotherapy-induced myelosuppression.

ETHNOPHARMACOLOGICAL RELEVANCE: Yiqi Shengsui formula (YQSSF) is a commonly used formula to treat chemotherapy-induced myelosuppression, but little is known about its therapeutic mechanisms. AIM OF THIS STUDY: This study aims to examine the effect of YQSSF in treating myelosuppression and explore its mechanism. MATERIALS AND METHODS: A myelosuppression BALB/c mouse model was established by intraperitoneal (i.p.) injection of cyclophosphamide (CTX). The efficacy of YQSSF in alleviating chemotherapy-induced myelosuppression was evaluated by blood cell count, immune organ (thymus, spleen, liver) index, bone marrow nucleated cell (BMNC) count and histopathological analysis of bone marrow and spleen. Then, ultra-performance liquid chromatograph quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to analyze the ingredients of YQSSF extract. Key effects and potential mechanism of YQSSF extract in alleviating myelosuppression were predicted by network pharmacology method. Finally, cell cycle and TUNEL staining of bone marrow cells was detected to verify the key effects, and RT-qPCR or Western blotting were performed to measure the gene and protein expressions of the effect targets respectively to confirm the predicted mechanism of YQSSF for myelosuppression. RESULTS: YQSSF up-regulated the number of peripheral blood leukocytes and BMNC, reduced spleen index and liver index, improved the pathological morphology of bone marrow and spleen. A total of 40 ingredients were isolated from YQSSF extract using UPLC-Q/TOF-MS analysis. Network pharmacology revealed that YQSSF regulated both proliferation and apoptosis to alleviate myelosuppression. Finally, YQSSF decreased G0/G1 ratio, increased the proportion of bone marrow cells in S phase and proliferation index (PI), and reduced apoptotic cells in femur bone marrow. RT-qPCR and Western blotting showed that YQSSF up-regulated the expression levels of CDK4, CDK6, CyclinB1, c-Myc and Bcl-2, as well as down-regulated the expression levels of Cyt-c, Fas, Caspase-8/3 and p53. CONCLUSIONS: YQSSF promotes the proliferation and inhibits the apoptosis of bone marrow cells to relieve chemotherapy-induced myelosuppression.

Interactions between NLRP3 inflammasome and glycolysis in macrophages: New insights into chronic inflammation pathogenesis.

NLRP3 inflammasome activation in macrophages fuels sterile inflammation, which has been tied with metabolic reprogramming characterized by high glycolysis and low oxidative phosphorylation. The key enzymes in glycolysis and glycolysis-related products can regulate and activate NLRP3 inflammasome. In turn, NLRP3 inflammasome is considered to affect glycolysis, as well. However, the exact mechanism remains ambiguous. On the basis of these findings, the focus of this review is mainly on the developments in our understanding of interaction between NLRP3 inflammasome activation and glycolysis in macrophages, and small molecule compounds that influence the activation of NLRP3 inflammasomes by regulating glycolysis in macrophages. The application of this interaction in the treatment of diseases is also discussed. This paper may yield valuable clues for development of novel therapeutic agent for NLRP3 inflammasome-related diseases.

Circular RNA Circ-0002570 Accelerates Cancer Progression by Regulating VCAN via MiR-587 in Gastric Cancer.

BACKGROUND: Circular RNAs (circRNAs) are closely associated with the occurrences and progress of gastric cancer (GC). We aimed to delve into the function and pathological mechanism of Circular RNA-0002570 (circ-0002570) in GC progression. METHODS: CircRNAs differentially expressed in GC were screened using bioinformatics technology. The expression of circ-0002570 was detected in GC specimens and cells via qRT-PCR, and the prognostic values of circ-0002570 were determined. The functional roles of circ-0002570 on proliferation, migration, and invasion in GC cells were explored in vitro and in vivo. Interaction of circ-0002570, miR-587, and VCAN was confirmed by dual-luciferase reporter assays, Western blotting, and rescue experiments. RESULTS: Circ-0002570 expression was distinctly increased in GC tissues compared to adjacent normal specimens, and GC patients with higher circ-0002570 expressions displayed a short survival. Functionally, knockdown of circ-0002570 resulted in the inhibition of cell proliferation, migration, and invasion, and suppressed tumor growth in vivo. Mechanistically, miR-587 was sponged by circ-0002570. VCAN expression in NSCLC was directly inhibited by miR-587. Overexpression of circ-0002570 prevented VCAN from miR-587-mediated degradation and thus facilitated GC progression. CONCLUSION: The circ-0002570-miR-587-VCAN regulatory pathway promoted the progression of GC. Our findings provided potential new targets for the diagnosis and therapy of GC.

The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages.

NLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE-/- mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE-/- mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE-/- mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1ß and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

Binding of Duck Tembusu Virus Nonstructural Protein 2A to Duck STING Disrupts Induction of Its Signal Transduction Cascade To Inhibit Beta Interferon Induction.

Duck Tembusu virus (DTMUV), which is similar to other mosquito-borne flaviviruses that replicate well in most mammalian cells, is an emerging pathogenic flavivirus that has caused epidemics in egg-laying and breeding waterfowl. Immune organ defects and neurological dysfunction are the main clinical symptoms of DTMUV infection. Preinfection with DTMUV makes the virus impervious to later interferon (IFN) treatment, revealing that DTMUV has evolved some strategies to defend against host IFN-dependent antiviral responses. Immune inhibition was further confirmed by screening for DTMUV-encoded proteins, which suggested that NS2A significantly inhibited IFN-ß and IFN-stimulated response element (ISRE) promoter activity in a dose-dependent manner and facilitated reinfection with duck plague virus (DPV). DTMUV NS2A was able to inhibit duck retinoic acid-inducible gene-I (RIG-I)-, and melanoma differentiation-associated gene 5 (MDA5)-, mitochondrial-localized adaptor molecules (MAVS)-, stimulator of interferon genes (STING)-, and TANK-binding kinase 1 (TBK1)-induced IFN-ß transcription, but not duck TBK1- and interferon regulatory factor 7 (IRF7)-mediated effective phases of IFN response. Furthermore, we found that NS2A competed with duTBK1 in binding to duck STING (duSTING), impaired duSTING-duSTING binding, and reduced duTBK1 phosphorylation, leading to the subsequent inhibition of IFN production. Importantly, we first identified that the W164A, Y167A, and S361A mutations in duSTING significantly impaired the NS2A-duSTING interaction, which is important for NS2A-induced IFN-ß inhibition. Hence, our data demonstrated that DTMUV NS2A disrupts duSTING-dependent antiviral cellular defenses by binding with duSTING, which provides a novel mechanism by which DTMUV subverts host innate immune responses. The potential interaction sites between NS2A and duSTING may be the targets of future novel antiviral therapies and vaccine development.IMPORTANCE Flavivirus infections are transmitted through mosquitos or ticks and lead to significant morbidity and mortality worldwide with a spectrum of manifestations. Infection with an emerging flavivirus, DTMUV, manifests with clinical symptoms that include lesions of the immune organs and neurological dysfunction, leading to heavy egg drop and causing serious harm to the duck industry in China, Thailand, Malaysia, and other Southeast Asian countries. Mosquito cells, bird cells, and mammalian cell lines are all susceptible to DTMUV infection. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and may pose a threat to mammalian health. However, the pathogenesis of DTMUV is largely unclear. Our results show that NS2A strongly blocks the STING-induced signal transduction cascade by binding with STING, which subsequently blocks STING-STING binding and TBK1 phosphorylation. More importantly, the W164, Y167, or S361 residues in duSTING were identified as important interaction sites between STING and NS2A that are vital for NS2A-induced IFN production and effective phases of IFN response. Uncovering the mechanism by which DTMUV NS2A inhibits IFN in the cells of its natural hosts, ducks, will help us understand the role of NS2A in DTMUV pathogenicity.

Lewis Acid Promoted Aerobic Oxidative Coupling of Thiols with Phosphonates by Simple Nickel(II) Catalyst: Substrate Scope and Mechanistic Studies.

Exploring new catalysts for efficient organic synthesis is among the most attractive topics in chemistry. Here, using Ni(OAc)2/LA as catalyst (LA: Lewis acid), a novel catalyst strategy was developed for oxidative coupling of thiols and phosphonates to phosphorothioates with oxygen oxidant. The present study discloses that when Ni(OAc)2 alone was employed as the catalyst, the reaction proceeded very sluggishly with low yield, whereas adding non-redox-active metal ions such as Y3+ to Ni(OAc)2 dramatically promoted its catalytic efficiency. The promotional effect is highly Lewis acidity dependent on the added Lewis acid, and generally, a stronger Lewis acid provided a better promotional effect. The stopped-flow kinetics confirmed that adding Y(OTf)3 can obviously accelerate the activation of thiols by Ni(II) and next accelerate its reaction with phosphonate to generate the phosphorothioate product. ESI-MS characterizations of the catalyst disclosed the formation of the heterobimetallic Ni(II)/Y(III) species in the catalyst solution. Additionally, this Ni(II)/LA catalyst can be applied in the synthesis of a series of phosphorothioate compounds including several commercial bioactive compounds. This catalyst strategy has clearly supported that Lewis acid can significantly improve the catalytic efficiency of these traditional metal ions in organic synthesis, thus opening up new opportunities in their catalyst design.

FACEDOWN POSITIONING AFTER VITRECTOMY WILL NOT FACILITATE MACULAR HOLE CLOSURE BASED ON SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY IMAGING IN GAS-FILLED EYES: A Prospective, Randomized Comparative Interventional Study.

PURPOSE: To compare clinical outcomes in eyes with macular hole (MH) managed by either facedown (FD) or no-FD (nFD) postoperative positioning protocols. METHODS: This is a prospective randomized cohort study. Eighty eyes of 80 consecutive patients with MH who had undergone vitrectomy surgery with internal limiting membrane peeling and gas tamponade were included in this study. Forty eyes of 40 patients who were kept in FD position for 3 days after surgery were assigned to the FD group, 40 eyes of 40 patients with nFD positioning were assigned to the nFD group. Macular hole was examined with swept-source optical coherence tomography images at 1 day, 2 days, 3 days, 2 weeks, 1 month, and 3 months after surgery. The MH closure rate and change of best-corrected visual acuity were compared. RESULTS: At postoperative Day 1, MH was closed in 24 of 32 eyes (with clear optical coherence tomography images) (75%) in the FD group and 23 of 30 eyes (with clear optical coherence tomography images) (77%) in the nFD group (P = 0.97). At postoperative Day 2, MH closure was confirmed in 32 of 36 eyes (88.9%) in the FD group and in 31 of 33 eyes (94%) in the nFD group (P = 0.84), and the results were unchanged at Day 3. At 2 weeks after surgery, clear optical coherence tomography images were acquired from all eyes in both groups, and MH closure was confirmed in 36 of 40 eyes (90%) in the FD group and in 37 of 40 (92.5%) eyes in the nFD group (P = 0.91). Macular hole closure was not achieved in eyes that were kept open by Day 3 after surgery, and none of the eyes with confirmed MH closure by Day 3 had a reopening of the MH by 3 months. The distribution of macular configuration at 3 months was not significantly different between the two groups (P = 0.96). There was no difference in terms of the improvement in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letters gain) between the 2 groups at 1 month (P = 0.22) and 3 months (P = 0.45). CONCLUSION: The nFD protocol neither delayed the MH closure nor decreased the final closure rate after vitrectomy surgery. Therefore, postoperative prone position seems to be unnecessary for all MH repair procedures.

Lung Adenocarcinoma has a Higher Risk of Lymph Node Metastasis than Squamous Cell Carcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: Controversy still exists in which subtype of non-small-cell lung cancer [squamous cell carcinoma (SCC) or adenocarcinoma] is more likely to have lymph node (LN) metastasis. The aim of this study is to compare the pattern of LN metastasis in two cohorts of matched patients surgically treated for SCC or adenocarcinoma. METHODS: A retrospective analysis of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy without preoperative treatment for lung SCC or adenocarcinoma was conducted in this study. Data for analysis consisted of age, gender, tumor size, lobe-specific tumor location, tumor location (peripheral or central), and pathologic findings. We conducted the propensity score-matched (PSM) analysis to eliminate potential bias effects of possible confounding factors. RESULTS: From January 2015 to December 2016 in our department, we finally included a total of 387 patients (including 63 patients with SCC and 324 patients with adenocarcinoma) for analysis. For the unmatched cohort, there was no sufficient evidence of significantly different number of positive LNs (P = 0.90) and rate of LN metastasis (P = 0.23) between SCC patients and adenocarcinoma patients. However, potential confounding factors, for example gender, tumor size, tumor location, tumor differentiation, and total number of dissected LNs, were significantly different between patients with SCC and those with adenocarcinoma. In the analysis of matched cohort after PSM analysis, those above confounding factors were comparable between the two groups. However, patients with adenocarcinoma had significantly more mean positive LNs (2.2 and 0.7; P = 0.008) and a higher rate of LN metastasis (53% and 29%; P = 0.016) than those with SCC. CONCLUSIONS: Lung adenocarcinoma had a higher risk of LN metastasis than SCC, suggesting that different therapeutic modalities may be indicated for the two different subtypes of lung cancer.