Dynamic Interchain Motion in 1D Tetrathiafulvalene-Based Coordination Polymers for Highly Sensitive Molecular Recognition.

The application of electrically conductive 1D coordination polymers (1D CPs) in nanoelectronic molecular recognition is theoretically promising yet rarely explored due to the challenges in their synthesis and optimization of electrical properties. In this regard, two tetrathiafulvalene-based 1D CPs, namely [Co(m-H2TTFTB)(DMF)2(H2O)]n (Co-m-TTFTB), and {[Ni(m-H2TTFTB)(CH3CH2OH)1.5(H2O)1.5]·(H2O)0.5}n (Ni-m-TTFTB) are successfully constructed. The shorter S···S contacts between the [M(solvent)3(m-H2TTFTB)]n chains contribute to a significant improvement in their electrical conductivities. The powder X-ray diffraction (PXRD) under different organic solvents reveals the flexible and dynamic structural characteristic of M-m-TTFTB, which, combined with the 1D morphology, lead to their excellent performance for sensitive detection of volatile organic compounds. Co-m-TTFTB achieves a limit of detection for ethanol vapor down to 0.5 ppm, which is superior to the state-of-the-art chemiresistive sensors based on metal-organic frameworks or organic polymers at room temperature. In situ diffuse reflectance infrared Fourier transform spectroscopy, PXRD measurements and density functional theory calculations reveal the molecular insertion sensing mechanism and the corresponding structure-function relationship. This work expands the applicable scenario of 1D CPs and opens a new realm of 1D CP-based nanoelectronic sensors for highly sensitive room temperature gas detection.

Exclusive Coordination between Melem and Silver(I) Ions: From Irregular Aggregates to Nanofibers to Crystal Cubes.

There is growing focus on metal-free molecules and polymers owing to their potential applications in various energy and catalysis-related applications. Melem (2,5,8-triamino-s-heptazine, C6H6N10) has emerged as a metal-free material for solar-to-fuel conversion. However, its reactivity with metal ions or organic molecules has never been reported although it possesses multiple supramolecular interaction sites. In this work, we report on the synthesis of a novel metal-organic coordination framework (melem-Ag) by simply introducing Ag+ into the aqueous suspension of aggregated melem particles. Notably, as the reaction progresses, the melem disappears, and the morphology of the newly formed complex spontaneously evolves from nanofibers to single-crystalline blocks, which possess the same chemical structure, indicating that the morphology evolution is driven by Ostwald ripening. The structure of melem-Ag displays infinite nanocages of triangular pyramids consisting of melem molecules and Ag+, linked via Ag-N coordinate bonding and Ag-Ag argentophilic interactions. It is noteworthy that Ag+ is the only transition-metal cation that reacts with melem suspensions, even in the presence of other transition-metal cations (Co2+, Ni2+, Cu2+, and Zn2+). The coordination of Ag+ to melem results in metal-to-ligand charge transfer (MLCT), resulting in a quenched photoluminescence and enhanced light absorption. Exposing the melem-Ag crystals to UV light for varying time intervals results in the formation of colorful powders, which may be used for Ag-decorated photocatalysts.

Retracted: Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study. Reference: Jin-Cheng Zheng, Ke-Jie Chang, Yu-Xiang Jin, Xue-Wei Zhao, Bing Li, Meng-Hang Yang. Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling. Med Sci Monit 2019; 25:2228-2237. DOI: 10.12659/MSM.913091.

Neuropilin-1 Facilitates Pseudorabies Virus Replication and Viral Glycoprotein B Promotes Its Degradation in a Furin-Dependent Manner.

Pseudorabies virus (PRV), which is extremely infectious and can infect numerous mammals, has a risk of spillover into humans. Virus-host interactions determine viral entry and spreading. Here, we showed that neuropilin-1 (NRP1) significantly potentiates PRV infection. Mechanistically, NRP1 promoted PRV attachment and entry, and enhanced cell-to-cell fusion mediated by viral glycoprotein B (gB), gD, gH, and gL. Furthermore, through in vitro coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays, NRP1 was found to physically interact with gB, gD, and gH, and these interactions were C-end Rule (CendR) motif independent, in contrast to currently known viruses. Remarkably, we illustrated that the viral protein gB promotes NRP1 degradation via a lysosome-dependent pathway. We further demonstrate that gB promotes NRP1 degradation in a furin-cleavage-dependent manner. Interestingly, in this study, we generated gB furin cleavage site (FCS)-knockout PRV (Δfurin PRV) and evaluated its pathogenesis; in vivo, we found that Δfurin PRV virulence was significantly attenuated in mice. Together, our findings demonstrated that NRP1 is an important host factor for PRV and that NRP1 may be a potential target for antiviral intervention. IMPORTANCE Recent studies have shown accelerated PRV cross-species spillover and that PRV poses a potential threat to humans. PRV infection in humans always manifests as a high fever, tonic-clonic seizures, and encephalitis. Therefore, understanding the interaction between PRV and host factors may contribute to the development of new antiviral strategies against PRV. NRP1 has been demonstrated to be a receptor for several viruses that harbor CendR, including SARS-CoV-2. However, the relationships between NRP1 and PRV are poorly understood. Here, we found that NRP1 significantly potentiated PRV infection by promoting PRV attachment and enhanced cell-to-cell fusion. For the first time, we demonstrated that gB promotes NRP1 degradation via a lysosome-dependent pathway. Last, in vivo, Δfurin PRV virulence was significantly attenuated in mice. Therefore, NRP1 is an important host factor for PRV, and NRP1 may be a potential target for antiviral drug development.

Salidroside regulates tumor microenvironment of non-small cell lung cancer via Hsp70/Stub1/Foxp3 pathway in Tregs.

BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) is challenging due to immune tolerance and evasion. Salidroside (SAL) is an extract in traditional Chinese medicine and has a potential antitumor effect. However, the mechanism of SAL in regulating the immunological microenvironment of NSCLC is yet to be clarified. METHODS: The mouse model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established. And then, the percentage of tumor-infiltrating T cell subsets including Treg was detected in tumor-bearing mice with or without SAL treatment. In vitro, the effect of SAL on the expression of IL-10, Foxp3 and Stub1 and the function of Treg were detected by flow cytometry. Network pharmacology prediction and molecular docking software were used to predict the target of SAL and intermolecular interaction. Furthermore, the effect of SAL on the expression of Hsp70 and the co-localization of Stub1-Foxp3 in Treg was confirmed by flow cytometry and confocal laser microscopy. Finally, Hsp70 inhibitor was used to verify the above molecular expression. RESULTS: We discovered that SAL treatment inhibits the growth of tumor cells by decreasing the percentage of tumor-infiltrated CD4+Foxp3+T cells. SAL treatment downregulates the expression of Foxp3 in Tregs, but increases the expression of Stub1, an E3 ubiquitination ligase upstream of Foxp3, and the expression of Hsp70. Inhibiting the expression of Hsp70 reverses the inhibition of SAL on Foxp3 and disrupts the colocalization of Stub1 and Foxp3 in the nucleus of Tregs. CONCLUSIONS: SAL inhibits tumor growth by regulating the Hsp70/stub1/Foxp3 pathway in Treg to suppress the function of Treg. It is a new mechanism of SAL for antitumor therapy.

Coordination-Modulated Metal Tetrathiafulvalene Octacarboxylate Frameworks for High-Performance Lithium-Ion Battery Anodes.

Modulation of the ligands and coordination environment of metal-organic frameworks (MOFs) has been an effective and relatively unexplored avenue for improving the anode performance of lithium-ion batteries (LIBs). In this study, three MOFs are synthesized, namely, M4 (o-TTFOB)(bpm)2 (H2 O)2 (where M is Mn, Zn, and Cd; o-H8 TTFOB is ortho-tetrathiafulvalene octabenzoate; and bpm is 2,2'-bipyrimidine), based on a new ligand o-H8 TTFOB with two adjacent carboxylates on one phenyl, which allows us to establish the impact of metal coordination on the performance of these MOFs as anode materials in LIBs. Mn-o-TTFOB and Zn-o-TTFOB, with two more uncoordinated oxygen atoms from o-TTFOB8- , show higher reversible specific capacities of 1249 mAh g-1 and 1288 mAh g-1 under 200 mA g-1 after full activation. In contrast, Cd-o-TTFOB shows a reversible capacity of 448 mAh g-1 under the same condition due to the lack of uncoordinated oxygen atoms. Crystal structure analysis, cyclic voltammetry measurements of the half-cell configurations, and density functional theory calculations have been performed to explain the lithium storage mechanism, diffusion kinetics, and structure-function relationship. This study demonstrates the advantages of MOFs with high designability in the fabrication of LIBs.

Evaluating angiotensin-converting enzyme 2-mediated SARS-CoV-2 entry across species.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.

Endoplasmic reticulum stress-related secretory proteins as biomarkers of early myocardial ischemia-induced sudden cardiac deaths.

Early myocardial ischemia-induced sudden cardiac deaths (EMI-SCD) remain a great diagnostic challenge for forensic pathologists due to no gross or non-specific histological pathology. The goal of this study was to assess whether three secretory proteins, related with cellular endoplasmic reticulum stress, can be applied in forensic diagnosis of EMI-SCD. These markers included LMAN2, CAPN-1, and VCP and were compared with two clinically used markers (CK-MB and cTnI). A total of 21 EMI-SCD cases with a mean age of 53.0 (± 10.5) years and a mean ischemia interval of < 2.77 (± 2.56) hours were collected. Another 23 cases (mean 44.6 ± 15.0 year old) that died from non-cardiac causes served as control. Enzyme-linked immunosorbent assay (ELISA) was performed to detect target proteins' serum concentrations in the EMI-SCD and control groups. We found that LMAN2, CAPN-1, and VCP were all significantly increased in the EMI-SCD group as compared with control serum, with the fold changes ranging from 1.48 (p = 0.0022, LMAN2), 1.33 (p = 0.041, CAPN-1), to 1.26 (p = 0.021, VCP), respectively. The concentrations of these proteins remained highly stable within 6 h and were not affected by death time, postmortem interval (< 4 h), age, and month at death. Receiver operating characteristic (ROC) curves showed that the areas under the curve (AUC) were 0.8178 (LMAN2), 0.6988 (CAPN-1), and 0.7267 (VCP), all of which were higher than CK-MB (AUC 0.5590) and cTn-I (AUC 0.5911). The diagnostic specificity (all above 60%) was obviously higher than CK-MB (43.48%) and cTnI (34.78%). In conclusion, LMAN-2, CAPN-1, and VCP could be stable serological biomarkers for diagnosis of EMI-SCD cases.

Notch pathway inhibition mediated by arsenic trioxide depletes tumor initiating cells in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is the most malignant type of lung cancer. We previously reported that arsenic trioxide (As2O3) inhibited tumor initiating cells (TICs) of SCLC in vitro. In the present study, we aimed to identify the above effect in vivo and shed light on its underlying mechanism. METHODS AND RESULTS: TICs were enriched by culturing human SCLC cell line as sphere cells in specified serum-free medium. The expression of stem cell markers, CD133 and CD44, and the in vivo tumorigenicity of both TICs and their parental cells were examined. To demonstrate the inhibitory effect of As2O3 on TICs, cell proliferation, clone formation and sphere formation assays were performed. CD133 and Notch pathway-related factors were also measured after As2O3 treatment. Xenograft models were established by injecting TICs into nude mice. Mice were treated with As2O3 for 14 days. Afterwards, the tumor volume and the expression of CD133 and Notch1 were evaluated. TICs obtained by the above-mentioned method showed elevated levels of stem cell markers and increased tumorigenicity compared with their parental cells. As2O3 treatment largely inhibited TICs proliferation, sphere formation and clonogenic capacity. As2O3 also reduced the expression of CD133 and down-regulated Notch pathway in TICs. Furthermore, As2O3 potently inhibited tumor growth, decreased the expression of CD133 and down-regulated Notch1 in tumors originating from TICs. CONCLUSIONS: Our data demonstrate that As2O3 has a remarkable inhibitory effect on TICs of SCLC both in vitro and in vivo, and the mechanism might involve the down-regulation of Notch pathway.

The safety of early administration of oral fluid following general anesthesia in children undergoing tonsillectomy: a prospective randomized controlled trial.

BACKGROUND: The feasibility and safety of administrating a small amount of oral fluid to children in the early recovery period following tonsillectomy under general anesthesia to reduce the thirst and its associated restlessness remain unknown. METHODS: This study was approved by the institutional ethics committee and adhered to the CONSORT guidelines. Pediatric patients undergoing tonsillectomy who met the inclusion and exclusion criteria of our study were randomized into the study and control groups. In the study group, patients were given a small amount of water instantly after recovering from general anesthesia, which included the recovery of the cough and deglutition reflex, and attaining grade V of muscle strength. The control group was given a small amount of water at 4 to 6 h after the operation. The incidence of nausea and vomiting and the degree of thirst relief were measured and compared between the two groups. RESULTS: Three hundred patients were randomized into each group. There was no significant difference in the incidence of nausea and vomiting at 20 min after drinking water between the two groups (P > 0.05). The thirst score of children over 5 years old in the study group was significantly lower than that of the control group (P < 0.05). CONCLUSION: Early administration of a small amount of oral fluid to children following tonsillectomy and recovering from general anesthesia is not only safe but also effective in reducing postoperative thirst. TRIAL REGISTRATION: Current Controlled Trials ChiCTR1800020058 , 12-12-2018.

Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling.

BACKGROUND The inhibitory effect of arsenic trioxide (As2O3) on lung cancer has been reported in some preclinical studies. However, its effect on small cell lung cancer (SCLC) has been poorly explored. Calcineurin and its substrate, nuclear factor of activated T cells (NFAT), mediate the downstream signaling of VEGF, and is critical in the process endothelium activation and tumor metastasis. In this study, we aimed to evaluate whether As2O3 had inhibitory effects on endothelial cells activation and the metastasis of SCLC, and to explore the possible mechanisms. MATERIAL AND METHODS In vitro, human umbilical vein endothelial cells (HUVECs) were used. Cell Counting Kit-8 assay and cell migration assay were performed to determine the effect of As2O3 on HUVECs proliferation and migration. The level of calcineurin, NFAT, downstream factors for Down syndrome candidate region 1 (DSCR1), and the endogenous inhibitor of calcineurin, were evaluated by quantitative PCR and western blotting. In vivo, SCLC metastasis models were established by injecting NCI-H446 cells into tail veins of nude mice. Tumor-bearing mice were treated with As2O3 or calcineurin inhibitor for 10 days, after which tumor metastasis in target organs was evaluated. RESULTS As2O3 significantly inhibited the proliferation and migration of endothelial cells. Also, As2O3 inhibited the expression levels of calcineurin, NFAT, and the downstream target genes CXCR7 and RND1, while it upregulated the level of DSCR1. Both As2O3 and calcineurin inhibitor exhibited notable inhibitory effect on the metastasis of SCLC, without obvious side effects. CONCLUSIONS These findings suggested that As2O3 had remarkable inhibitory effects on the endothelial cell activation and SCLC metastasis, and the mechanism might be related to the blocking of calcineurin-NFAT signaling by upregulating DSCR1.

Heart proteomic profiling discovers MYH6 and COX5B as biomarkers for sudden unexplained death.

Sudden unexplained death (SUD) is not uncommon in forensic pathology. Yet, diagnosis of SUD remains challenging due to lack of specific biomarkers. This study aimed to screen differentially expressed proteins (DEPs) and validate their usefulness as diagnostic biomarkers for SUD cases. We designed a three-phase investigation, where in the discovery phase, formalin-fixed paraffin-embedded (FFPE) heart specimens were screened through label-free proteomic analysis of cases dying from SUD, mechanical injury and carbon monoxide (CO) intoxication. A total of 26 proteins were identified to be DEPs for the SUD cases after rigorous criterion. Bioinformatics and Adaboost-recursive feature elimination (RFE) analysis further revealed that three of the 26 proteins (MYH6, COX5B and TNNT2) were potential discriminative biomarkers. In the training phase, MYH6 and COX5B were verified to be true DEPs in cardiac tissues from 29 independent SUD cases as compared with a serial of control cases (n = 42). Receiver operating characteristic (ROC) analysis illustrated that combination of MYH6 and COX5B achieved optimal diagnostic sensitivity (89.7 %) and specificity (84.4 %), with area under the curve (AUC) being 0.91. A diagnostic software based on the logistic regression formula derived from the training phase was then constructed. In the validation phase, the diagnostic software was applied to eight authentic SUD cases, seven (87.5 %) of which were accurately recognized. Our study provides a valid strategy towards practical diagnosis of SUD by integrating cardiac MYH6 and COX5B as dual diagnostic biomarkers.

Training of spatial cognitive abilities reduces symptoms of visually induced motion sickness.

Purpose: This study aims to explore the effectiveness of enhancing individual spatial cognitive abilities in alleviating the negative symptoms of visually induced motion sickness (VIMS). Additionally, it seeks to develop innovative intervention methods to improve spatial cognition and identify new treatment approaches for VIMS. Methods: The study investigated the impact of innovative interventions on spatial cognitive abilities and their modulation of VIMS susceptibility. A total of 43 participants were recruited (23 in the experimental group and 20 in the control group). The experimental group underwent six sessions of spatial cognitive ability training, while the control group engaged in activities unrelated to spatial cognition. Results: The analysis revealed that the spatial cognitive ability scores of the experimental group significantly improved after the intervention. Furthermore, the experimental group exhibited significant differences in nausea, oculomotor, disorientation, and total SSQ scores before and after the intervention, indicating that the intervention effectively mitigated VIMS symptoms. Conclusion: This study developed a virtual reality training method that effectively enhances individual spatial cognitive abilities and significantly alleviates VIMS symptoms, providing a novel and effective approach for VIMS intervention and treatment.

Arsenic trioxide elicits anti-tumor activity by inhibiting polarization of M2-like tumor-associated macrophages via Notch signaling pathway in lung adenocarcinoma.

Drug-resistant advanced lung adenocarcinoma (LUAD) is an aggressive malignancy with limited treatment options. A therapeutic strategy for drug-resistant LUAD is to target the tumor associated macrophages (TAMs), because they play an important role in tumor immune escape, progression and metastasis. In this study, we conducted in vivo and in vitro investigation of the inhibitory effect of arsenic trioxide (ATO) on polarization of TAMs educated by LUAD. We found that ATO at a concentration of 4 µM disrupted the Notch-dependent positive feedback loop between LUAD and TAMs. In this loop, ATO inhibited the expression of Jagged1 and Notch1 in LUAD and suppressed M2 polarization via down-regulating Notch-dependent paracrine of CCL2 and IL1ß. As a result, the secretion of M2-derived TGF-ß1 decreased, thus inducing inhibitions of LUAD proliferation, migration, invasion, colony formation and epithelial-mesenchymal transition. In xenograft mouse models, ATO significantly inhibited tumor growth and down-regulated infiltration of M2-like TAMs in tumor tissues. In clinical LUAD biopsy samples, high Jagged1/Notch1 expression positively correlated with tumor-infiltrated M2-like TAMs, leading to poor prognosis. In conclusion, our results identified a novel tumor immunomodulating function for ATO, which can inhibit the polarization of M2-type TAMs to exert anti-tumor effects in the tumor microenvironment. Our results demonstrated the translational potential of repurposing ATO to target TAMs for lung adenocarcinoma treatment.

[Determination of 18 caine anesthetics in animal meat using solid phase extraction combined with ultra-performance liquid chromatography-tandem mass spectrometry].

Because of the widespread application of anesthetic drugs in the fields of animal breeding and transportation, demand for the rapid, sensitive detection of anesthetic drugs in animal meat is increasing. The complex animal meat matrix contains various interfering substances, such as proteins, fats, and phospholipids, along with anesthetic drug residues at very low concentrations. Therefore, adopting appropriate pretreatment methods is necessary to improve the sensitivity of detection. In this study, a rapid, accurate analytical method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and solid phase extraction (SPE) was established to determine the contents of 18 caines in animal meat. The MS parameters, such as the collision energies of 18 caines, were optimized. Furthermore, the chromatographic separation conditions and response intensities of the caine in different mobile phases were compared. The effects of different pretreatment conditions on the extraction efficiencies of the 18 caines in meat samples and those of different purification conditions, such as extraction solvent, SPE column, and dimethylsulfoxide (DMSO) dosage, on their recoveries were investigated. Combined with the external standard method, the 18 caines in meat were successfully quantified. Sample pretreatment is a three-step process. First, in ultrasound-assisted extraction, 2.0 g samples were added to 2.0 mL water and extracted using 10 mL 0.1% (v/v) formic acid in acetonitrile under ultrasound conditions for 10 min. SPE was then performed using an Oasis PRIME HLB column. Finally, DMSO-assisted concentration was employed: the organic layer was collected and dried at 40 ℃ under a stream of N2 gas with the addition of 100 µL DMSO. Acetonitrile-water (1∶9, v/v) was added to the residue to yield a final volume of 1.0 mL for use in UPLC-MS/MS. The 18 caines were separated using an HSS T3 (100 mm×2.1 mm, 1.8 µm) column with 0.1% (v/v) formic acid in water (containing 0.02 mmol/L ammonium acetate) and methanol as mobile phases. Samples were detected using an electrospray ion source (ESI) in the positive ion and multiple reaction monitoring (MRM) modes during UPLC-MS/MS. Under the optimized conditions, the 18 target caine anesthetics displayed good linearities in the range of 1.00-50.0 µg/L, and the correlation coefficients (R2) were >0.999. The respective limits of detection (LODs) and quantification (LOQs) were 0.2-0.5 µg/kg, and 0.6-1.5 µg/kg. In pork, beef, and mutton samples, the recoveries obtained at three spiked levels were 83.4%-100.4% with relative standard deviations (RSDs) of 3.1%-8.5%. This simple, rapid, sensitive method may be applied in the detection of 18 caine anesthetics in animal meat and may provide technical support to the food safety department in China in monitoring the residues of caine anesthetics in animal meat.

MDM2-mediated Inhibitory Effect of Arsenic Trioxide on Small Cell Lung Cancer Cell Line by Degrading Mutant p53.

INTRODUCTION: Small cell lung cancer (SCLC) is featured by a high TP53 mutant rate. Our previous research found that arsenic trioxide (As2O3) could significantly inhibit the growth and metastasis of SCLC. Studies have shown that the degradation of mutant p53 mediated by murine double minute 2 (MDM2) can be induced by As2O3, which probably contributes to the inhibition of SCLC, but the detailed mechanism is still unclear. We aimed to testify that As2O3 can inhibit the growth of SCLC cells by degrading mutant p53 protein via binding to MDM2. METHODS: CCK-8 assay, cell cycle analysis, and western blot of apoptosis markers were used to evaluate the inhibitory effect of As2O3 on NCI-H446 cells (containing mutant p53) and NCI-H1299 cells (p53 null). The effects of As2O3 on p53 and its downstream proteins were identified by western blot using mut-p53-knockdown and overexpressed cell models. MDM2-knockdown cell models were constructed, and western blot, co-IP of mut-p53, and ubiquitin were carried out to explore the mediating effect of MDM2 in As2O3 induced mut-p53 degradation. RESULTS: As2O3 inhibited proliferation and induced cell cycle arrest and apoptosis of SCLC cells in a dose- and timedependent manner. After mut-p53 knockdown or overexpressed, the inhibitory effect of As2O3 was dampened or enhanced. Additionally, As2O3-induced mut-p53 ubiquitination was significantly weakened after MDM2 knockdown. CONCLUSION: As2O3 could inhibit SCLC cells by inhibiting proliferation and inducing cell cycle arrest and apoptosis. These inhibitory effects were achieved at least in part by upregulating MDM2, which, in turn, promotes ubiquitination and degradation of mut-p53.

Small cell lung cancer transformation and tumor heterogeneity after sequential targeted therapy and immunotherapy in EGFR-mutant non-small cell lung cancer: A case report.

Background: Histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of mechanisms of the acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI). However, SCLC transformation and tumor heterogeneity have never been reported in sequential targeted therapy and immunotherapy. Case presentation: Here, we described a patient with advanced EGFR-mutant NSCLC, who received erlotinib and underwent the resistance with EGFR T790M (-). The patient then received chemotherapy plus immunotherapy of programmed cell death 1 (PD-1) inhibitor, encountered progression with pathological transformation from NSCLC to SCLC that was overcome by chemotherapy of etoposide plus carboplatin (EC) with the main lesion significantly shrinking while metastatic nodules increasing. The pathology of the metastatic nodule showed NSCLC with EGFR T790M (+). Based on the tumor heterogeneity, EC chemotherapy combined with osimertinib was used, and patients responded well. The patient experienced four lung biopsies in all, which helped to provide the patient with precise treatment. Conclusions: This case suggested that SCLC transformation and tumor heterogeneity should be paid attention to when disease progression occurred in advanced NSCLC whether receiving targeted therapy or immunotherapy.

Arsenic Trioxide Restrains Lung Cancer Growth and Metastasis by Blocking the Calcineurin-NFAT Pathway by Upregulating DSCR1.

BACKGROUND: Anti-angiogenesis therapy mostly aimed at targeting vascular endothelial growth factor (VEGF) and its receptors have been widely applied to lung cancer. However, the improvement in the patient's overall survival remains dissatisfying. Previously, we demonstrated that arsenic trioxide (As2O3) exerts an anti-lung cancer effect through anti-angiogenesis, but the details of the mechanism in play remain unclear. Herein, we focused on the calcineurin-NFAT pathway, downstream of VEGF, and its endogenous inhibitor DSCR1. OBJECTIVE: To demonstrate the mechanism of As2O3 restraining lung cancer growth and metastasis by blocking the calcineurin-NFAT pathway by upregulating DSCR1. METHODS: We constructed xenografts and metastasis models based on wild-type (WT) and DSCR1 knockout (DSCR1-/-) mice, and carried out qPCR, Western blot, immunohistochemistry, in vivo imaging and calculated microvessel density to evaluate the effects of As2O3 on angiogenesis, tumor growth, metastasis, and the protein expression levels of DSCR1 and calcineurin-NFAT pathway-related molecules. RESULTS: As2O3 inhibited tumor growth and metastasis, reduced microvessel formation, and induced vascular lumen malformation in WT mice. At the protein level, As2O3 upregulated DSCR1, downregulated NFAT2 and its downstream molecules, but had no effect on calcineurin A. However, in DSCR1-/- mice, the above-mentioned effects of As2O3 were abolished. CONCLUSION: As2O3 can suppress lung cancer growth and metastasis through anti-angiogenesis effects by blocking the calcineurin-NFAT pathway by upregulating DSCR1. The results shed light on the antitumor mechanism of As2O3 and are a step forward in the identification of As2O3 as a new drug in the treatment of lung cancer.

[The clinical features and perioperational managements of craniopharyngiomas in posterior fossa].

OBJECTIVE: To investigate the clinical features and perioperational managements of craniophayngiomas located in posterior fossa. METHODS: Nine patients with craniopharyngioma situated in posterior fossa were included in the study. The clinical manifestations, neuroimage features, operational treatment, and perioperational managments were retrospectively analyzed. RESULTS; All tumors associated with big or huge volume, arised from sellar/suprasellar region and extended into posterior fossa. Tumors showed cystic lesions in 2 cases and cystic-solid lesions in 7 cases. Headache was the most common symptoms (6/9), followed by cranial nerve deficit (4/9) and endocrine dysfunction(3/9). The supra- and infra-tentorial approaches were the optimal approaches for removal these tumors (7/9). Cranial nerves deficit was the most common complication in perioperative period. No perioperational death occured, most of the patients showed good recovery during the fellow-up period. CONCLUSION: Craniophayngiomas in posterior fossa shows different clinical manifestations, radiological features, surgical complications to the tumor in sellar/suprasellar region.

[Costicartilage analysis inspection technology in the application of forensic medicine].

The traditional costicartilage analysis inspection is limited to morphological inspection. In recent years, with the development of forensic radiology and molecular genetics, the costicartilage analysis inspection technology has been further enriched and developed. At present, the costicartilage analysis inspection technology have been able to be used in the practice of forensic medicine. This paper reviews the research advances about the costicartilage analysis inspection technology in the identification of human gender, age and so on in order to provide the references for forensic appraisers.