Efficacy and safety of perioperative immunotherapy combinations for resectable non-small cell lung cancer: a systematic review and network meta-analysis.

INTRODUCTION: Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear. METHOD: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences. RESULTS: We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.45-0.71) than CT. There existed no difference between Neo-Adj and Neo in EFS (HR = 0.87, 95% CI: 0.53-1.46) and overall survival (OS) (HR = 1.04, 95% CI: 0.38-2.57). Neo might have lower incidence of treatment-related adverse events (TRAEs) (relative risk [RR] = 0.96, 95% CI: 0.87-1.12) than Neo-Adj. Subgroup analysis of PD-L1 ≥ 50% suggested that EFS of Neo-Adj (HR = 0.46, 95% CI: 0.27-0.76) and Neo (HR = 0.24, 95% CI: 0.06-0.89) was better than CT, and Neo-Adj potentially caused shorter EFS than Neo (HR = 1.92, 95% CI: 0.46-7.84). CONCLUSIONS: Our results suggest that Neo-Adj and Neo have similar EFS for patients with PD-L1 < 1% or 1-49%. However, patients with PD-L1 ≥ 50% may obtain more EFS benefit from Neo than Neo-Adj. Neo might present a more favorable assessment than Neo-Adj when evaluating OS. Moreover, adding adjuvant immunotherapy may increase toxicity.

In Situ Spontaneous Construction of Zinc Phosphate Coating Layer Toward Highly Reversible Zinc Metal Anodes.

Aqueous zinc ion batteries have received widespread attention due to their merits of high safety, high theoretical specific capacity, low cost, and environmental benignity. Nevertheless, the irreversible issues of Zn anode deriving from side reactions and dendrite growth have hindered its commercialization in large-scale energy storage systems. Herein, a zinc phosphate tetrahydrate (Zn3(PO4)2·4H2O, ZnPO) coating layer is in situ formed on the bare Zn by spontaneous redox reactions at room temperature to tackle the above issues. Particularly, the dense and brick-like ZnPO layer can effectively separate the anode surface from the aqueous electrolyte, thus suppressing the serious side reactions. Moreover, the ZnPO layer with high ionic conductivity, high Zn2+ transference number, and low nucleation barrier permits rapid Zn2+ transport and enables uniform Zn deposition, ensuring dendrite-free Zn deposition. As a result, the ZnPO@Zn symmetric battery achieves a high Coulombic efficiency of 99.8% and displays ultrahigh cycle stability over 6000 h (> 8 months), far surpassing its counterparts. Furthermore, the ZnPO@Zn||MnO2 full battery exhibits excellent electrochemical performances. Therefore, this work provides a new reference for simple and large-scale preparation of highly reversible Zn metal anodes, and has great potential for practical applications.

Photochemical Mechanisms of Hydroxyquinoline Benzimidazole: Insights from Electronic Structure Calculations and Nonadiabatic Dynamics Simulations.

Excited-state intramolecular double proton transfer (ESIDPT) has received much attention because of its widespread existence in the life reactions of living organisms, and materials with this property are significant for their special luminescent properties. In this work, the complete active space self-consistent field (CASSCF) and OM2/multireference configuration interaction (OM2/MRCI) methods have been employed to study the static electronic structure calculations of the photochemistry and the possibility of ESIDPT process of hydroxyquinoline benzimidazole (HQB) molecule, along with the nonadiabatic dynamics simulations. The computational results show that the HQB molecule is relaxed to the S1-ENOL minimum after being excited to the Franck-Condon point in the S1 state. Subsequently, during the nonadiabatic deactivation process, the OH···N proton transfer and the twisting of benzimidazole occur before arriving at the single proton transfer conical intersection S1S0-KETO. Finally, the system can either return to the initial ground-state structure S0-ENOL or to the single proton transfer ground-state structure S0-KETO, both of which have almost the same probability. The dynamics simulations also show that no double proton transfer occurs. The excited-state lifetime of HQB is fitted to 1.1 ps, and only 64% of the dynamic trajectories return to the ground state within the 2.0 ps simulation time. We hope the detailed reaction mechanism of the HQB molecule will provide new insights into similar systems.

Photocyclization and Photoisomerization Mechanisms of an Indolylfulgide Derivative in Acetonitrile Solution by Using the QM (MS-CASPT2)/MM Method.

The indolylfulgide systems have been extensively investigated due to their potential applications as photochromic materials. In this work, the photoinduced ring-closure/opening and isomerization reactions of a photochromic indolylfulgide in vacuum and acetonitrile solvent have been investigated by means of MS-CASPT2//CASSCF and QM(MS-CASPT2)//CASSCF/MM. The deactivation mechanisms of indolylfulgide have been proposed based on the optimized structures in the S0 and S1 states, S1/S0 conical intersections, and the calculated minimum-energy paths. After excitation into the first singlet excited-state, which is spectroscopically bright in the Franck-Condon point of the E, the photoprocesses proceed toward a nearby S1 minimum. Then, two possible nonadiabatic relaxation paths exist to repopulate the ground state. In the ring closure reaction, the S1 E isomer evolves directly into one S1/S0 conical intersection and decays to the ground state with bifurcation toward C or E. In the E → Z tautomerization pathway, the excited system can deactivate to the S0 state via a distinct conical intersection. The minimum-energy paths of the indolylfulgide revealed that the ring closure reaction in the solvent is more facile to take place than the E → Z isomerization after irradiation of the same E. Furthermore, for the ring opening reaction from the C side, there exists an energy barrier (11.1 kcal/mol) in the S1 state before arriving at the conical intersection. The computational results showed that the solvent has some influence on the system compared with that in the gas phase. The present work could contribute to comprehending the photoreactions of indolylfulgide and its derivatives in solution.

Mechanistic Insights into the Excited-State Intramolecular Proton Transfer (ESIPT) Process of 2-(2-Aminophenyl)naphthalene.

The 2-(2-aminophenyl)naphthalene molecule attracted much attention due to excited-state intramolecular proton transfer (ESIPT) from an amino NH2 group to a carbon atom of an adjacent aromatic ring. The ESIPT mechanisms of 2-(2-aminophenyl)naphthalene are still unclear. Herein, the decay pathways of this molecule in vacuum were investigated by combining static electronic structure calculations and nonadiabatic dynamics simulations. The calculations indicated the existence of two stable structures (S0-1 and S0-2) in the S0 and S1 states. For the S0-1 isomer, upon excitation to the Franck-Condon point, the system relaxed to the S1 minimum quickly, and then there exist four decay pathways (two ESIPT ones and two decay channels with C atom pyramidalization). In the ESIPT decay pathways, the system encounters the S1S0-PT-1 or S1S0-PT-2 conical intersection, which funnels the system rapidly to the S0 state. In the other two pathways, the system de-excited from the S1 to the S0 state via the S1S0-1 or S1S0-2 conical intersection. For the S0-2 structure, the decay pathways were similar to those of S0-1. The dynamics simulations showed that 75 and 69% of trajectories experienced the two ESIPT conical intersections for the S0-1 and S0-2 structures, respectively. Our simulations showed that the lifetime of the S1 state of S0-1 (S0-2) is estimated to be 358 (400) fs. Notably, we not only found the detailed reaction mechanism of the system but also found that the different ground-state configurations of this system have little effect on the reaction mechanism in vacuum.

Structures and Energetics of E2H3+ (E = As, Sb, and Bi) Cations.

E2H2 (E = As, Sb, Bi) structures involving multiple bonds have attracted much attention recently. The E2H3+ cations (protonated E2H2) are predicted to be viable with substantial proton affinities (>180 kcal/mol). Herein, the bonding characters and energetics of a number of E2H3+ isomers are explored through CCSD(T) and DFT methods. For the As2H3+ system, the CCSD(T)/cc-pVQZ-PP method predicts that the vinylidene-like structure lies lowest in energy, with the trans and cis isomers higher by 6.7 and 9.3 kcal/mol, respectively. However, for Sb2H3+ and Bi2H3+ systems, the trans isomer is the global minimum, while the energies of the cis and vinylidene-like structures are higher, respectively, by 2.0 and 2.4 kcal/mol for Sb2H3+ and 1.6 and 15.0 kcal/mol for Bi2H3+. Thus, the vinyledene-like structure is the lowest energy for the arsenic system but only a transition state of the bismuth system. With permanent dipole moments, all minima may be observable in microwave experiments. Besides, we have also obtained transition states and planar-cis structures with higher energies. The current results should provide new insights into the various isomers and provide a number of predictions for future experiments.

Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.

Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal-epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.

Evaluation of Data-Dependent MS/MS Acquisition Parameters for Non-Targeted Metabolomics and Molecular Networking of Environmental Samples: Focus on the Q Exactive Platform.

Non-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a widely used tool for metabolomics analysis, enabling the detection and annotation of small molecules in complex environmental samples. Data-dependent acquisition (DDA) of product ion spectra is thereby currently one of the most frequently applied data acquisition strategies. The optimization of DDA parameters is central to ensuring high spectral quality, coverage, and number of compound annotations. Here, we evaluated the influence of 10 central DDA settings of the Q Exactive mass spectrometer on natural organic matter samples from ocean, river, and soil environments. After data analysis with classical and feature-based molecular networking using MZmine and GNPS, we compared the total number of network nodes, multivariate clustering, and spectrum quality-related metrics such as annotation and singleton rates, MS/MS placement, and coverage. Our results show that automatic gain control, microscans, mass resolving power, and dynamic exclusion are the most critical parameters, whereas collision energy, TopN, and isolation width had moderate and apex trigger, monoisotopic selection, and isotopic exclusion minor effects. The insights into the data acquisition ergonomics of the Q Exactive platform presented here can guide new users and provide them with initial method parameters, some of which may also be transferable to other sample types and MS platforms.

Characterizing the lavage and serum cytokine profiles of interstitial pneumonia with autoimmune features and their implications for progressive fibrosis.

OBJECTIVE: To explore whether cytokines could be potential biomarkers to predict the occurrence of progressive fibrosis (PF) phenotype among interstitial pneumonia with autoimmune features (IPAF) patients. METHODS: This study prospectively collected 51 IPAF and 15 Idiopathic Pulmonary Fibrosis (IPF) patients who were diagnosed at First Affiliated Hospital of Guangzhou Medical University from July 2020 to June 2021. All IPAF patients were followed up for one year to assess the development of PF phenotype. Paired Broncho Alveolar Lavage Fluid (BALF) and serum samples were collected at enrolment and analyzed for differences in 39 cytokines expression. Principal component analysis (PCA) and cluster analysis were conducted to identify a high-risk subgroup of IPAF patients for developing the PF phenotype. Finally, cytokine differences were compared between subgroups to identify potential biomarkers for PF-IPAF occurrence. RESULTS: According to the PCA analysis, 81.25% of PF-IPAF patients share overlapped BALF cytokine profiles with IPF. Cluster analysis indicated IPAF patients in subtype 2 had a higher risk to develop PF phenotype within one year (P = 0.048), characterized by higher levels of CCL2, CXCL12 and lower lymphocyte proportion (LYM%) in BALF. Elevated levels of BALF CCL2 (>299.16 pg./ml) or CXCL12 (>600.115 pg./ml) were associated with a significantly higher risk of developing PF phenotype within one year follow-up period (P = 0.009, 0.001). CONCLUSION: PF-IPAF phenotype exhibits similar inflammatory cytokine profiles to IPF. Cytokine CCL2, CXCL12, and LYM% in BALF serving as potential biomarkers for predicting the PF phenotype in IPAF patients. CLINICAL TRIAL REGISTRATION: Register: Qian Han, Website: http://www.chictr.org.cn/showproj.aspx?proj=61619, Registration number: ChiCTR2000040998.

Non-adiabatic dynamics simulations of the S1 excited-state relaxation of diacetyl phenylenediamine.

The small molecule built around the benzene ring, diacetyl phenylenediamine (DAPA), has attracted much attention due to its synthesis accessibility, large Stokes shift, etc. However, its meta structure m-DAPA does not fluoresce. In a previous investigation, it was found that such a property is due to the fact that it undergoes an energy-reasonable double proton transfer conical intersection during the deactivation of the S1 excited-state, then returns to the ground state by a nonradiative relaxation process eventually. However, our static electronic structure calculations and non-adiabatic dynamics analysis results indicate that only one reasonable non-adiabatic deactivation channel exists: after being excited to the S1 state, m-DAPA undergoes an ultrafast and barrierless ESIPT process and reaches the single-proton-transfer conical intersection. Subsequently, the system either returns to the keto-form S0 state minimum with proton reversion or returns to the single-proton-transfer S0 minimum after undergoing a slight twist of the acetyl group. The dynamics results show that the S1 excited-state lifetime of m-DAPA is 139 fs. In other words, we propose an efficient single-proton-transfer non-adiabatic deactivation channel of m-DAPA that is different from previous work, which can provide important mechanistic information of similar fluorescent materials.

Excited-state relaxation mechanisms of 2,2'-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)diphenol: single- or double-proton transfer?

Triazole compounds are important organic systems with excellent electronic properties, which have diagnostic potential in the fields of organic electronics and organic photovoltaics. The important photophysical nature of these systems is the transformation between the enol and keto forms after excited-state proton transfer. In this study, the IR vibrational spectrum, ESIPT mechanism, and excited-state decay dynamics of 2,2'-(1-phenyl-1H-1,2,4-triazole-3,5-diyl)diphenol (ExPh) were explored using electronic structure calculations and non-adiabatic dynamics simulations. Two S1/S0 conical intersections with distinct proton transfer (ESIPT-I and ESIPT-II) involved were obtained. The associated two-dimensional S1 minimum-energy potential energy surface indicated that the dynamical roles of these two S1/S0 conical intersections in the S1 excited-state decay were quite different. The ESIPT-I reaction was more favorable to occur than the ESIPT-II process. Our dynamics simulations supported this hypothesis with the whole trajectories decaying to the ground state via the S1S0-1 conical intersection, which involved the ESIPT-I process. The ESIPT-Involved efficient deactivation pathway could be partially responsible for the decrease in fluorescence emission. These results and ESIPT mechanisms are helpful for understanding the decay pathways of similar systems.

SOX2 Promotes Radioresistance in Non-small Cell Lung Cancer by Regulating Tumor Cells Dedifferentiation.

Background: Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC). However, the radiocurability is greatly limited because of radioresistance which leads to treatment failure, tumor recurrence, and metastasis. Cancer stem cell (CSC) has been identified as the main factor that contributes to radiation resistance. SOX2, one of the transcription factors specifically expressed in CSC, is involved in tumorigenesis, progression, and maintenance of cell stemness. But the association between SOX2 and NSCLC radioresistance is not clear now. Methods: We constructed the radiotherapy-resistant cell line of NSCLC by multiple radiotherapy treatments. Colony formation assay, western blot, and immunofluorescence were performed to detect the radiosensitivity of cells. Western blot, qRT-PCR, and sphere formation assay were used to detect CSC characteristics of cells. Wound healing assay and Transwell assay were used to determine cell migration motility. The SOX2-upregulated model and SOX2-downregulated model was constructed by lentivirus transduction. Finally, the expression and clinical relevance of SOX2 in NSCLC were investigated by bioinformatics analysis based on TCGA and GEO datasets. Results: The expression of SOX2 was increased in radioresistant cells and a trend of dedifferentiation were observed. The results of wound healing assay and Transwell assay showed that SOX2 overexpression significantly promote the migration and invasion of NSCLC cells. Mechanistically, overexpression of SOX2 enhanced radioresistance and DNA damage repair capability of parental cells, while down-regulation of SOX2 led to decreased radioresistance and DNA repair ability in radioresistant cells, all of which were related to cells dedifferentiation regulated by SOX2. In addition, bioinformatics analysis show that high expression of SOX2 was strongly associated with the progression and poor prognosis of patients with NSCLC. Conclusions: Our study revealed that SOX2 regulates radiotherapy resistance in NSCLC via promoting cell dedifferentiation. Therefore, SOX2 may be a promising therapeutic target for overcoming radioresistance in NSCLC, providing a new perspective to improve the curative effect.

Upregulation of FGF7 Induced Intravesical Prostatic Protrusion of Benign Prostatic Hyperplasia via the ERK1/2 Signaling Pathway.

INTRODUCTION: Intravesical prostatic protrusion (IPP) has been reported to be associated with bladder outlet obstruction and is the main cause of lower urinary tract symptoms (LUTS) during the development of benign prostatic hyperplasia (BPH). However, the molecular mechanism of IPP remains unclear. METHODS: Clinical data analysis was performed to analyze the association between IPP and long-term complications in patients with BPH. RNA sequencing was performed on prostate tissues (IPP or not). Stromal cells were obtained from IPP-derived primary cultures to explore the molecular mechanism of IPP formation. Cell proliferation was evaluated by a CCK-8 assay. Multiple proteins in the signaling pathway were assessed using Western blot. RESULTS: First, we confirmed that IPP is a prognostic factor for long-term complications in patients with BPH. Then, we observed that FGF7 was upregulated in both IPP tissues and IPP primary stromal cells through immunohistochemistry, Western blot, and quantitative real-time PCR. Furthermore, FGF7 was significantly upregulated in high IPP-grade prostate tissues. The coculture experiments showed that the downregulation of FGF7 in IPP-derived stromal cells inhibited the proliferation and migration of the prostate epithelial cells. Additionally, FGF7 was bound to FGFR2 to induce the epithelial-mesenchymal transition process through binding to FGFR2. RNA sequencing analysis also revealed the activation of the MAPK/ERK1/2 signaling pathway. The MAPK/ERK1/2 was downregulated by a specific inhibitor affecting the FGF7 stimulation in vitro. CONCLUSIONS: Our data reveal a novel amplification effect, i.e., stromal cell-derived FGF7 promotes epithelial cell proliferation and stromal cell phenotype, ultimately inducing IPP formation. Targeting FGF7 can significantly reduce epithelial to stromal transition and provide a potential therapeutic target for BPH progression.

Exploring lemology teaching with "internet plus" flipped classroom pedagogy.

BACKGROUND: To investigate the use of flipped classroom pedagogy based on "Internet plus" in teaching viral hepatitis in the lemology course during the COVID-19 epidemic. METHODS: This study included students from the clinical medicine general practitioner class at Nanjing Medical University's Kangda College, with the observation group consisting of 67 students from the 2020-2021 school year and the control group consisting of 70 students from the 2019-2020 school year. The observation group used "Internet plus" flipped classroom pedagogy, while the control group used conventional offline instruction. The theory course and case analysis ability scores from the two groups were compared and analyzed, and questionnaire surveys were administered to the observation group. RESULT: After the flipped classroom, the observation group had significantly higher theoretical test scores (38.62 ± 4.52) and case analysis ability scores (21.08 ± 3.58) than the control group (37.37 ± 2.43) (t = 2.024, P = 0.045) and (19.16 ± 1.15) (t = 4.254, P < 0.001), respectively. The questionnaire survey in the observation group revealed that the "Internet plus" flipped classroom pedagogy approach can help enhance students' enthusiasm to learn, clinical thinking ability, practical application ability, and learning efficiency, with satisfaction rates of 81.7%, 85.0%, 83.3%, and 78.8%, respectively; 89.4% of students expressed hope that whenever physical classes resumed, the offline courses could be combined with this pedagogy approach. CONCLUSION: The use of the "Internet plus" flipped classroom pedagogy technique for teaching viral hepatitis in a lemology course boosted students' theory learning ability as well as their case analysis ability. The majority of students were pleased with this type of instruction and hoped that whenever physical classes resumed, the offline courses may be integrated with the "Internet plus" flipped classroom pedagogical approach.

ROS-NLRP3 signaling pathway induces sterile inflammation after thulium laser resection of the prostate.

The sterile inflammation (SI) of the urinary tract is a common problem requiring serious consideration after prostatectomy. This study mainly focuses on the role of the reactive oxygen species-NLR family, pyrin domain-containing 3 (ROS-NLRP3) signaling pathway in SI after thulium laser resection of the prostate (TmLRP). Urinary cytokines were determined in patients who received TmLRP, and heat shock protein 70 (HSP70) was detected in the resected tissues. The involvement of ROS signaling in HSP70-induced inflammation was explored in THP-1 cells with or without N-acetyl- l-cysteine (NAC) pretreatment. The function of NLRP3 and Caspase-1 was determined by Western blot analysis, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction. These phenomena and mechanisms were verified by the beagle models that received TmLRP. Clinical urine samples after TmLRP showed high expression of inflammatory factors and peaked 3-5 days after surgery. The high expression of HSP70 in the resected tissues was observed. After HSP70 stimulation, the expression of ROS, NLRP3, Caspase-1, and interleukin-18 (IL-18) increased significantly and could be reduced by ROS inhibitor NAC. The expression of IL-1ß and IL-18 could be inhibited by NLRP3 or Caspase-1 inhibitors. In beagle models that received TmLRP, HSP70, NLRP3, Caspase-1, IL-1ß, and IL-18 were highly expressed in the wound tissue or urine, and could also be reduced by NAC pretreatment. Activation of the ROS-NLRP3 signaling pathway induces SI in the wound after prostatectomy. Inhibition of this pathway may be effective for clinical prevention and treatment of SI and related complications after prostatectomy.

Annexin A1 promotes the progression of bladder cancer via regulating EGFR signaling pathway.

BACKGROUND: Bladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear. METHODS: The clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments. RESULTS: Bioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling. CONCLUSIONS: These findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.

SENP1 regulates the transformation of lung resident mesenchymal stem cells and is associated with idiopathic pulmonary fibrosis progression.

BACKGROUND: Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as ß-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs. METHODS: LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice. RESULTS: In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/ß-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation. CONCLUSIONS: SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis. Video Abstract.

Excited-state photochemistry dynamics of 2-(1-naphthyl) phenol: electronic structure calculations and non-adiabatic dynamics simulations.

The excited-state proton transfer processes and the formation mechanism of quinone methide of (1-naphthyl)phenol were investigated by combining static electronic structure calculations and non-adiabatic dynamics simulations in vacuum. The results indicated the existence of two minimum energy structures (S0-ENOL-1 and S0-ENOL-2) in the ground and excited states, which correspond to two ESIPT pathways. Upon excitation of S0-ENOL-1 to the bright S1 state, the system relaxes to the S1 minimum quickly in the enol region, for which two decay pathways have been described. The first is a barrierless ESIPT-1 process that generates keto species. Afterwards, the system encounters a keto conical intersection, which funnels the system to the ground state. The generated keto species, in the S0 state, either regenerated the starting material via ground-state proton transfer or yielded the keto product at the end of the simulations. In the other pathway, the system de-excites from the S1 state to the S0 state via one enol-type conical intersection. The dynamics simulations showed that 58.8% of trajectories experience keto-type conical intersection and the rest undergo enol-type conical intersection. Besides the ESIPT-1 process, a new-type ESIPT (ESIPT-2), which was not observed experimentally, was found with the irradiation of S0-ENOL-2. The ESIPT-2 process occurs after overcoming a small barrier (0.9 kcal mol-1) and yields a distinct quinone methide. Our simulation results also showed that the S1 lifetime of S0-ENOL-1 (S0-ENOL-2) would be 437 (617) fs in the gas phase. These results provide detailed and important mechanistic insights into the systems in which ESPT to carbon atoms occurs.

Combined QM (MS-CASPT2)/MM studies on photocyclization and photoisomerization of a fulgide derivative in toluene solution.

Photocyclization and photoisomerization of fulgides have been extensively studied experimentally and computationally due to their significant potential applications for example as photoswitches in memory devices. However, the reported excited-state decay mechanisms of fulgides do not include the effects of solvation explicitly to date. Herein, calculations using the high-level MS-CASPT2//CASSCF method were conducted to explore the photoinduced excited-state decay processes of the Eα conformer of a fulgide derivative in toluene with solvent effects treated by implicit PCM and explicit QM/MM models, respectively. Several minima and conical intersections were optimized successfully in and between the S0 and S1 states; then, two nonadiabatic excited-state decay channels that could efficiently drive the system to the ground state were proposed based on the excited-state ring-closure and isomerization paths. In addition, we also found that in the ring-closure path, the potential energy surface is essentially barrierless before approaching the conical intersection, while it needs to overcome a small energy barrier along the E → Z photoisomerization path for the nonadiabatic S1 → S0 internal conversion process. The present computational results could provide useful mechanistic insights into the photoinduced cyclization and isomerization reactions of fulgide and its derivatives.

Excited-State Deactivation Mechanism of 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole: Electronic Structure Calculations and Nonadiabatic Dynamics Simulations.

3,5-bis(2-Hydroxyphenyl)-1H-1,2,4-triazole (bis-HPTA) has attracted wide attention due to the important application in the detection of microorganisms and insecticidal activity. However, the mechanisms of excited-state intramolecular proton transfer (ESIPT) process and decay pathways are still a matter of debate. In this work, we have comprehensively investigated the photodynamics of bis-HPTA by executing combined electronic structure calculations and nonadiabatic surface-hopping dynamics simulations. Based on the computed electronic structure and dynamics information, we propose two nonadiabatic deactivation channels that efficiently populate the ground state from the Franck-Condon region. In the first one, after being excited to the bright S1 state, bis-HPTA molecule undergoes an ultrafast and barrierless ESIPT-1 process. Then, the system encounters with an energetically accessible S1/S0 conical intersection (CI), which funnels the system to the ground state speedily. Afterward, the keto species either arrives at the keto product or return to its enol species via a ground-state proton transfer in the S0 state. In the other excited-state decay channel, the S1 system hops to the ground state through a different CI, which involves the ESIPT-2 process. In our dynamics simulations, about 79.6% of the trajectories decay to the S0 state via the first CI, while the remaining ones employ the second conical intersection. The results of dynamics simulations also demonstrated that the lifetime of the S1 state is estimated as 315 fs. The present work will give elaborating mechanistic information of similar compounds in various environments.