Transition metal-free C(sp3)-H selenation of ß-ketosulfones.

The installation of selenium groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. However, direct C(sp3)-H selenation, which is most atom economical, remains a formidable challenge, and only a few examples have been reported to date. In this article, we introduce the transition metal-free C(sp3)-H selenation with the easily available ß-ketosulfones and diselenides as the material source. This benign protocol permits access to a broad spectrum of α-aryl(alkyl) seleno-ß-ketosulfones in high yields with outstanding functional group compatibility. Distinct advantages of this protocol over all previous methods encompass the utilization of base and air as an oxidant, room temperature, and enhanced green chemistry matrices.

Open-Cage Fullerene as Molecular Container for F- , Cl- , Br- and I.

A 19-membered open-cage fullerene derivative was prepared from C60 in 7 steps and 5.5 % yield through the peroxide-mediate pathway. There are four carbonyl groups, an ether oxygen and a quinoxaline moiety on the rim of the orifice. A chloride anion could be inserted into its cavity by heating with hydrochloric acid at 60 °C for 4 h. Encapsulation of fluoride, bromide and iodide anions was also achieved at slightly more forcing conditions, 90 °C for 14 h. Single crystal X-ray structures of the sodium salt of the chloride and the bromide encapsulated derivatives were obtained, which showed the halide anion in the center of the cavity and two sodium cations connecting two cages through coordination to the oxygen atoms on the rim of the orifices. The halide encapsulation ratio is quantitative in the isolated products.

Human CD8+CD28- T suppressor cells expanded by common gamma chain (γc) cytokines retain steady allospecific suppressive capacity in vivo.

BACKGROUND: CD8+CD28- T suppressor (Ts) cells play critical role in transplant tolerance. Our previous study has generated CD8+CD28- Ts cells in vitro which exert robust allospecific suppressive capacity in vitro. RESULTS: CD8+CD28- Ts cells were expanded by stimulating human CD8+ T cells with allogeneic antigen presenting cells in the presence of the common gamma chain cytokines IL-2, IL-7 and IL-15 in vitro, and were further verified in vitro through day 7 to 11 for their persistency of the allospecific suppressive capacity. When CD8+CD28- Ts cells were adoptively transferred into NOG mice, their capacity to inhibit CD4+ T cell proliferation in allospecific manner remained potent on 11 days after their injection. The mechanisms for expansion of CD8+CD28- Ts cells by the common gamma chain cytokines were investigated. These included promoting CD8+CD28- T cells proliferation, converting CD8+CD28+ T cells to CD8+CD28- T cells and decreasing CD8+CD28- T cell death. Furthermore, the expanded CD8+CD28- Ts cells showed upregulation of the co-inhibitory molecule Tim-3 and down-regulation of the cytotoxic molecule granzyme B. CONCLUSIONS: In summary, these results demonstrated that the in vitro-expanded human CD8+CD28- T cells retained potent allospecific suppressive capacity in vivo and depicted multiple mechanisms for the expansion of Ts cells, which might promote further bench to clinic research.

Construction of a novel gene-based model for prognosis prediction of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) comprises the majority of kidney cancer death worldwide, whose incidence and mortality are not promising. Identifying ideal biomarkers to construct a more accurate prognostic model than conventional clinical parameters is crucial. METHODS: Raw count of RNA-sequencing data and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA). Tumor samples were divided into two sets. Differentially expressed genes (DEGs) were screened in the whole set and prognosis-related genes were identified from the training set. Their common genes were used in LASSO and best subset regression which were performed to identify the best prognostic 5 genes. The gene-based risk score was developed based on the Cox coefficient of the individual gene. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival analysis were used to assess its prognostic power. GSE29609 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to screen independent prognostic parameters to construct a nomogram. The predictive power of the nomogram was revealed by time-dependent ROC curves and the calibration plot and verified in the validation set. Finally, Functional enrichment analysis of DEGs and 5 novel genes were performed to suggest the potential biological pathways. RESULTS: PADI1, ATP6V0D2, DPP6, C9orf135 and PLG were screened to be significantly related to the prognosis of ccRCC patients. The risk score effectively stratified the patients into high-risk group with poor overall survival (OS) based on survival analysis. AJCC-stage, age, recurrence and risk score were regarded as independent prognostic parameters by Cox regression analysis and were used to construct a nomogram. Time-dependent ROC curves showed the nomogram performed best in 1-, 3- and 5-year survival predictions compared with AJCC-stage and risk score in validation sets. The calibration plot showed good agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis suggested several enriched biological pathways related to cancer. CONCLUSIONS: In our study, we constructed a gene-based model integrating clinical prognostic parameters to predict prognosis of ccRCC well, which might provide a reliable prognosis assessment tool for clinician and aid treatment decision-making in the clinic.

Interactive Aggregation-Induced Emission Systems Controlled by Dynamic Covalent Chemistry.

Aggregation-induced emission (AIE) molecules show all kinds of application in biological research, chemical sensing, and medical study. However, most of the reported molecules are based on the performance of the single molecular entity. In this paper, a molecular system for real-time sensing through combination of dynamic covalent chemistry and aggregation-induced emission was rationally designed and tested. The aggregated particles exhibit different fluorescence emission colors upon the addition of various kinds of chemical reagents. The LC-MS analysis reveals that the breakage, formation, and exchange of the disulfide bonds in the molecular system occur spontaneously upon different reagents (base/acid and cysteine), which leads to a change in the proportion of different components in the system accordingly. Meanwhile, the fluorescence emission of the AIE system exhibits blue/red shift accompanied by intensity changes. Moreover, the particle size of the aggregated molecules gradually increased with the change of the chemical environment, which could be the result of the nucleus growing through intermolecular hydrogen bonding among molecular components. Thus, the chemical environment change results in the interactions of molecules, which further leads to the variation of dynamic fluorescence emission and morphology. The result represents a promising future for a dynamic AIE molecular system in the bioimaging and sensing study.

[Establishment of a nomogram model to predict systemic inflammatory response syndrome after transrectal ultrasound-guided prostate biopsy].

OBJECTIVE: To access the risk factors of systemic inflammatory response syndrome (SIRS) after transrectal ultrasound-guided biopsy of the prostate (TRUS-Bp) and establish a model and a nomogram for the prediction of SIRS after TRUS-Bp. METHODS: We retrospectively analyzed the clinical data on 752 cases of TRUS-Bp in our hospital from January 2010 to January 2017 and included 570 of the cases in this study. We investigated the independent risk factors for SIRS after TRUS-Bp by univariate and logistic regression analyses, constructed a prediction model and nomogram with the R-Statistics software, evaluated the discrimination of the model with the ROC curve, and measured the conformity by SPSS25.0 Bootstrap sampling. RESULTS: At 1－2 postoperative days, 58 (10.2%) of the 570 patients were diagnosed with SIRS, 22 (3.9%) with bacteremia, and 6 (1.1%) with septic shock, but none died. Logistic regression analysis showed that the independent risk factors for SIRS after TRUS-Bp included old age (>70 yr; OR = 1.1, P = 0.01), high number of biopsy needles (>10; OR = 2.3, P < 0.01), diabetes mellitus (OR = 3.4, P < 0.01), and hypoproteinemia (OR = 2.5, P < 0.01). The area under the ROC curve was 0.947 and internal validation showed a conformity of 92%. CONCLUSIONS: Old age (>70 yr), high number of biopsy needles (>10), diabetes mellitus and hypoproteinemia may increase the risk of SIRS after TRUS-Bp. Evaluation with a model nomogram may help predict the probability of SIRS after TRUS-Bp.

Lipid Raft Formation: Key Role of Polyunsaturated Phospholipids.

The forces that drive lipid raft formation are poorly understood. To date, most of the attention has focused on attractive interactions between cholesterol and high-melting lipids. Remarkably little attention has been paid to repulsive forces. Here, we show that repulsive interactions between an exchangeable mimic of cholesterol and an exchangeable mimic of a low-melting phospholipid in liquid-disordered bilayers can be much stronger than the attractive forces between this same sterol and an exchangeable mimic of a high-melting phospholipid in liquid-ordered bilayers. We conclude that polyunsaturated phospholipids have been largely overlooked as major players in lipid raft formation. This knowledge should stimulate considerable interest in controlling the levels of polyunsaturated phospholipids for the proper functioning of cell membranes.

Simple Strategy for Taming Membrane-Disrupting Antibiotics.

A strategy has been devised for increasing the cellular selectivity of membrane-disrupting antibiotics based on the attachment of a facially amphiphilic sterol. Using Amphotericin B (AmB) as a prototype, covalent attachment of cholic acid bound to a series of α,ω-diamines has led to a dramatic reduction in hemolytic activity, a significant reduction in toxicity toward HEK293T cells, and significant retention of antifungal activity.

Anesthetic constituents of Zanthoxylum bungeanum Maxim.: A pharmacokinetic study.

A sensitive and selective ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for the simultaneous determination of hydroxy-α-sanshool, hydroxy-ß-sanshool, and hydroxy-γ-sanshool in rat plasma after the subcutaneous and intravenous administration of an extract of the pericarp of Zanthoxylum bungeanum Maxim. Piperine was used as the internal standard. The analytes were extracted from rat plasma by liquid-liquid extraction with ethyl acetate and separated on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 µm) with a gradient elution system at a flow rate of 0.4 mL/min. The mobile phase consisted of acetonitrile/0.05% formic acid in water and the total analysis time was 4 min. Positive electrospray ionization was performed using multiple reaction monitoring mode for the analytes. The calibration curves of the three analytes were linear over the tested concentration range. The intra- and interday precision was no more than 13.6%. Extraction recovery, matrix effect, and stability were satisfactory in rat plasma. The developed and validated method was suitable for the quantification of hydroxy-α-sanshool, hydroxy-ß-sanshool, and hydroxy-γ-sanshool and successfully applied to a pharmacokinetic study of these analytes after subcutaneous and intravenous administration to rats.

Taming Amphotericin B.

A strategy is introduced for enhancing the cellular selectivity of Amphotericin B (AmB) and other classes of membrane-disrupting agents. This strategy involves attaching the agent to a molecular umbrella to minimize the disruptive power of aggregated forms. Based on this approach, AmB has been coupled to a molecular umbrella derived from one spermidine and two cholic acid molecules and found to have antifungal activities approaching that of the native drug. However, in sharp contrast to AmB, the hemolytic activity and the cytotoxcity of this conjugate toward HEK293 T cells have been dramatically reduced.

Near-infrared absorbing compounds based on π-extended tetrathiafulvalene open-cage fullerenes.

Tetrathiafulvalene (TTF) is attached to open-cage fullerenes through a quinoxaline junction. The resulting linear π-conjugation system shows intense absorption in the near-infrared region. A unique o-diaminobenzene-induced furan ring formation process from a conjugated 1,4-dione moiety was observed on the rim of a 18-membered orifice.

Protective Effect of Hop Ethyl Acetate Extract on Corticosterone-Induced PC12 and Improvement of Depression-like Behavior in Mice.

Depression is a common mental disorder. In recent years, more and more attention has been paid to depression and its etiology and pathogenesis. This review aims to explore the neuroprotective and antidepressant effects of hop components. By establishing an in vitro cell damage model using PC12 cells induced by corticosterone (CORT) and an in vivo depression model through the intracranial injection of lipopolysaccharide (LPS) in mice, hop ethyl acetate extract (HEA) was used to study the protective effect and mechanism of HEA on neuronal cells in vitro and the antidepression effect and mechanism in vivo. The results showed that HEA increased the survival and decreased the rate of lactate dehydrogenase (LDH) release, apoptosis, and the ROS and NO content of CORT-induced PC12 cells. HEA alleviated depressive-like behavior, neuroinflammation, reduction of norepinephrine, and dendritic spines induced by intracerebroventricular injection of LPS in mice and increases the expression levels of BDNF, SNAP 25, and TrkB proteins without any significant side effects or toxicity. Hops demonstrated significant comprehensive utilization value, and this work provided an experimental basis for the role of hops in the treatment of depression and provided a basis for the development of HEA for antidepressant drugs or dietary therapy products.

Construction and validation of programmed cell death-based molecular clusters for prognostic and therapeutic significance of clear cell renal cell carcinoma.

As the dominant histological subtype of kidney cancer, clear cell renal cell carcinoma (ccRCC) poorly responds to conventional chemotherapy and radiotherapy. Although novel immunotherapies such as immune checkpoint inhibitors could have a durable effect in treating ccRCC patients, the limited availability of dependable biomarkers has restricted their application in clinic. In the study of carcinogenesis and cancer therapies, there has been a recent emphasis on researching programmed cell death (PCD). In the current study, we discovered the enriched and prognostic PCD in ccRCC utilizing gene set enrichment analysis (GSEA) and investigate the functional status of ccRCC patients with different PCD risks. Then, genes related to PCD that had prognostic value in ccRCC were identified for the conduction of non-negative matrix factorization to cluster ccRCC patients. Next, the tumor microenvironment, immunogenicity, and therapeutic response in different molecular clusters were analyzed. Among PCD, apoptosis and pyroptosis were enriched in ccRCC and correlated with prognosis. Patients with high PCD levels were related to poor prognosis and a rich but suppressive immune microenvironment. PCD-based molecular clusters were identified to differentiate the clinical status and prognosis of ccRCC. Moreover, the molecular cluster with high PCD levels may correlate with high immunogenicity and a favorable therapeutic response to ccRCC. Furthermore, a simplified PCD-based gene classifier was established to facilitate clinical application and used transcriptome sequencing data from clinical ccRCC samples to validate the applicability of the gene classifier. We thoroughly extended the understanding of PCD in ccRCC and constructed a PCD-based gene classifier for differentiation of the prognosis and therapeutic efficacy in ccRCC.

Identification of a basement membrane-based risk scoring system for prognosis prediction and individualized therapy in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) belongs to one of the 10 most frequently diagnosed cancers worldwide and has a poor prognosis at the advanced stage. Although multiple therapeutic agents have been proven to be curative in ccRCC, their clinical application was limited due to the lack of reliable biomarkers. Considering the important role of basement membrane (BM) in tumor metastasis and TME regulation, we investigated the expression of BM-related genes in ccRCC and identified prognostic BM genes through differentially expression analysis and univariate cox regression analysis. Then, BM-related ccRCC subtypes were recognized through consensus non-negative matrix factorization based on the prognostic BM genes and evaluated with regard to clinical and TME features. Next, utilizing the differentially expressed genes between the BM-related subtypes, a risk scoring system BMRS was established after serial analysis of univariate cox regression analysis, lasso regression analysis, and multivariate cox regression analysis. Time-dependent ROC curve revealed the satisfactory prognosis predictive capacity of BMRS with internal, and external validation. Multivariate analysis proved the independent predictive ability of BMRS and a BMRS-based nomogram was constructed for clinical application. Some featured mutants were discovered through genomic analysis of the BMRS risk groups. Meanwhile, the BMRS groups were found to have distinct immune scores, immune cell infiltration levels, and immune-related functions. Moreover, with the help of data from The Cancer Immunome Atlas (TCIA) and Genomics of Drug Sensitivity in Cancer (GDSC), the potential of BMRS in predicting therapeutic response was evaluated and some possible therapeutic compounds were proposed through ConnectivityMap (CMap). For the practicability of BMRS, we validated the expression of BMRS-related genes in clinical samples. After all, we identified BM-related ccRCC subtypes with distinct clinical and TME features and constructed a risk scoring system for the prediction of prognosis, therapeutic responses, and potential therapeutic agents of ccRCC. As ccRCC systemic therapy continues to evolve, the risk scoring system BMRS we reported may assist in individualized medication administration.

Identification of pyroptosis-related subtypes and comprehensive analysis of characteristics of the tumor microenvironment infiltration in clear cell renal cell carcinoma.

Pyroptosis is a kind of programmed cell death triggered by the inflammasome. Growing evidence has revealed the crucial utility of pyroptosis in tumors. However, the potential mechanism of pyroptosis in clear cell renal cell carcinoma (ccRCC) is still unclear. In this research, we systematically analyze the genetic and transcriptional alterations of pyroptosis-related genes (PRGs) in ccRCC, identify pyroptosis-related subtypes, analyze the clinical and microenvironmental differences among different subtypes, develop a corresponding prognostic model to predict the prognosis of patients, and interpret the effect of pyroptosis on ccRCC microenvironment. This study provides a new perspective for a comprehensive understanding of the role of pyroptosis in ccRCC and its impact on the immune microenvironment, and a reliable scoring system was established to predict patients' prognosis.

Photophysical Properties of Naphthalene-oxacalix[m]arene and Recognition of Fullerene C60.

Three different pore sizes of oxacalix[m]arene[n]pyrimidines modified with a naphthalene substituent were synthesized and characterized by HRMS, 1H NMR, and single-crystal analysis (8OA and 8OA-N). Steady-state spectroscopy indicates these naphthalene-oxacalix[m]arenes exhibit good fluorescence properties, which isattributed to the locally excited (LE) state emission, and electrochemical results show that the photoinduced electron transfer (PET) process occurs from the naphthalene substituent to the linked pyrimidine. Nanosecond transient absorption spectra, singlet oxygen quantum yields (ΦΔ4OA-N = 45.1%, ΦΔ6OA-N = 56.6%, and ΦΔ8OA-N = 65.7%) and theoretical calculations demonstrate that the torsion angle between the donor (naphthalene) and the acceptor (pyrimidine) promotes intersystem crossing (ISC), and the lifetime of the triplet state reaches ca. 8 ms. Interestingly, all three host molecules (4OA-N, 6OA-N, and 8OA-N) showed a high affinity for fullerene C60, and significant binding constants in the range of 4.10-6.68 × 104 M-1 were obtained by fluorescence titration; in contrast, previous reports indicated that the similar oxacalix[m]arene[n]pyrimidine scaffold could not efficiently complex with C60. In the frontier molecular orbital theory calculations of the supramolecular system of 4OA-N@C 60 , the HOMO is distributed on 4OA-N and the LUMO is localized on fullerene. The calculation results further demonstrated that there are strong interactions between the host and the fullerene guest, which is consistent with the result of the experiments. The characteristic photophysical properties of these novel naphthyl-decorated oxacalix[m]arene[n]pyrimidines broaden their application field, and the stable host-guest system with fullerene can be applied to supramolecular chemistry.

Amphotericin B Tamed by Salicylic Acid.

Although Amphotericin B (AmB) is considered as the "gold standard" treatment for deep fungal infections, owing to its excellent antifungal effect, it often causes severe hemolytic toxicity and nephrotoxicity, which limits its clinical use. We designed and synthesized AmB derivatives by attaching salicylic acid (SA) to the carboxyl group and confirmed their structures using 1H NMR, 13C NMR, HR-MS, and IR. We evaluated its biological activity in vitro and measured its ultraviolet-visible (UV-vis) absorption spectrum. The AmB-SA conjugates exhibited good antifungal effects against Candida albicans, Candida glabrata, and Cryptococcus neoformans compared with AmB, and the renal cytotoxicity toward HEK 293T cells in vitro was significantly reduced, with almost no nephrotoxicity in the therapeutic window of the drug. At the same time, the hemolytic toxicity was significantly reduced. Therefore, modification of AmB by introducing SA is an effective strategy to maintain the broad antifungal activity of AmB and reduce its cytotoxicity. These AmB derivatives could be applied in clinical therapy in the future.

Integrative Analysis of the Genomic and Immune Microenvironment Characteristics Associated With Clear Cell Renal Cell Carcinoma Progression: Implications for Prognosis and Immunotherapy.

Unlike early clear cell renal cell carcinoma (ccRCC), locally advanced and metastatic ccRCC present poor treatment outcomes and prognosis. As immune checkpoint inhibitors have achieved favorable results in the adjuvant treatment of metastatic ccRCC, we aimed to investigate the immunogenomic landscape during ccRCC progression and its potential impact on immunotherapy and prognosis. Using multi-omics and immunotherapy ccRCC datasets, an integrated analysis was performed to identify genomic alterations, immune microenvironment features, and related biological processes during ccRCC progression and evaluate their relevance to immunotherapy response and prognosis. We found that aggressive and metastatic ccRCC had higher proportions of genomic alterations, including SETD2 mutations, Del(14q), Del(9p), and higher immunosuppressive cellular and molecular infiltration levels. Of these, the Del(14q) might mediate immune escape in ccRCC via the VEGFA-VEGFR2 signaling pathway. Furthermore, immune-related pathways associated with ccRCC progression did not affect the immunotherapeutic response to ccRCC. Conversely, cell cycle pathways not only affected ccRCC progression and prognosis, but also were related to ccRCC immunotherapeutic response resistance. Overall, we described the immunogenomic characteristics of ccRCC progression and their correlations with immunotherapeutic response and prognosis, providing new insights into their prediction and the development of novel therapeutic strategies.

Synthesis of 18-membered open-cage fullerenes through controlled stepwise fullerene skeleton bond cleavage processes and substituent-mediated tuning of the redox potential of open-cage fullerenes.

Oxidation of the fullerenediol C(60)(OH)(2)(O)(OAc)(OOtBu)(3) with PhI(OAc)(2) yields the open-cage fullerene derivative C(60)(O)(2)(O)(OAc)(OOtBu)(3)2 with an 11-membered orifice. Compound 2 reacts with aniline to form a new open-cage derivative with a 14-membered orifice, which yields an 18-membered open-cage fullerene derivative upon addition of another molecule of aniline. Two different types of aniline derivatives with either electron-donating or electron-withdrawing substituents can be added sequentially, affording an unsymmetrical moiety in the open-cage structure. Reduction potentials of the 18-membered open-cage fullerene derivatives can be fine-tuned by changing the substituents on the aniline. The results provide new insights about the mechanism of open-cage reactions of fullerene-mixed peroxide.

Heating a bowl of single-molecule-soup: structure and desorption energetics of water-encapsulated open-cage [60] fullerenoid anions in the gas-phase.

The gas-phase unimolecular decay kinetics of an anionic, open-cage [60] fullerene derivative encapsulating one water molecule is studied by means of black-body IR radiation induced dissociation (BIRD) in the temperature programmable ion trap of a Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. The primary reaction channel observed is escape of the water molecule from the fullerenoid bowl. The rate constants for this water loss as a function of temperature are evaluated using the Arrhenius equation to yield an activation energy of 104 ± 4 kJ mol(-1). A complementary ion mobility spectrometry study contrasting the water-encapsulated and the empty fullerene cages finds identical collision cross sections to within experimental error-supporting the structural assignment of this gas-phase anion as an endohedral (i.e. encapsulated) species. Both experiments were compared with quantum-chemical computations which well-describe the transition state for water desorption and the concomitant binding and activation energies.