A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Wave aberration corrections in PSF ellipticity measurements of astronomical telescopes using a multi-objective optimization.

The weak gravitational lensing (WGL) produces a shear effect on the observed galactic ellipticity that is much smaller than the endogenous ellipticity of the galaxy itself. Achieving such a high-level astronomical observation requires the superior performance of telescopes. To ensure the optical properties of telescopes to be competent in WGL detections, it is very necessary to measure point spread function (PSF) ellipticity of telescopes in labs. In this paper, a 2 m off-axis telescope that would be used to detect WGL in space is analyzed and studied. A collimator whose aperture is 2 m has been built to measure PSF ellipticity of the telescope. The wave aberrations of the collimator are roughly equal to those of the telescope, so they are important systematical errors and must be removed. However, it is difficult to precisely measure the wave aberrations of optical systems that have large apertures and long focal lengths. In addition, a 2 m flat mirror, which is indispensable to measure wave aberrations of optical systems, has significant surface errors. In this paper, a multi-objective optimization method is proposed to eliminate the effects of wave aberrations on PSF ellipticity measurements of the telescope. By constructing an equivalent model, the wave aberrations from collimators and flat mirrors can be corrected so that PSF ellipticity measurement error is reduced to within 0.01. Measurement accuracy of PSF ellipticity of the telescopes can be improved significantly.

Systemic administration of STING agonist promotes myeloid cells maturation and antitumor immunity through regulating hematopoietic stem and progenitor cell fate.

STING is a pivotal mediator of effective innate and adaptive anti-tumor immunity; however, intratumoral administration of STING agonists have shown limited therapeutic benefit in clinical trials. The systemic effect of the intravenous delivery of STING agonists in cancer is not well-defined. Here, we demonstrated that systemic administration of STING agonist inhibited melanoma growth, improved inflammatory effector cell infiltration, and induced bone marrow mobilization and extramedullary hematopoiesis, causing widespread changes in immune components in the peripheral blood. The systemically administered STING agonist promoted HSC expansion and influenced lineage fate commitment, which was manifested as the differentiation of HSPCs was skewed toward myeloid cells at the expense of B-cell lymphopoiesis and erythropoiesis. Transcriptome analysis revealed upregulation of myeloid lineage differentiation-related and type I interferon-related genes. This myeloid-biased differentiation promoted the production and maturation of myeloid cells toward an activated phenotype. Furthermore, depletion of Gr-1+ myeloid cells attenuated the anti-tumor immunity of STING agonist. Our findings reveal the anti-tumor mechanism of systemic administration of STING agonist that involves modulating HSPC differentiation and promoting myeloid cells maturation. Our study may help explain the limited clinical activity of STING agonists administered intratumorally.

Design of low polarization off-axis three-mirror reflective optical systems.

Off-axis optical systems have several important advantages over on-axis ones. However, high polarization aberrations, which play important roles in many applications, become critical disadvantages of off-axis systems. Thanks to the seven free design parameters, three-mirror reflective systems have a good potential to achieve low polarization. A general method to design low polarization off-axis three-mirror reflective optical systems is proposed in this paper. Based on genetic algorithms, several off-axis three-mirror systems with both low polarization aberrations and good wave aberrations are designed. The method proposed in this paper is versatile and can be used to design other types of optical systems that demand low polarization aberrations.

Alignment algorithm of nonsymmetric off-axis reflective astronomical telescopes based on the modified third-order nodal aberration theory.

For pupil-offset off-axis reflective astronomical telescopes with designed tilts and decenters, owing to the absence of symmetry, axial and lateral misalignments exhibit strong coupling. The astigmatic and coma aberration fields of the misaligned optical systems are not only effected by lateral misalignments but also closely related to axial misalignments. However, the traditional misalignment algorithm based on nodal aberration theory (NAT) usually ignore the effect of axial misalignments on the aberration fields of optical systems when constructing calculation models. As a result, the presence of axial misalignments in pupil-offset off-axis telescopes with designed tilts and decenters will invalidate the traditional NAT-based lateral misalignment algorithm, which makes it difficult to be applied to actual computer-aided alignment experiments. In order to solve this issue, on the framework of modified NAT, third-order astigmatic, third-order coma, and third-order spherical net aberration fields of pupil-offset off-axis systems with designed tilts and decenters induced by axial and lateral misalignments are separated from the total aberration fields, and their inherent relations are analytically expressed. On this basis, in order to construct a solution model that can simultaneously and quantitatively calculate the axial and lateral misalignments, a method is proposed to fit the partial derivative coefficient matrix of misalignments according to field dependence of the net aberrations induced by misalignments. The simulation and actual alignment experiments were performed on a real wide-field off-axis three-mirror telescope using the constructed solution model, which proved the feasibility of the proposed method. Simulation experiments show that for different misalignment conditions generated randomly, both axial and lateral misalignments have achieved convergent solution results. In the actual alignment experiment, the average RMS wavefront errors of the nine field of views is corrected from 1.9 λ to 0.12 λ (λ = 632.8nm) through 3-5 iterations.

Introducing A New Class of Sulfonyl Fluoride Hubs via Radical Chloro-Fluorosulfonylation of Alkynes.

Sulfonyl fluorides have widespread applications in many important fields, including ligation chemistry, chemical biology, and drug discovery. Therefore, new methods to increase the synthetic efficiency and expand the available structures of sulfonyl fluorides are highly in demand. Here, we introduce a new and powerful class of sulfonyl fluoride hubs, ß-chloro alkenylsulfonyl fluorides (BCASF), which can be constructed via radical chloro-fluorosulfonyl difunctionalization of alkynes under photoredox conditions. BCASF molecules exhibit versatile reactivities and well undergo a series of transformations at the chloride site while keeping the sulfonyl fluoride group intact, including reduction, Suzuki coupling, Sonogashira coupling, as well as nucleophilic substitution with various nitrogen, oxygen, and sulfur nucleophiles. By using BCASF as a synthetic hub, a wide range of sulfonyl fluorides becomes readily accessible, such as cis alkenylsulfonyl fluorides, dienylsulfonyl fluorides, and ynenylsulfonyl fluorides, which are challenging or even not possible to synthesize before with the known methods. Moreover, further application of BCASF to the late-stage modification of peptides and drugs is also demonstrated.

Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl Fluorides from Alkenes.

Sulfonyl fluorides have widespread applications in many fields. In particular, their unique biological activity has drawn considerable research interest in the context of chemical biology and drug discovery in the past years. Therefore, new and efficient methods for the synthesis of sulfonyl fluorides are highly in demand. In contrast to extensive studies on FSO2+ -type reagents, a radical fluorosulfonylation reaction with a fluorosulfonyl radical (FSO2. ) remains elusive so far, probably owing to its instability and difficulty in generation. Herein, the development of the first radical fluorosulfonylation of alkenes based on FSO2 radicals generated under photoredox conditions is reported. This radical approach provides a new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established cross-coupling methods. Moreover, extension to the late-stage fluorosulfonylation of natural products is also demonstrated.

High G2 and S-phase expressed 1 expression promotes acral melanoma progression and correlates with poor clinical prognosis.

G2 and S-phase expressed 1 (GTSE1) regulates cell cycle progression in human cancers. However, its significance and mechanism of action in acral melanoma (AM) remain unknown. In the present study, we found that GTSE1 expression was upregulated in advanced stage/metastatic AM tissues and metastatic cell lines, and correlated with higher stage (P = .028) and poor disease-free survival (DFS) in patients with AM (P = .003). Cox regression assays validated GTSE1 expression to be an independent prognostic factor of DFS for patients with AM (P = .004). Ectopic expression of GTSE1 enhanced primary AM cell proliferation, invasion, and migration. Loss-of-function in GTSE1 attenuated metastatic AM cell proliferation and metastatic ability in vitro and in vivo. We additionally observed that inhibition of migration and invasion occurred concomitantly with a GTSE1 knockdown-mediated increase in E-cadherin and decreases in N-cadherin and Slug. We further showed that integrin subunit alpha 2 (ITGA2) interacts with GTSE1 and is a downstream effector of GTSE1. Further, ITGA2 levels were positively correlated with GTSE1 expression in human AM tissues. Ectopic ITGA2 expression rescued siGTSE1-mediated inhibition of migration and invasion, thereby restoring epithelial-to-mesenchymal transition (EMT). In conclusion, GTSE1 expression promotes AM progression and correlates with clinical outcomes of patients with AM, and may represent a promising therapeutic target to suppress AM progression.

Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy.

BACKGROUND: Coexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. In this study, we aim to explore the coexistence status of BRAF V600E mutation and the copy number variation of EZH2 and explore the potential of this combination as a therapeutic target. METHODS: A total of 138 cases of melanoma samples harboring BRAF V600E mutation were included, and EZH2 copy numbers were examined by QuantiGenePlex DNA Assays. Clinical pathological distinction between patient groups with or without EZH2 amplification (hereafter referred to as EZH2 gain) was statistically analyzed. The sensitivity of melanoma cell lines and patient-derived xenograft (PDX) models containing BRAF V600E mutation with or without EZH2 gain to vemurafenib (BRAF inhibitor), GSK2816126 (EZH2 inhibitor) and a combination of both agents was evaluated. RESULTS: In our cohort, the coexistence rate of BRAF V600E mutation and EZH2 gain was up to 29.0%, and significant differences in overall survival and disease-free survival were found between no EZH2 copy number gain and gain groups (P = 0.038, P = 0.030), gain and high EZH2 copy number gain groups (P = 0.006, P = 0.010). Combination with BRAF and EZH2 inhibition showed better inhibitory efficacy in melanoma prevention compared with vemurafenib monotherapy. More importantly, this improved therapeutic effect was observed especially in melanoma cell lines and PDX models containing concurrently BRAF V600E mutation and EZH2 gain. CONCLUSIONS: Coexistence of BRAF V600E mutation and EZH2 gain is rather prevalent in melanoma. Our findings provided evidence for the feasibility of combination therapy with EZH2 and BRAF inhibitors in melanoma with concurrent BRAF V600E mutation and EZH2 gain.

Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor.

Sulfonyl fluorides have attracted considerable and growing research interests from various disciplines, which raises a high demand for novel and effective methods to access this class of compounds. Radical flurosulfonylation is recently emerging as a promising approach for the synthesis of sulfonyl fluorides. However, the scope of applicable substrate and reaction types are severely restricted by limited known radical reagents. Here, we introduce a solid state, redox-active type of fluorosulfonyl radical reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts, which enable the radical fluorosulfonylation of olefins under photoredox conditions. In comparison with the known radical precursor, gaseous FSO2Cl, FABI salts are bench-stable, easy to handle, affording high yields in the radical fluorosulfonylation of olefins with before challenging substrates. The advantage of FABIs is further demonstrated in the development of an alkoxyl-fluorosulfonyl difunctionalization reaction of olefins, which forges a facile access to useful ß-alkoxyl sulfonyl fluorides and related compounds, and would thus benefit the related study in the context of chemical biology and drug discovery in the future.

EZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma.

STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. However, STING is commonly suppressed in melanoma through mechanisms that remain unclear. We found that STING expression was epigenetically suppressed by H3K27me3 in melanoma, and EZH2 inhibitor could induce an H3K27 shift from trimethylation to acetylation, resulting in increased expression of STING. Furthermore, a combination of STING agonist and EZH2 inhibitor upregulated major histocompatibility complex class I expression and chemokine production. Whole-transcriptome analysis showed that IFN-1‒related genes were significantly upregulated in the combination treatment group. In addition, the combination treatment synergistically reduced tumor growth and increased CD8+ T-cell infiltration in a poorly immunogenic melanoma mouse model B16-F10. These results showed, to our knowledge, a previously unreported mechanism underlying the epigenetic regulation of STING expression in melanoma; a combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for patients with melanoma who are refractory to current immunotherapies.

Erratum: MicroRNA-23a-3p Inhibits Mucosal Melanoma Growth and Progression through Targeting Adenylate Cyclase 1 and Attenuating cAMP and MAPK Pathways: Erratum.

[This corrects the article DOI: 10.7150/thno.30516.].

Optical Coherence Tomography-Derived Changes in Plaque Structural Stress Over the Cardiac Cycle: A New Method for Plaque Biomechanical Assessment.

Introduction: Cyclic plaque structural stress has been hypothesized as a mechanism for plaque fatigue and eventually plaque rupture. A novel approach to derive cyclic plaque stress in vivo from optical coherence tomography (OCT) is hereby developed. Materials and Methods: All intermediate lesions from a previous OCT study were enrolled. OCT cross-sections at representative positions within each lesion were selected for plaque stress analysis. Detailed plaque morphology, including plaque composition, lumen and internal elastic lamina contours, were automatically delineated. OCT-derived vessel and plaque morphology were included in a 2-dimensional finite element analysis, loaded with patient-specific intracoronary pressure tracing data, to calculate the changes in plaque structural stress (ΔPSS) on vessel wall over the cardiac cycle. Results: A total of 50 lesions from 41 vessels were analyzed. A significant ΔPSS gradient was observed across the plaque, being maximal at the proximal shoulder (45.7 [32.3, 78.6] kPa), intermediate at minimal lumen area (MLA) (39.0 [30.8, 69.1] kPa) and minimal at the distal shoulder (35.1 [28.2, 72.3] kPa; p = 0.046). The presence of lipidic plaques were observed in 82% of the diseased segments. Larger relative lumen deformation and ΔPSS were observed in diseased segments, compared with normal segments (percent diameter change: 8.2 ± 4.2% vs. 6.3 ± 2.3%, p = 0.04; ΔPSS: 59.3 ± 48.2 kPa vs. 27.5 ± 8.2 kPa, p < 0.001). ΔPSS was positively correlated with plaque burden (r = 0.37, p < 0.001) and negatively correlated with fibrous cap thickness (r = -0.25, p = 0.004). Conclusions: ΔPSS provides a feasible method for assessing plaque biomechanics in vivo from OCT images, consistent with previous biomechanical and clinical studies based on different methodologies. Larger ΔPSS at proximal shoulder and MLA indicates the critical sites for future biomechanical assessment.

Decarboxylative thiolation of redox-active esters to free thiols and further diversification.

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

Metal-free dehydrosulfurization of thioamides to nitriles under visible light.

A visible light-mediated, metal-free dehydrosulfurization reaction of thioamides to nitriles is described. This reaction features high yields, mild reaction conditions, and the use of a cheap organic dye as the photoredox catalyst and air as the oxidant.

Decarboxylative Thiolation of Redox-Active Esters to Thioesters by Merging Photoredox and Copper Catalysis.

Thioesters and related thiols are critically important to biological systems and also widely employed in the synthesis of pharmaceutically important molecules and polymeric materials. However, known synthetic methods often suffer from the disadvantage of being specific only to certain substrates. Herein, we describe a facile decarboxylative thioesterification of alkyl acid derived redox-active esters by merging photoredox catalysis and copper catalysis. This reaction is applicable to a wide range of carboxylic acids, as well as natural products and drugs, allowing for the synthesis of various thioesters with diverse structures, including tertiary ones that are not accessible via traditional nucleophilic substitution from tertiary halides. Moreover, product utilization is demonstrated with a direct transformation of thioesters to sulfonyl fluorides.

A Functional Synonymous Variant in PDGFRA Is Associated with Better Survival in Acral Melanoma.

Purpose: Polymorphisms of genes in the platelet-derived growth factor (PDGF) signaling pathway have been found to predict cutaneous melanoma (CM) survival, but their clinical effects in acral melanoma (AM) patients have not been explored. The aim of this study was to characterize the functional effect of the tag single-nucleotide polymorphism (SNP) rs2228230:C>T and assess its association with clinical outcomes in AM patients. Methods: The effect of rs2228230:C>T on mRNA structures and codon usage values were evaluated using in silico analyses. PDGF receptor alpha (PDGFRA) expression vectors with the rs2228230:C or rs2228230:T allele were constructed to evaluate the expression and signaling activity of PDGFRA. The expression of PDGFRA in AM samples was measured using in situ RNAscope hybridization and immunohistochemical staining. The association of the rs2228230 genotype with survival was analyzed in two independent AM cohorts. Results: In silico analyses indicated that the rs2228230:T allele increases the minimum free energy and reduces synonymous codon usage. The rs2228230:T allele decreased the expression of PDGFRA by reducing the stability of its mRNA and protein as well as the signaling activity of the MAPK and PI3K/AKT pathways. PDGFRA mRNA and protein expression was significantly reduced in AM tissues with the rs2228230:T allele. The progression-free survival and overall survival of AM patients with the rs2228230:T allele were significantly longer than those of patients with the CC genotype. Conclusion: Our study indicated that rs2228230:T can reduce the expression of PDGFRA and downstream signaling activity and is associated with better survival in AM patients.

A rapid access to aliphatic sulfonyl fluorides.

The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

Visible-Light-Induced Deaminative Thioesterification of Amino Acid Derived Katritzky Salts via Electron Donor-Acceptor Complex Formation.

A visible-light-mediated deaminative thioesterification of amino acid derived Katritzky salts with thiobenzoic acid has been developed, which provides a novel synthetic method for the synthesis of α-mercapto acid derivatives under mild conditions. This photoredox catalyst-free generation of alkyl radicals via C-N bond cleavage is enabled by the formation of an electron-donor-acceptor (EDA) complex between the Katritzky salt and thiobenzoic acid anion, which represents a new entry for EDA complex chemistry.

Prognostic role of NRAS isoforms in Chinese melanoma patients.

Neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) isoforms are expressed in melanoma tumor tissues, which have been described in Caucasian melanoma. However, the status and the clinical significance of NRAS isoforms in the Asian population have not been investigated on a large scale. We examined the expression levels of NRAS isoforms of 140 melanoma samples using quantitative real-time PCR. Furthermore, the relationship of mRNA expression of NRAS isoforms to clinicopathological characteristics and survival of patients was analyzed. Statistical analysis showed that NRAS isoform 2 expression was correlated with melanoma subtypes (P=0.007), and NRAS isoform 4 expression was correlated with tumor thickness (P=0.031) and clinical stage (P=0.006). The median overall survival for patients with high expression of NRAS isoform 3 was significantly shorter than that for patients with low expression of NRAS isoform 3 (P=0.007). In addition, high expression of NRAS isoform 5 was associated with a worse prognosis (P=0.049 and 0.002 for overall survival and disease-free survival, respectively). Multivariate Cox regression analysis showed that high expression levels of NRAS isoform 3 and isoform 5 were independent poor prognostic factors for patients. Our results indicated that the mRNA expressions of NRAS isoform 3 and isoform 5 may be novel indicators of the prognosis of Chinese melanoma patients.