Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPß1 mediated by induction of antitumorigenic macrophages.

The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPß1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRPß1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPß1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPß1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPß1 is a potential target for cancer immunotherapy.

Functionalized Polyamine Synthesis with Photoredox Catalysis.

Polyamines, such as putrescine and spermidine, are pivotal in various biological processes across living organisms. Despite their significance, structurally modified polyamines offer a less-explored avenue for discovering bioactive compounds. The limitation is attributed to the synthetic difficulty of accessing functionalized polyamines. In this study, we accomplished photoredox-catalyzed functionalization of polyamines to diversify their structure. The rapid functionalization allows attaching fluorophores to the target polyamine, facilitating the development of molecular probes for advancing chemical biology studies.

Polymorphism of Two-Dimensional Semiconducting Coordination Polymers: Impact of a Lead-Sulfur Network on Photoconductivity.

Sulfur-coordinated coordination polymers (S-CPs) have unique optoelectrical properties that originate from infinite M-S bond networks. In this study, we synthesized and characterized two polymorphs of a two-dimensional (2D) Pb(II) S-CP with a formula of [Pb(tzdt)(OAc)] (Htzdt=1,3-thiazolidine-2-thione, OAc=acetate). Our findings revealed that the thermodynamic product (KGF-26) possesses quasi-2D (-Pb-S-)n layers with weak nonbonded Pb-S bonds, whereas the kinetic product (KGF-27) has intrinsic 2D (-Pb-S-)n layers with Pb-S bonds. The results of time-resolved microwave conductivity measurements and first-principles calculations confirmed that KGF-27 exhibits higher photoconductivity than KGF-26, which establishes that the inorganic (-Pb-S-)n networks with Pb-S bonds are crucial for achieving high photoconductivity. This is the first experimental demonstration of the impact of the (-M-S-)n networks in S-CPs on photoconductivity through the comparison of crystal polymorphisms.

Detection of four isomers of the human cytomegalovirus genome using nanopore long-read sequencing.

Human cytomegalovirus has a linear DNA genome with a total length of approximately 235 kb. This large genome is divided into two domains, "Long" and "Short". There are four isomers of the cytomegalovirus genome with different orientations of each domain. To confirm the presence of four types of isomers, it is necessary to identify the sequence of the junction between the domains. However, due to the presence of repeat sequences, it is difficult to determine the junction sequences by next-generation sequencing analysis. To solve this problem, long-read sequencing was performed using the Oxford Nanopore sequencer and the junctions were successfully identified in four isomers in strain Merin and ATCC-2011-3. Nanopore sequencing also revealed the presence of multiple copies of the "a" sequence (a-seq) in the junctions, indicating the diversity of the junction sequences. These results strongly suggest that long-read sequencing using the nanopore sequencer would be beneficial for identifying the complex structure of the cytomegalovirus genome.

[18F]FB(ePEG12)12-exendin-4 noninvasive imaging of insulinoma negative for insulin immunostaining on specimen from endoscopic ultrasonography-guided fine needle aspiration: a case report with review of literature.

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by 18F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from the anomalous accumulation of pathogenic CD1a+ CD207+ dendritic cells (DCs). SIRPα is a transmembrane protein highly expressed in myeloid cells such as DCs and macrophages. Here we show that SIRPα is a potential therapeutic target for LCH. We found that SIRPα is expressed in CD1a+ cells of human LCH lesions as well as in CD11c+ DCs in the spleen, liver, and lung of a mouse model of LCH (BRAFV600ECD11c mouse), in which an LCH-associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAFV600ECD11c mice manifested markedly increased numbers of CD4+ T cells, regulatory T cells, and macrophages as well as of CD11c+ MHCII+ DCs in the spleen. Monotherapy with a mAb to SIRPα greatly reduced the percentage of CD11c+ MHCII+ DCs in peripheral blood, LCH-like lesion size in the liver, and the number of CD11c+ MHCII+ DCs in the spleen of the mutant mice. Moreover, this mAb promoted macrophage-mediated phagocytosis of CD11c+ DCs from BRAFV600ECD11c mice, whereas it had no effects on the viability or CCL19-dependent migration of such CD11c+ DCs or on their expression of the chemokine genes Ccl5, Ccl20, Cxcl11, and Cxcl12. Our results thus suggest that anti-SIRPα monotherapy is a promising approach to the treatment of LCH that is dependent in part on the promotion of the macrophage-mediated killing of LCH cells.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Copper-Catalyzed Heterocyclic Recombination of Aziridine and Diazetidine for the Synthesis of Imidazolidine.

The discovery of new catalytic applications for metals remains an important goal in organic synthesis. If a catalyst has multiple functions, such as inducing bond cleavage and formation, it can streamline multi-step transformations. Herein, the Cu-catalyzed synthesis of imidazolidine through heterocyclic recombination between aziridine and diazetidine is reported. Mechanistically, Cu catalyzes the conversion of diazetidine into the corresponding imine, which then reacts with aziridine to form imidazolidine. The scope is sufficiently wide to form various imidazolidines, as many functional groups are compatible with the reaction conditions.

Stabilization of kidney function and reduction in heart failure events with sodium-glucose co-transporter 2 inhibitors: A meta-analysis and meta-regression analysis.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) events regardless of diabetes status. However, factors associated with their efficacy in HF reduction remain unknown. This study aims to identify clinically relevant markers for the efficacy of SGLT2 inhibitors in HF risk reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE and EMBASE for randomized placebo-controlled trials of SGLT2 inhibitors reporting a composite of HF hospitalization or cardiovascular death in participants with or without type 2 diabetes published until 28 February 2023. Random-effects meta-analysis and mixed-effects meta-regression were conducted to evaluate the association between the outcomes and clinical variables, including changes in glycated haemoglobin, body weight, systolic blood pressure, haematocrit and overall/chronic estimated glomerular filtration rate (eGFR) slope. RESULTS: Thirteen trials with 90 413 participants were included. SGLT2 inhibitors reduced the hazard ratio of the composite of HF hospitalization or cardiovascular death (hazard ratio 0.77; 95% confidence interval, 0.74-0.81; p < .0001). In meta-regression analysis, chronic eGFR slope (eGFR change after the initial dip) was significantly associated with the composite outcome (p = .017), and each 1 ml/min/1.73 m2 /year improvement in chronic eGFR slope led to a 14% reduction in the composite outcome. By contrast, changes in the other parameters showed no significant associations. CONCLUSIONS: Improvement in chronic eGFR slope, which reflects the stabilization of kidney function, is significantly associated with the efficacy of the SGLT2 inhibitor in HF, highlighting the cardiorenal axis role in the beneficial effects on HF. The chronic eGFR slope can be a surrogate marker of the effects of SGLT2 inhibitors on HF reduction.

Purification and Characterization of the Lecithin-Dependent Thermolabile Hemolysin Vhe1 from the Vibrio sp. Strain MA3 Associated with Mass Mortality of Pearl Oyster (Pinctada fucata).

In a previous study, we isolated a Vibrio sp. strain MA3 and its virulence factor, a hemolysin encoded by vhe1. This strain is associated with mass mortalities of the pearl oyster Pinctada fucata. In the present study, the vhe1 gene from strain MA3 was cloned and its encoded product was purified and characterized. Our results show that the vhe1 gene encodes a protein of 417 amino acids with an estimated molecular mass of 47.2 kDa and a pI of 5.14. The deduced protein, Vhe1, was found to contain the conserved amino acid sequence (GDSL motif) of the hydrolase/esterase superfamily and five conserved blocks characteristic of SGNH hydrolases. A BLAST homology search indicated that Vhe1 belongs the lecithin-dependent hemolysin/thermolabile hemolysin (LDH/TLH) family. In activity analyses, the optimal temperature for both the hemolytic and phospholipase activities of Vhe1 was 50 °C. Vhe1 hemolytic activity and phospholipase activity were highest at pH 8.5 and pH 8.0, respectively. However, both enzymatic activities sharply decreased at high temperature (> 50 °C) and pH < 7.0. Compared with previously reported hemolysins, Vhe1 appeared to be more thermal- and pH-labile. Both its hemolytic activity and phospholipase activity were significantly inhibited by CuCl2, CdCl2, ZnCl2, and NiCl2, and slightly inhibited by MnCl2 and CoCl2. Vhe1 showed higher phospholipase activity toward medium-chain fatty acids (C8-C12) than toward shorter- and longer-chain fatty acids. These results accumulate knowledge about the LDH/TLH of V. alginolyticus, which detailed characterization has not been reported, and contribute to solving of the mass mortality of pearl oyster.

Tin(II)-Based Metal-Organic Frameworks Enabling Efficient, Selective Reduction of CO2 to Formate under Visible Light.

Certain metal complexes are known as high-performance CO2 reduction photocatalysts driven by visible light. However, most of them rely on rare, precious metals as principal components, and integrating the functions of light absorption and catalysis into a single molecular unit based on abundant metals remains a challenge. Metal-organic frameworks (MOFs), which can be regarded as intermediate compounds between molecules and inorganic solids, are potential platforms for the construction of a simple photocatalytic system composed only of Earth-abundant nontoxic elements. In this work, we report that a tin-based MOF enables the conversion of CO2 into formic acid with a record high apparent quantum yield (9.8 % at 400 nm) and >99 % selectivity without the need for any additional photosensitizer or catalyst. This work highlights a new MOF with strong potential for photocatalytic CO2 reduction driven by solar energy.

Development and evaluation of a rapid, specific, and sensitive loop-mediated isothermal amplification assay to detect Tenacibaculum sp. strain pbs-1 associated with black-spot shell disease in Akoya pearl oysters.

Black-spot shell disease decreases pearl quality and threatens pearl oyster survival. Establishment of a rapid, specific, and sensitive assay to detect Tenacibaculum sp. strain Pbs-1 associated with black-spot shell disease is of commercial importance. We developed a rapid, specific, and highly sensitive loop-mediated isothermal amplification (LAMP) assay to detect Tenacibaculum sp. Pbs-1 in Akoya pearl oysters Pinctada fucata. A set of five specific primers (two inner, two outer, and a loop) were designed based on the 16S-23S internal spacer region of strain Pbs-1. The optimum reaction temperature was 63 °C, and concentrations of the inner and loop primers were 1.4 and 1.0 µM, respectively. The LAMP product can be detected using agarose gel electrophoresis, and the color change in the reaction tube can be detected visually (by the naked eye) following the addition of malachite green. Our assay proved to be specific for strain Pbs-1, with no cross-reactivity with five other species of Tenacibaculum. The detection limit of the LAMP assay at 35 min is 50 pg, and at 60 min it is 5 fg. We evaluated the LAMP assay using diseased and healthy pearl oysters. The results demonstrate the suitability and simplicity of this test for rapid field diagnosis of strain Pbs-1.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: A meta-analysis and meta-regression analysis.

AIM: To evaluate the cardiovascular and renal outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the associations between these outcomes and HbA1c or weight reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE, EMBASE, and CENTRAL databases for randomized, placebo-controlled trials of GLP-1 RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes. RESULTS: We extracted data of 60 800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1 RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80-0.93; P < .001) and secondary outcomes including the composite renal outcome (0.80; 0.73-0.87; P < .001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = .044; R2  = 0.65) and the composite renal outcome (P = .040; R2  = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = .390). CONCLUSIONS: The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for the cardiovascular and renal benefits of treatment with GLP-1 RAs.

Failure-Experiment-Supported Optimization of Poorly Reproducible Synthetic Conditions for Novel Lanthanide Metal-Organic Frameworks with Two-Dimensional Secondary Building Units*.

Novel metal-organic frameworks containing lanthanide double-layer-based secondary building units (KGF-3) were synthesized by using machine learning (ML). Isolating pure KGF-3 was challenging, and the synthesis was not reproducible because impurity phases were frequently obtained under the same synthetic conditions. Thus, dominant factors for the synthesis of KGF-3 were identified, and its synthetic conditions were optimized by using two ML techniques. Cluster analysis was used to classify the obtained powder X-ray diffractometry patterns of the products and thus automatically determine whether the experiments were successful. Decision-tree analysis was used to visualize the experimental results, after extracting factors that mainly affected the synthetic reproducibility. Water-adsorption isotherms revealed that KGF-3 possesses unique hydrophilic pores. Impedance measurements demonstrated good proton conductivities (σ=5.2×10-4  S cm-1 for KGF-3(Y)) at a high temperature (363 K) and relative humidity of 95 % RH.

Failure-Experiment-Supported Optimization of Poorly Reproducible Synthetic Conditions for Novel Lanthanide Metal-Organic Frameworks with Two-Dimensional Secondary Building Units.

Invited for the cover of this issue are Daisuke Tanaka at Kwansei Gakuin University and co-workers at Kwansei Gakuin University, Hokkaido University, Kyoto University, Japan and KU Leuven, Belgium. The image is a depiction of exploring the desired crystal by decision tree analysis. Read the full text of the article at 10.1002/chem.202102404.

Redox-Active Tin Metal-Organic Framework with a Thiolate-Based Ligand.

Metal-organic frameworks (MOFs) and coordination polymers composed of thiolates as coordinating functional groups are interesting materials with unique optical and electronical properties. Herein, we report the preparation of KGF-4 and KGF-10, two Sn-MOF crystal structures with bonds between Sn and thiolate. KGF-10 was isolated as a pure phase and found to exhibit redox properties and a semiconducting band structure, as confirmed by first-principles (density functional theory) calculations.

Photoconductive Coordination Polymer with a Lead-Sulfur Two-Dimensional Coordination Sheet Structure.

Coordination polymers with metal-sulfur (M-S) bonds in their nodes have interesting optical properties and can be used as photocatalysts for water splitting. A wide range of inorganic-organic hybrid materials with M-S bonds have been prepared in recent years. However, there is a dearth of structural information because of their low crystallinity, which has hampered the understanding of their underlying chemistry and physics. Thus, we conducted a structural study of a novel, highly crystalline coordination polymer with M-S bonds. Theoretical calculations were performed to elucidate its photoconductivity mechanism. The photoconductive, three-dimensional coordination polymer [Pb(tadt)]n (denoted as KGF-9; tadt = 1,3,4-thiadiazole-2,5-dithiolate) was synthesized and confirmed to have a three-dimensional structure containing a two-dimensional Pb-S framework by single-crystal X-ray diffraction. We also performed diffuse-reflectance ultraviolet-visible-near-infrared spectroscopy, time-resolved microwave conductivity, and photoelectron yield spectroscopy measurements on the bulk powder samples, as well as first-principles calculations. Additionally, direct-current photoconductivity measurements were conducted on a single-crystal sample.

Machine-Learning-Assisted Selective Synthesis of a Semiconductive Silver Thiolate Coordination Polymer with Segregated Paths for Holes and Electrons.

Coordination polymers (CPs) with infinite metal-sulfur bond networks have unique electrical conductivities and optical properties. However, the development of new (-M-S-)n -structured CPs is hindered by difficulties with their crystallization. Herein, we describe the use of machine learning to optimize the synthesis of trithiocyanuric acid (H3 ttc)-based semiconductive CPs with infinite Ag-S bond networks, report three CP crystal structures, and reveal that isomer selectivity is mainly determined by proton concentration in the reaction medium. One of the CPs, [Ag2 Httc]n , features a 3D-extended infinite Ag-S bond network with 1D columns of stacked triazine rings, which, according to first-principle calculations, provide separate paths for holes and electrons. Time-resolved microwave conductivity experiments show that [Ag2 Httc]n is highly photoconductive (φΣµmax =1.6×10-4  cm2 V-1 s-1 ). Thus, our method promotes the discovery of novel CPs with selective topologies that are difficult to crystallize.

Semiconductive Nature of Lead-Based Metal-Organic Frameworks with Three-Dimensionally Extended Sulfur Secondary Building Units.

Recently, metal-organic frameworks (MOFs) composed of sulfur secondary building units (sulfur-SBUs) have attracted significant attention as unique electronic materials with high conductivities and photo- and electrocatalytic properties. Herein we report the crystal structure of KGF-1, an example of a Pb-MOF composed of three-dimensionally extended sulfur-SBUs that displays molecular sieving behavior, visible-light absorption, and a semiconductor band structure and is a hydrogen-evolution photocatalyst.

Tumor mutation burden and immunological, genomic, and clinicopathological factors as biomarkers for checkpoint inhibitor treatment of patients with non-small-cell lung cancer.

Cancer treatment using immune checkpoint inhibitors is widely used, although biomarkers predictive of response are not well established. However, both the expressions of programmed cell death ligand 1 (PD-L1) and the tumor mutation burden (TMB) hold promise as such biomarkers for immune checkpoint inhibitors; however, its characteristics and clinical and immunological impacts have not been fully analyzed. We, therefore, evaluated the clinical and immunological parameters related to TMB to identify potential new biomarkers. We enrolled 92 patients with non-small-cell lung cancer who underwent surgery at Fukushima Medical University Hospital from 2013 to 2016. TMB of individual tumors was calculated by whole-exome sequencing analysis. Major cancer-related gene mutations were evaluated using panel sequencing. Expression of PD-L1 and abundance of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry using surgical samples. The median TMB value was 60. TMB was significantly higher in men, current or former smokers, and in patients with squamous cell carcinoma, tumor size ≥ 2.8 cm, wild-type EGFR, TP53 gene mutation-positive status, and cyclin-dependent kinase-inhibitor gene 2A mutation-positive status. According to multivariate analysis, TMB was significantly associated with EGFR gene mutation-negative status (p = 0.0111) and TP53 gene mutation-positive status (p = 0.0425). If TMB is identified as a robust biomarker for immune checkpoint inhibitor administration, analysis of TP53 and EGFR mutations may provide a relatively rapid and easy proxy for predicting TMB.