Catecholamine Derivatives: Natural Occurrence, Structural Diversity, and Biological Activity.

Catecholamines (CAs) are aromatic amines containing a 3,4-dihydroxyphenyl nucleus and an amine side chain. Representative CAs included the endogenous neurotransmitters epinephrine, norepinephrine, and dopamine. CAs and their derivatives are good resources for the development of sympathomimetic or central nervous system drugs, while they also provide ligands important for G-protein coupled receptor (GPCR) research. CAs are of broad interest in the fields of chemical, biological, medical, and material sciences due to their high adhesive capacities, chemical reactivities, metal-chelating abilities, redox activities, excellent biocompatibilities, and ease of degradability. Herein, we summarize CAs derivatives isolated and identified from microorganisms, plants, insects, and marine invertebrates in recent decades, alongside their wide range of reported biological activities. The aim of this review is to provide an overview of the structural and biological diversities of CAs, the regularity of their natural occurrences, and insights toward future research and development pertinent to this important class of naturally occurring compounds.

Heterogeneity of the tumor immune microenvironment and its clinical relevance.

During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies.

Somatostatin Receptor 2: A Potential Predictive Biomarker for Immune Checkpoint Inhibitor Treatment.

Somatostatin receptor 2 (SSTR2), the most abundant receptor of somatostatin (SST), possesses immunoreactivity and is altered in many cancers. However, the association between SSTR2 and efficacy of immune checkpoint inhibitors (ICIs) has not yet been reported. Immunohistochemistry (IHC) information across 20 cancers was collected from the Human Protein Atlas (HPA) and used to analyze the expression of SSTR2. Immune signatures collected from public databases, such as BioCarta or Reactome, were used to investigate the association between SSTR2 and the tumor microenviroment in the Cancer Genome Atlas (TCGA). Data from cohorts treated with ICIs were collected to assess whether SSTR2 is associated with benefits from ICIs treatment. In the HPA, we found the SSTR2 IHC-positive rate of 13 cancers to be above 50%. Five types of cancer express SSTR2 mildly (positive rate: 25%-50%), while the remaining two types of cancer barely stained SSTR2-positive (positive rate: 0%-24%). In TCGA analysis, immune cell signatures and immune function pathways were enriched in high SSTR2 expression groups in most cancers. In each ICIs treated cohort, patients with high SSTR2 expression experienced numerically superior objective response rate (Braun: 14.8% vs 13.4%, p = 0.85; Gide: 69.4% vs 40.5%, p = 0.025; Mariathasan: 22.4% vs 16.7%, p = 0.233; Miao: 37.5% vs 11.8%; Riaz: 32.0% vs 7.7%, p = 0.067) and overall survival (Braun: HR (95%CI): 0.80 [0.62-1.04], p = 0.80; Gide: HR (95%CI): 0.61 [0.29-1.30], p = 0.20; Mariathasan: HR (95%CI): 0.83 [0.64-1.08], p = 0.16; Miao: HR (95%CI): 0.24 [0.086-0.65], p = 0.0028; Nathanson cohort: HR (95%CI): 0 [0-inf], p = 0.18; Riaz: HR (95%CI): 0.24 [0.086-0.65], p = 0.028) than patients with low SSTR2 expression. In pooled cohort, we found these differences were significant (Pool: 24.6% vs 16.7%, p = 0.0077; HR (95% CI): 0.77 [0.65-0.91], p = 0.0018). Our results suggest that SSTR2 is a potential predictive biomarker for response to ICIs.

ENPEP as a potential predictor of immune checkpoint inhibitor efficacy.

BACKGROUND: The gene ENPEP encodes glutamyl aminopeptidase, which can cut N-terminal aspartic acid from angiotensin II, and is related to tumorigenesis and immune microenvironment, however, the association between the expression of ENPEP and benefits of immune checkpoint inhibitors (ICIs) has had no investigation. METHODS: We assess the immunotherapeutic predictive performance of ENPEP expression and mutation in multiple cohorts, including one discovery cohort (Pender cohort), four validation cohorts (Hugo cohort; Liu cohort; Mariathasan cohort; Zhao cohort), and one mutation cohort (Miao cohort). Cohorts from The Cancer Genome Atlas (TCGA) were used to explore mechanism and analysis prognosis. RESULTS: In the discovery cohort, patients with lower ENPEP expression had superior response rates (47.2% vs. 36.1%) and over-all survival (OS) (HR [95% CI] = 0.61 [0.39-0.96]; p = 0.032) compared with those with higher ENPEP expression. The association between ENPEP and immunotherapy efficacy was consistently observed in validation cohorts (Hugo: OS HR [95% CI] = 0.41 [0.11-1.45], p = 0.158; Liu: OS HR [95% CI] = 0.73 [0.44-1.20], p = 0.211; Mariathasan: OS HR [95% CI] = 0.84 [0.65-1.09], p = 0.181; Zhao: OS HR [95% CI] = 0.20 [0.04-1.01], p = 0.033; Pooled cohort: OS HR [95% CI] = 0.76 [0.61-0.95], p = 0.015), and in the mutation cohort (ENPEP mutation vs. wild type (WT), OS HR [95% CI] = 0.46 [0.26-0.93], p = 0.017). Reliably, ENPEP is associated with M2 macrophage infiltration and activation in TCGA. CONCLUSIONS: Our results demonstrated ENPEP is a potential biomarker to classify patients' response to ICIs treatment.

Programmed Cell Death Protein Ligand 2 Is a Potential Biomarker That Predicts the Efficacy of Immunotherapy.

Immune checkpoint inhibitor (ICI) responses vary, and biomarkers for predicting responders are urgently needed. Growing evidence points to the association between programmed cell death protein ligand 2 (PDL2) and ICI benefits, while clinical evidences were lacking. Thus, we consolidated five public ICI-treated cohorts to investigate the association between PDL2 expression and ICI treatment prognosis. Immune cell signatures and IFN-γ signatures are investigated in The Cancer Genome Atlas (TCGA) dataset and later in ICI-treated cohorts to explore the association between PDL2 and antitumor immunity in the tumor microenvironment (TME). We found that immune cell signatures and IFN-γ signatures were enriched in the PDL2-high group in TCGA pooled cohorts and most cancers. Consistently, in ICI-treated cohorts, patients with high PDL2 expression experienced longer overall survival time (OS) and were more likely responsive to ICIs than patients with low PDL2 expression. Immune cell scores of the high PDL2 expression patients were significantly higher (P < 0.05) than those of the low PDL2 expression patients in ICI-treated cohorts. In conclusion, our findings suggest that PDL2 is a potential predictive biomarker for ICIs.

Suppression of IGF1R in Melanoma Cells by an Adenovirus-Mediated One-Step Knockdown System.

Abnormal activation of the IGF1R signaling pathway accelerates melanoma development and metastases. RNAi systems with complex cloning procedures and unsatisfactory efficiency in suppressing gene expression have become the technical difficulties that hinder their utility when studying gene knockdown. Here we established a simplified adenovirus-mediated gene knockdown system by which a single adenoviral vector carries multiple siRNA fragments that can effectively suppress IGF1R expression in melanoma cells. We first generated the adenovirus that simultaneously expresses three human or mouse siRNAs targeting IGF1R (AdRIGF1R-OK). qRT-PCR and immunofluorescence staining revealed that IGF1R expression was significantly decreased in the melanoma cells that were infected with AdRIGF1R-OK. Bioluminescence imaging showed that the size of the tumor formed by the xenografts infected with AdRIGF1R-OK was significantly smaller than that of the controls. Annexin V-FITC flow cytometry assay, immunofluorescence staining for cleaved caspase-3, and Hoechst staining showed that more cells underwent apoptosis after infection with AdRIGF1R-OK. Luciferase reporter assay, crystal violet cell viability assay, and cell-cycle analysis showed that the proliferation of melanoma cells infected with AdRIGF1R-OK was significantly decreased compared to the controls. This study demonstrates that the OK system is effective in silencing gene expression, with promising potential to treat melanoma and other diseases.

Acidic ionic liquid based UiO-67 type MOFs: a stable and efficient heterogeneous catalyst for esterification.

A facile strategy for the synthesis of acidic ionic liquid based UiO-67 type MOFs was developed in this study. Brønsted acids (H2SO4, CF3SO3H and hifpOSO3H (hexafluoroisopropyl sulfuric acid)) were introduced into UiO-67-bpy (bpy = 2,2'-bipyridine-5,5'-dicarboxylic acid) frameworks by reacting with bipyridyl nitrogen to introduce the properties of an acidic ionic liquid into the frameworks. The prepared catalysts, denoted as UiO-67-HSO4, UiO-67-CF3SO3 and UiO-67-hifpOSO3, were characterized by XRD, SEM, FT-IR, EA, TGA and N2 adsorption-desorption studies. The relatively high surface area was still maintained and acidic active groups were uniformly dispersed in the frameworks. The catalytic performance of UiO-67-HSO4, UiO-67-CF3SO3 and UiO-67-hifpOSO3 was evaluated by the esterification of acetic acid with isooctyl alcohol. The prepared catalysts showed good catalytic activities in the esterification, of which UiO-67-CF3SO3 gave the maximum isooctyl alcohol conversion of 98.6% under optimized conditions. The catalyst could be reused five times without a significant decrease in the conversion of isooctyl alcohol, and almost no active species were leached, indicating the excellent stability and reusability of the catalyst. Our study provides one effective way to synthesize heterogeneous acidic ionic liquid catalysts consisting of isolated, well defined acidic groups that will probably attract interest in acid catalyst chemistry.