A meta-analysis of unilateral axillary approach for robotic surgery compared with open surgery for differentiated thyroid carcinoma.

OBJECTIVE: The Da Vinci Robot is the most advanced micro-control system in endoscopic surgical instruments and has gained a lot of valuable experience today. However, the technical feasibility and oncological safety of the robot over open surgery are still uncertain. This work is to systematically evaluate the efficacy of the unilateral axillary approach for robotic surgery compared to open surgery for differentiated thyroid carcinoma. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were utilized to search for relevant literatures of robotic thyroid surgery using unilateral axillary approach compared to open thyroid surgery, and a meta-analysis was performed using RevMan software version 5.3. Statistical analysis was performed through Mantle-Haenszel and inverse variance methods. RESULTS: Twelve studies with a total of 2660 patients were included in the meta-analysis. The results showed that compared with the open group, the robotic group had a longer total thyroidectomy time, shorter hospital stay, less intraoperative bleeding, more postoperative drainage, fewer retrieved central lymph nodes, and higher cosmetic satisfaction (all P < 0.05). In contrast, temporary and permanent laryngeal recurrent nerve injury, temporary and permanent hypoparathyroidism or hypocalcemia, brachial plexus nerve injury, number of retrieved central lymph nodes, number of retrieved lymph nodes in the lateral cervical region, number of lymph node metastases in the lateral cervical region, hematoma, seroma, lymphatic leak, stimulated thyroglobulin (sTg) and unstimulated thyroglobulin (uTg), and the number and recurrence rate of patients with sTg <1ng/ml were not statistically different between the two groups (P > 0.05). CONCLUSIONS: The unilateral axillary approach for robotic thyroid surgery may achieve outcomes similar to those of open surgery. Further validation is required in a prospective randomized controlled trial.

Direct Access to Thio- and Seleno-acetamides Bearing (Benzo)thiazoles by a Base-Promoted One-Pot Two-Step Three-Component Reaction of 2-Amino(benzo)thiazoles with Aryl Acetyl Chlorides and Dichalcogenides.

Highly efficient and practical carbon-chalcogen (S, Se) and amide bonds formation methodologies for the synthesis of thio- and seleno-acetamides were developed, via the base-promoted one-pot two-step reactions of 2-amino(benzo)thiazoles and aryl acetyl chlorides with dichalcogenides. This cross-coupling reaction afforded the goal products that had been chalcogenated regioselectively in moderate to good yields. Further transformations of the new synthesized compounds, DFT calculations and preliminary mechanism studies are discussed as well.

Copper-promoted S-arylation reactions with triarylbismuths for the synthesis of diaryl sulfides.

A simple approach for copper-promoted S-arylation reactions utilizing triarylbismuths or triarylantimonys as arylating reagents has been described. These reactions can be performed under mild conditions and exhibit remarkable functional group tolerance and chemoselectivity. The corresponding 2-arylthiopyridine 1-oxide derivatives and arylthioanilines/phenols have been successfully synthesized, achieving good to excellent yields across over 49 examples.

A PD-L1 Antibody-Conjugated PAMAM Dendrimer Nanosystem for Simultaneously Inhibiting Glycolysis and Promoting Immune Response in Fighting Breast Cancer.

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late-stage or metastatic disease. Here an effective strategy is reported for treating metastatic breast cancer. Specifically, a self-assembling dendrimer nanosystem decorated with an antibody against programmed cell death ligand 1 (PD-L1) is established for delivering a small interfering RNA (siRNA) to target 3-phosphoinositide-dependent protein kinase-1 (PDK1), a kinase involved in cancer metabolism and metastasis. This nanosystem, named PPD, is designed to target PD-L1 for cancer-specific delivery of the siRNA to inhibit PDK1 and modulate cancer metabolism while promoting programmed cell death 1 (PD-1)/PD-L1 pathway-based immunotherapy. Indeed, PPD effectively generates simultaneous inhibition of PDK1-induced glycolysis and the PD-1/PD-L1 pathway-related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor-bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor-targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of the tumor microenvironment and metabolism alongside a unique self-assembling dendrimer platform to achieve specific tumor targeting and siRNA-based gene silencing in combined and precision cancer therapy.

Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking.

Drug delivery systems (DDSs) that can overcome tumor heterogeneity and achieve deep tumor penetration are challenging to develop yet in high demand for cancer treatment. We report here a DDS based on self-assembling dendrimer nanomicelles for effective and deep tumor penetration via in situ tumor-secreted extracellular vesicles (EVs), an endogenous transport system that evolves with tumor microenvironment. Upon arrival at a tumor, these dendrimer nanomicelles had their payload repackaged by the cells into EVs, which were further transported and internalized by other cells for delivery "in relay." Using pancreatic and colorectal cancer-derived 2D, 3D, and xenograft models, we demonstrated that the in situ-generated EVs mediated intercellular delivery, propagating cargo from cell to cell and deep within the tumor. Our study provides a new perspective on exploiting the intrinsic features of tumors alongside dendrimer supramolecular chemistry to develop smart and effective DDSs to overcome tumor heterogeneity and their evolutive nature thereby improving cancer therapy.

Discovery of an insulin-induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element-binding protein-mediated lipogenesis.

BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.

Silica gel impregnated with deep eutectic solvent-based matrix solid-phase dispersion followed by high-performance liquid chromatography for extraction and detection of triazine herbicides in brown sugar.

A novel method was developed to determine six triazine herbicides from brown sugar samples using matrix solid-phase dispersion (MSPD) based on silica gel impregnated with deep eutectic solvent (DES) followed by high-performance liquid chromatography with photodiode array detector (HPLC/PDA). Several factors involved in the MSPD procedure such as DES type, DES content in impregnated silica gel, adsorbent-to-sample mass ratio, type and volume of washing solvent, type and volume of eluent, and grinding time were screened using single-factor experiments and then optimized using Box-Behnken design to accomplish the highest recoveries. The above method demonstrated a good linear range (20-1000 µg kg-1) with a determination coefficient exceeding 0.9962, low limits of determination (1.59-3.77 µg kg-1), acceptable limits of quantifications, and acceptable spiking recoveries (95.0-101.7%) for six triazines under optimized conditions. The proposed MSPD-HPLC/PDA method is a convenient, effective, and sensitive method for rapidly isolating and quantifying six triazines from brown sugar.

Novel recognition mechanism based on oxidative addition of Pt(II) complex-based luminescent probes for hypochlorite ion detection.

Platinum(II) complexes are the most commonly used anticancer drugs and potential optical materials, but the detectability of Pt(II) complex-based probes is seldom reported. In our previous work, a tetradentate Pt(II) complex Pt-CHO was utilised as a 'turn-off' probe to detect ClO- and image cancer cells. However, the recognition mechanism has not been completely clarified and there are still doubts. In this work, three Pt(II) complexes, Pt-H, Pt-CHO and Pt-COOH, were developed to elucidate the mechanism of this class of complexes and refine their property studies. As a result, the UV-visible absorption and luminescence emission experiments, as well as the mass spectrum, proved that the oxidation of Pt(II) to Pt(IV) was the real reason for luminescence quenching, which has nothing to do with aldehyde groups. This first reported mechanism introduces a new type of ClO- probe based on Pt(II) complexes, thereby expanding the application fields of platinum complexes. Moreover, the quantum yield measurements, the effect of biomolecules and reversibility were studied to improve the properties of the probes. Theoretical calculations were used to gain an in-depth understanding of optical characteristics and related mechanisms. The cell imaging of RAW264.7 cells under endogenous ClO- proved the potential of the probes in bioimaging.

A low-cost and effective bagasse-based magnetic porous biochar as an adsorbent for solid phase extraction of triazine herbicides in brown sugar.

A rapid and sensitive approach for enriching and extracting triazines from brown sugar samples was developed by combining magnetic dispersive solid-phase extraction and HPLC/UV. In this work, a magnetic porous biochar (MPB) derived from low-cost bagasse was prepared and successfully employed as an adsorbent. A particular emphasis was placed on optimizing the extraction conditions, including the amount of MPB, extraction time, pH, type and volume of eluent, and salt concentration. Under optimized MSPE conditions, the method showed satisfactory linearity over concentration ranges of 2-200 µg L-1 for four triazines, with correlation coefficient values no less than 0.9981. Low limits of detection (0.27-0.33 µg L-1), good recoveries (81.7-100.7%), and satisfactory repeatability (RSDs ≤ 8.1%) were also demonstrated with respect to the analytical performance. The results demonstrated that the developed method was simple, rapid, sensitive, and efficient, indicating that it could extract and enrich trace triazines from real samples.

Novel Platinum(II) Complex-based Luminescent Probe for Detection of Hypochlorite in Cancer Cells.

Hypochlorite (ClO⁻) is of great importance either for the metabolism of living organisms or as disinfectant in daily life. However, improper concentration levels of ClO⁻ lead to serious health problems including erythrocyte damage, cardiovascular problems, neuron degeneration, lung/kidney injury and cancer. Therefore, a sensitive and selective detection method is required for the visualization and measurement of ClO⁻. In this work, a novel platinum(II) complex-based luminescent probe Pt-CHO was synthesized and utilized to detect ClO⁻. This "turn-off" probe exhibits high sensitivity, excellent selectivity, good pH stability, low limit of detection and instantaneous response ability. Moreover, the luminescent response is caused by the oxidation of aldehyde into carboxyl groups combined with the coordination of hydroxyl groups at the Pt center, which is rarely reported. The cell imaging of HeLa cells proved the considerable potential of the probe for ClO⁻ imaging in living cells.

Synthesis and use of an amphiphilic dendrimer for siRNA delivery into primary immune cells.

Using siRNAs to genetically manipulate immune cells is important to both basic immunological studies and therapeutic applications. However, siRNA delivery is challenging because primary immune cells are often sensitive to the delivery materials and generate immune responses. We have recently developed an amphiphilic dendrimer that is able to deliver siRNA to a variety of cells, including primary immune cells. We provide here a protocol for the synthesis of this dendrimer, as well as siRNA delivery to immune cells such as primary T and B cells, natural killer cells, macrophages, and primary microglia. The dendrimer synthesis entails straightforward click coupling followed by an amidation reaction, and the siRNA delivery protocol requires simple mixing of the siRNA and dendrimer in buffer, with subsequent application to the primary immune cells to achieve effective and functional siRNA delivery. This dendrimer-mediated siRNA delivery largely outperforms the standard electroporation technique, opening a new avenue for functional and therapeutic studies of the immune system. The whole protocol encompasses the dendrimer synthesis, which takes 10 days; the primary immune cell preparation, which takes 3-10 d, depending on the tissue source and cell type; the dendrimer-mediated siRNA delivery; and subsequent functional assays, which take an additional 3-6 d.

Development of magnetic porous carbon nano-fibers for application as adsorbents in the enrichment of trace Sudan dyes in foodstuffs.

A novel kind of magnetic porous carbon nano-fibers (Fe3O4@P-CNFs) materials was successfully prepared and used as an adsorbent. Based on the above-mentioned adsorbent, a simple and effective magnetic disperse solid-phase extraction (MSPE) method was developed and first utilized to the enrichment and purification of five Sudan dyes (including Sudan I, Sudan II, Sudan III, Sudan IV, and Sudan Red 7B) in foodstuffs for the first time. High-performance liquid chromatography was used to determine the content of the Sudan dyes. The parameters affecting the extraction performance were studied and optimized, including the amount of the adsorbent and inorganic salt, type and the volume of the eluent, pH of the sample solution and extraction time. Under the optimized experimental conditions, the results show that the proposed method has a good linear relationship (r≥ 0.9993). The limits of detection range from 0.88 µg L-1 to 1.27 µg L-1. The recoveries range from 86.6% to 99.7% with the relative standard deviations ranging from 0.6% to 7.9% in the methodology validation. The above-mentioned results indicate that the proposed method is a sensitive and reliable procedure with good reproducibility for the detection of Sudan dyes residues in foodstuffs.

Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase.

Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1G184R/+) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1G184R/+ mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.

ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition.

Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo. Further mechanistic studies reveal that ACOT12 regulates the cellular acetyl-CoA levels and histone acetylation in HCC cells and that down-regulation of ACOT12 promotes HCC metastasis by epigenetically inducing TWIST2 expression and the promotion of epithelial-mesenchymal transition. Taken together, our findings link the alteration of acetyl-CoA with HCC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for combating HCC metastasis.

Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression.

PURPOSE: Steroidogenic enzymes are essential for prostate cancer development. Enzymes inactivating potent androgens were not investigated thoroughly, which leads to limited interference strategies for prostate cancer therapy. Here we characterized the clinical relevance, significance, and regulation mechanism of enzyme HSD17B2 in prostate cancer development. EXPERIMENTAL DESIGN: HSD17B2 expression was detected with patient specimens and prostate cancer cell lines. Function of HSD17B2 in steroidogenesis, androgen receptor (AR) signaling, and tumor growth was investigated with prostate cancer cell lines and a xenograft model. DNA methylation and mRNA alternative splicing were investigated to unveil the mechanisms of HSD17B2 regulation. RESULTS: HSD17B2 expression was reduced as prostate cancer progressed. 17ßHSD2 decreased potent androgen production by converting testosterone (T) or dihydrotestosterone (DHT) to each of their upstream precursors. HSD17B2 overexpression suppressed androgen-induced cell proliferation and xenograft growth. Multiple mechanisms were involved in HSD17B2 functional silencing including DNA methylation and mRNA alternative splicing. DNA methylation decreased the HSD17B2 mRNA level. Two new catalytic-deficient isoforms, generated by alternative splicing, bound to wild-type 17ßHSD2 and promoted its degradation. Splicing factors SRSF1 and SRSF5 participated in the generation of new isoforms. CONCLUSIONS: Our findings provide evidence of the clinical relevance, significance, and regulation of HSD17B2 in prostate cancer progression, which might provide new strategies for clinical management by targeting the functional silencing mechanisms of HSD17B2.See related commentary by Mostaghel, p. 1139.

Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol.

Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.

Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors.

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities.

Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ5,3ß-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3ß-hydroxysteroid dehydrogenase (3ßHSD). We found that galeterone is metabolized by 3ßHSD to Δ4-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3ß-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5ß-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ5,3ß-hydroxyl structure.