Search

Abstract The terminal isoprene unit, as the simplest branched 1,3-diene unit, exists in a wide range of natural products and bioactive molecules. Herein, we report a stereoselective rhodium-catalyzed reaction of allenes with readily available methyl pinacol boronic ester, providing a straightforward approach to isoprene derivatives with a very high E-stereoselectivity. Its synthetic potential has been illustrated by a concise synthesis of natural product schinitrienin. Such a protocol can be easily extended to aryl and alkenyl boronic reagents affording 2-aryl or -alkenyl substituted 1,3-dienes, which are also of high importance in organic synthesis but remain challenging for their selective synthesis, with a remarkable stereoselectivity. A series of deuterium-labeling experiments indicate a unique mechanism, which involves reversible β-H elimination as well as hydrometalation and isomerization of the allylic rhodium species.

Abstract Mitochondria are crucial organelles responsible for energy generation in eukaryotic cells. Oxidative stress, calcium disorders, and mitochondrial DNA abnormalities can all cause mitochondrial dysfunction. It is now well documented that mitochondrial dysfunction significantly contributes to the pathogenesis of numerous illnesses. Hence, it is vital to investigate innovative treatment methods targeting mitochondrial dysfunction. Extracellular vesicles (EVs) are cell-derived nanovesicles that serve as intercellular messengers and are classified into small EVs (sEVs, 200 nm) based on their sizes. It is worth noting that certain subtypes of EVs are rich in mitochondrial components (even structurally intact mitochondria) and possess the ability to transfer them or other contents including proteins and nucleic acids to recipient cells to modulate their mitochondrial function. Specifically, EVs can modulate target cell mitochondrial homeostasis as well as mitochondria-controlled apoptosis and ROS generation by delivering relevant substances. In addition, the artificial modification of EVs as delivery carriers for therapeutic goods targeting mitochondria is also a current research hotspot. In this article, we will focus on the ability of EVs to modulate the mitochondrial function of target cells, aiming to offer novel perspectives on therapeutic approaches for diverse conditions linked to mitochondrial dysfunction. Graphical Abstract

Abstract Renal interstitial fibrosis (RIF) is a prevalent consequence of chronic renal diseases, characterized by excessive extracellular matrix (ECM) deposition. A Disintegrin and Metalloprotease 17 (ADAM17), a transmembrane metalloproteinase, plays a central role in driving renal fibrosis progression by activating Notch 1 protein and the downstream TGF-β signaling pathway. Our study investigated potential therapeutic interventions for renal fibrosis, focusing on human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs). We found that hucMSC-EVs inhibit ADAM17, thereby impeding renal fibrosis progression. Analysis of hucMSC-EVs miRNA profiles revealed significant enrichment of miR-13474, which effectively targeted and inhibited ADAM17 mRNA expression, subsequently suppressing Notch1 activation, TGF-β signaling, and collagen deposition. Overexpression of miR-13474 enhanced hucMSC-EVs' inhibitory effect on renal fibrosis, while its downregulation abolished this protective effect. Our findings highlight the efficacy of hucMSC-EVs overexpressing miR-13474 in mitigating renal fibrosis via ADAM17 targeting. These insights offer potential therapeutic strategies for managing renal fibrosis.

Abstract Small extracellular vesicles (sEV) derived from diverse natural killer (NK) cell lines have proven their exceptional antitumor activities. However, sEV from human primary NK cells, especially memory-like NK cells, are rarely utilized for cancer treatment. In this study, we obtained sEV from IL-12, IL-15 and IL-18 cultured human memory-like NK cells (mNK-sEV) that showed strong cytokine-secretory ability. It was uncovered that mNK-sEV entered cancer cells via macropinocytosis and induced cell apoptosis via caspase-dependent pathway. Compared to sEV from conventionally cultured NK cells (conNK-sEV), mNK-sEV inhibited tumor growth to a greater extent. Concomitantly, pharmacokinetics and biodistribution results validated a higher accumulation of mNK-sEV than conNK-sEV in tumors of xenografted murine models. Notably, elevated containment of granulysin (GNLY) within mNK-sEV, at least in part, may contribute to the enhanced therapeutic effect. Herein our results present that mNK-sEV can be a novel class of therapeutic reagent for effective cancer treatment. Graphical Abstract

Abstract Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-β1 +Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-β1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/β-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.

Abstract Tripartite motif 8 (TRIM8) is an E3 ligase that plays dual roles in various tumor types. The biological effects and underlying mechanism of TRIM8 in hepatocellular carcinoma (HCC) remain unknown. Hepatocyte nuclear factor 1α (HNF1α) is a key transcriptional factor that plays a significant role in regulating hepatocyte differentiation and liver function. The reduced expression of HNF1α is a critical event in the development of HCC, but the underlying mechanism for its degradation remains elusive. In this study, we discovered that the expression of TRIM8 was upregulated in HCC tissues, and was positively correlated with aggressive tumor behavior of HCC and shorter survival of HCC patients. Overexpression of TRIM8 promoted the proliferation, colony formation, invasion, and migration of HCC cells, while TRIM8 knockdown or knockout exerted the opposite effects. RNA sequencing revealed that TRIM8 knockout suppresses several cancer-related pathways, including Wnt/β-catenin and TGF-β signaling in HepG2 cells. TRIM8 directly interacts with HNF1α, promoting its degradation by catalyzing polyubiquitination on lysine 197 in HCC cells. Moreover, the cancer-promoting effects of TRIM8 in HCC were abolished by the HNF1α-K197R mutant in vitro and in vivo. These data demonstrated that TRIM8 plays an oncogenic role in HCC progression through mediating the ubiquitination of HNF1α and promoting its protein degradation, and suggests targeting TRIM8-HNF1α may provide a promising therapeutic strategy of HCC.

Abstract Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs. Graphical Abstract

Gastric cancer (GC) is a malignant cancer with the highest global rates of morbidity and death. Dietary factors have a close relationship with the occurrence of GC. Circular RNAs (circRNAs) and N6-methyladenine (m6A) are important factors in the onset and progression of GC and other malignancies. However, little is known about the role of circRNA m6A modifications in the occurrence and development of GC. Initially, a transformed malignant cell model generated by the chemical carcinogen N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) was established in this investigation. Furthermore, following exposure to MNNG, circ0049271 is substantially expressed in gastric epithelial cells (GES-1). Subsequent research revealed that the knockdown of circ0049271 prevented the epithelial-mesenchymal transition (EMT) as well as the migration, invasion, and proliferation of gastric epithelial cells induced by long-term exposure to MNNG. The opposite effects were observed when circ0049271 was overexpressed. Mechanistically, circ0049271 activates the TGFβ/SMAD signaling pathway and has m6A modifications mediated by WTAP. Our findings indicate that circ0049271 promotes the occurrence of GC by regulating the TGFβ/SMAD pathway, and WTAP may mediate the methylation of circ0049271 m6A. This study provides new insights into the regulation of circRNA-mediated m6A modifications and the discovery of early GC induced by dietary factors such as nitrite.

Abstract The immune system in humans is a defense department against both exogenous and endogenous hazards, where CD8+ T cells play a crucial role in opposing pathological threats. Various immunotherapies based on CD8+ T cells have emerged in recent decades, showing their promising results in treating intractable diseases. However, in the fight against the constantly changing and evolving cancers, the formation and function of CD8+ T cells can be challenged by tumors that might train a group of accomplices to resist the T cell killing. As cancer therapy stepped into the era of immunotherapy, understanding the physiological role of CD8+ T cells, studying the machinery of tumor immune escape, and thereby formulating different therapeutic strategies become the imperative missions for clinical and translational researchers to fulfill. After brief basics of CD8+ T cell-based biology is covered, this review delineates the mechanisms of tumor immune escape and discusses different cancer immunotherapy regimens with their own advantages and setbacks, embracing challenges and perspectives in near future.

Abstract The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Abstract The uniformity of remolded loess is crucial for engineering stability and in laboratory testing, as it affects physical and mechanical properties. It is important to have an index which can accurately and conveniently evaluate the uniformity of remolded loess. This study demonstrated and verified the feasibility of using hydraulic conductivity (K) as an indicator for evaluating the uniformity of remolded loess through laboratory experiments and theoretical analysis. In laboratory research, nine loess samples under different preparation conditions were meticulously prepared in duplicate, which were divided into three sets according to the whole dry density (WDD) of approximately 1.3 g/cm3, 1.4 g/cm3, and 1.5 g/cm3 respectively. For the nine duplicate samples, two procedures were performed for each of the sample. One is the uniformity analysis by cutting the soil column and weighing. The other is the hydraulic conductivity experiment. Results showed that sample uniformity is affected by sample preparation conditions, and there are differences in the uniformity of the same WDD samples. The values of K positively correlate with the degree of sample uniformity. In theoretical analysis, based on Darcy’s Law and Kozeny-Carman equation, it is found K is inversely proportional to the variance ( $$\sigma^{2}$$ σ 2 ) of the sample dry density. That is, K is positively proportional to the sample uniformity. Since K can be easily determined in the laboratory, the application of this new index in the field of geotechnical engineering makes it very convenient and simple to evaluate the uniformity of remolded loess.

Diabetic retinopathy (DR) is a leading cause of blindness worldwide with limited treatment options. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) hold promise as a cell-free therapy for retinal diseases. In this study, we present evidence that the intravitreal injection of MSC-sEVs improved retinal function and alleviated retinal apoptosis, inflammation, and angiogenesis in both db/db mice and streptozotocin-induced diabetic rats. Mechanistically, hyperglycemia-induced activation of hypoxia-inducible factor-1α (HIF-1α) inhibited the tripartite motif 21 (TRIM21)-mediated ubiquitination and degradation of enhancer of zeste homologue 2 (EZH2), ultimately resulting in the downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) through EZH2-induced methylation modification. The presence of miR-5068 and miR-10228 in MSC-sEVs targeted the HIF-1α/EZH2/PGC-1α pathway. The blockade of miR-5068 and miR-10228 abolished the retinal therapeutic effects of MSC-sEVs. Additionally, we engineered MSC-sEVs with elevated levels of miR-5068 and miR-10228 to enhance retinal repair efficiency. Together, our findings provide novel insights into the mechanism underlying DR progress and highlight the potential of MSC-sEVs, especially engineered MSC-sEVs, as a therapeutic option for DR.

To investigate the fatigue behaviour of stainless steel (SS) reinforcement, monotonic tensile and cyclic fatigue loading tests on 1.4362 duplex SS bars with diameters of 12 mm, 16 mm, and 20 mm are conducted. To keep the characteristics of reinforcement used in engineering construction, the specimens remain unprocessed. Two loading schemes for cyclic tests are considered in this work: (i) constant strain-amplitude, and (ii) variable strain-amplitude. The Ramberg-Osgood model was used to fit the experimental results. The strain-based and energy-based fatigue life equations are obtained. The strain-based fatigue life equation is compared with the present fatigue life estimation equations. Moreover, the ReinforcingSteel material model in OpenSees is calibrated with the experimental data. The results show that SS bars under cyclic experience hardening followed by softening. The bar diameter does not significantly affect the fatigue life prediction. The modified fatigue life equation suggests that SS bars have better fatigue resistance than conventional steel (CS) bars. The numerical analysis indicates that the calibrated steel material model (i.e. ReinforcingSteel) can produce a good simulation of SS bars under cyclic loading. It can improve the accuracy of numerical models of concrete components reinforced by SS bars.

Background: Exosomes, one of small extracellular vesicles, play a vital role in cell to cell communication and contribute to the advancement of tumors through their cargo molecules. Exosomal circRNAs have emerged as significant players in various types of tumors. Thus, this study aimed to investigate how exosomal circRNAs are involved in the diagnosis and progression of gastric cancer (GC). Methods: Serum exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis and Western blot. CCK-8, colony formation and transwell assays were conducted to study the function of hsa_circ_0050547 (named as circ50547). qRT-PCR was used to quantify the expression of circ50547 in GC tissues and serum exosomes. Fluorescence in situ hybridization was applied to detect the cellular distribution of circ50547. Stemness and drug-resistance were detected by sphere formation, WB, flow cytometry and half-maximal inhibitory concentration analyses. Bioinformatic analyses, luciferase experiments, qRT-PCR and WB were used to investigate molecular mechanisms. Results: We discovered for the first time a new type of GC-derived exosomal circRNA, circ50547. We found that circ50547 is highly expressed in both GC tissues and serum exosomes. Interestingly, we observed that the diagnostic value of exosomal circ50547 is superior to that of serum circ50547. Circ50547 overexpression enhanced the proliferation, migration, invasion, stemness and drug resistance of GC cells, while knockdown of circ50547 showed the opposite effect. Mechanistically, circ50547 acted as a sponge for miR-217 to regulate the expression of HNF1B, which promoted gastric cancer progression. Conclusion: Exosomal circ50547 may be a promising marker for the diagnosis and prognosis prediction of GC. These findings suggest that it plays an oncogenic role through miR-217/HNF1B signaling pathway in GC.

A new kind of functional gradient material (FGM) based on engineering cementitious composites (ECC) and normal concrete (NC) was proposed in this study. This material offers enhanced crack control while minimizing ECC consumption. Foremost, uniaxial compression tests were carried out on single-layer NC-ECC composites featuring varying ECC volume fractions (0%, 20%, 40%, 60%, 80%, and 100%). These tests yield an elastic modulus formula, E(y), for the NC-ECC composite. Subsequently, based on the E(y) formula, a 5-layer NC-ECC FGM is designed, with each sub-layer having distinct ECC volume fractions. This is contrasted with pure ECC and 2-layer NC-ECC specimens for reference. The study concludes with an analysis of the failure patterns, load-displacement curves, and elastic moduli of the NC-ECC FGM. The results demonstrate consistent performance trends of elastic modulus in single-layer NC-ECC composite specimens, confirming the feasibility of employing a functional gradient between NC and ECC. Utilizing the formula E(y) derived from single-layer NC-ECC, the ECC volume fractions in the 5-layer NC-ECC FGM are computed as 100%, 86.89%, 68.13%, 41.55%, and 0% for each layer. Importantly, the NC-ECC FGM exhibits a failure mode resembling ECC specimens, with primary cracks not extending along interfacial layers. In contrast, 2-layer NC-ECC specimens experience cracking along interfacial boundaries. The compressive strength of NC-ECC FGM surpasses that of ECC specimens by 1.42 times while retaining ECC-like ductility, showcasing a 25.85% improvement over 2-layer NC-ECC. The findings from this study provide valuable insights for the design and subsequent engineering applications of functional gradient materials.

BackgroundThe current survival prediction methodologies for primary bone lymphoma (PBL) of the spine are deficient. This study represents the inaugural utilization of conditional survival (CS) to assess the outcome of this disease. Moreover, our objective was to devise a CS-based nomogram for predicting overall survival (OS) in real-time for spinal PBL.MethodsPatients with PBL of the spine diagnosed between January 2000 and December 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The OS was determined through the Kaplan–Meier method. The CS characteristic of patients with spinal PBL was delineated, with the CS being estimated utilizing the formula: CS(α|β) = OS(α+β)/OS(β). CS(α|β) denotes the probability of additional α-year survivorship, assuming the patient has already survived β years after the time of observation. Three methods including univariate Cox regression, best subset regression (BSR) and the least absolute shrinkage and selection operator (LASSO) regression were used to identify predictors for CS-based nomogram construction.ResultsKaplan-Meier analysis was executed to determine the OS rate for these patients, revealing a survival rate of 68% and subsequently 63% at the 3-year and 5-year mark respectively. We then investigated the CS patterning exhibited by these patients and discovered the survival of PBL in the spine progressively improved with time. Meanwhile, through three different prognostic factor selection methods, we identified the best predicter subset including age, tumor histology, tumor stage, chemotherapy and marital status, for survival prediction model construction. Finally, we successfully established and validated a novel CS-based nomogram model for real-time and dynamic survival estimation. Moreover, we further designed a risk stratification system to facilitate the identification of high-risk patients.ConclusionsThis is the first study to analyze the CS pattern of PBL of the spine. And we have also developed a CS-based nomogram that provide dynamic prognostic data in real-time, thereby aiding in the formulation of personalized treatment strategies in clinical practice.

Abstract Renal interstitial fibrosis (RIF) is a fundamental pathological feature of chronic kidney disease (CKD). However, toxicity and poor renal enrichment of fibrosis inhibitors limit their further applications. In this study, a platform for CKD therapy is developed using superparamagnetic iron oxide nanoparticles (SPION) decorated mesenchymal stem cells derived extracellular vesicles with carboxyl terminus of Hsc70-interacting protein (CHIP) high expression (SPION-EVs) to achieve higher renal-targeting antifibrotic therapeutic effect. SPION-EVs selectively accumulate at the injury renal sites under an external magnetic field. Moreover, SPION-EVs deliver CHIP to induce Smad2/3 degradation in renal tubular cells which alleviates Smad2/3 activation-mediated fibrosis-like changes and collagen deposition. The extracellular vesicle engineering technology provides a potential nanoplatform for RIF therapy through CHIP-mediated Smad2/3 degradation.

Abstract MicroRNA (miRNA) delivery by extracellular vesicles (EVs) has recently inspired tremendous developments in cancer treatments. However, hybridization between miRNA and its target mRNA is still difficult to be imaged in vivo to assess the therapeutic effects in time. Herein we design a nano-scale fluorescent “off–on” complex encapsulated by small extracellular vesicles (sEVs) for real-time visualization and evaluation of gene therapy efficiency in human gastric cancer cells and murine xenograft tumor models. The complex is formed by π–π stacking between graphene quantum dots (GQDs) and tumor suppressor miR-193a-3p conjugated fluorescent tag whose signals remain off when binding to GQDs. Loaded into sEVs using tunable sonication techniques, the GQDs/Cy5-miR particles enter the tumor cells and promote miR-193a-3p escape from endosomes. The miR-193a-3p in GQDs/Cy5-miR is unleashed to pair the specific target oncogene cyclin D1 (CCND1), therefore turning on the fluorescence of miRNA tags. We find out that GQDs/Cy5-miR@sEVs can activate the “turn-on” fluorescent signal and exhibit the longest retention time in vivo, which suggests a minimized degradation of miR-193a-3p in dynamic processes of miRNA-mRNA binding. More importantly, GQDs/Cy5-miR@sEVs significantly promote cancer apoptosis in vitro and in vivo via the enhanced cellular uptake. Our study demonstrates that GQDs/Cy5-miR@sEVs represent an efficient and refined theranostic platform for gene therapy in cancers. Graphical Abstract

Abstract Spinal cord injury (SCI) is a traumatic condition of the central nervous system that causes paralysis of the limbs. Micro electric fields (EF) have been implicated in a novel therapeutic approach for nerve injury repair and regeneration, but the effects of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles that are induced by micro electric fields (EF-sEVs) stimulation on SCI remain unknown. The aim of the present study was to investigate whether EF-sEVs have therapeutic effects a rat model of SCI. EF-sEVs and normally conditioned human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (CON-sEVs) were collected and injected intralesionally into SCI model rats to evaluate the therapeutic effects. We detect the expression of candidate long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA-MALAT1) in EF-sEVs and CON-sEVs. The targets and downstream effectors of lncRNA-MALAT1 were investigated using luciferase reporter assays. Using both in vivo and in vitro experiments, we demonstrated that EF-sEVs increased autophagy and decreased apoptosis after SCI, which promoted the recovery of motor function. We further confirmed that the neuroprotective effects of EF-sEVs in vitro and in vivo correlated with the presence of encapsulated lncRNA-MALAT1 in sEVs. lncRNA-MALAT1 targeted miR-22-3p via sponging, reducing miR-22-3p’s suppressive effects on its target, SIRT1, and this translated into AMPK phosphorylation and increased levels of the antiapoptotic protein Bcl-2. Collectively, the present study identified that the lncRNA-MALAT1 in EF-sEVs plays a neuroprotective role via the miRNA-22-3p/SIRT1/AMPK axis and offers a fresh perspective and a potential therapeutic approach using sEVs to improve SCI.

Abstract Purpose The purpose of this study was to investigate the use of thromboelastography (TEG) in patients with colorectal cancer and to examine whether the TEG parameters can be used as potential markers for disease screening and prediction of disease severity. Methods One-hundred fifteen healthy controls (HC), 43 patients with benign adenoma (BA), and 387 patients with colorectal cancers (CRC) were included in the study. TEG parameters (reaction time, R; clot kinetics, K; alpha angle, α-angle; maximum amplitude, MA), conventional laboratory parameters, and clinical information were collected and analyzed among the HC, BA, and CRC groups. Receiver operating characteristics (ROC) were used for differential analysis. The correlation between TEG parameters and pathological information of CRC (differentiation degree, vaso-nerve infiltration, TNM stage) was analyzed. The differences in TEG parameters at different stages of disease and pre-/post operation were compared. Results Shorter K and higher α-angle/MA were found in patients with CRC compared with HC and BA (P

Abstract Stereoselectivity control and understanding in the metal-catalyzed reactions are fundamental issues in catalysis. Here we report sterically controlled rhodium-catalyzed SN2’-type substitution reactions of optically active tertiary propargylic alcohols with arylmetallic species affording the non-readily available enantioenriched tetrasubstituted allenes via either exclusive syn- or anti-β-OH elimination, respectively, under two sets of different reaction parameters. Detailed mechanistic experiments and density functional theory (DFT) studies reveal that the exclusive anti-Rh(I)-OH elimination is dictated by the simultaneous aid of in situ generated boric acid and ambient water, which act as the shuttle in the hydroxy relay to facilitate the Rh(I)-OH elimination process via a unique ten-membered cyclic transition state (anti-TS2_u). By contrast, the syn-Rh(III)-OH elimination in C–H bond activation-based allenylation reaction is controlled by a four-membered cyclic transition state (syn- TS3) due to the steric surroundings around the Rh(III) center preventing the approach of the other assisting molecules. Under the guidance of these mechanistic understandings, a stereodivergent protocol to construct the enantiomer of optically active tetrasubstituted allenes from the same starting materials is successfully developed.

Preclinical efficacy evaluation and tumor drug sensitivity analysis are two main applications of efficacy evaluation. Preclinical efficacy evaluation is to predict whether candidate drugs or therapies may improve patient outcomes in clinical trials. Tumor drug sensitivity analysis is an approach for the personalized evaluation and optimization of approved anti-cancer drugs and treatment regimens. Overall survival (OS) is the gold standard to evaluate the outcome of drugs or therapies in both clinical trials and clinical treatment. Many efficacy evaluation models, such as cell model, tumor cell-line transplant model, patient-derived tumor xenograft model, tumor organoid model, have been developed to assess the inhibitory effect of tested drugs or therapies on tumor growth. In fact, many treatments may also lead to malignant progression of tumors, such as chemotherapy, which can lead to metastasis. Therefore, tumor growth inhibition does not necessarily predict OS benefit. Whether it can prevent or inhibit tumor recurrence and metastasis is the key to whether drugs and therapies can improve patient outcomes. In this perspective, we summarize the current understanding of the pathological progression of tumor recurrence and metastasis, point out the shortcomings of existing tumor transplant models for simulating the clinical scenario of malignant progression of tumors, and propose five improved indicators for comprehensive efficacy evaluation to predict OS benefit using tumor orthotopic transplant and resection model. Improvement in the accuracy of efficacy evaluation will accelerate the development process of anti-cancer drugs or therapies, optimize treatment regimens to improve OS benefit, and reduce drug development and cancer treatment costs.

Objective To prepare a whole-cell vaccine for murine Lewis lung carcinoma (LLC), and to investigate the role of this vaccine in enhancing the anti-LLC ability of immune system in C57BL/6N mice. Methods TCGA database was used to analyze the changes in the infiltration level of immune cells within human lung adenocarcinoma (LUAD) tissue in the context of MYC amplification, and the optimal duration of ultraviolet irradiation was explored for the preparation of LLC whole-cell vaccine. A mouse model was used to assess the effect of LLC whole-cell vaccine with targeted inhibition of Myc on resistance to LLC. Results In human LUAD tissue samples, compared with the low N-MYC expression group, the high N-MYC expression group had a significant reduction in the infiltration abundance of activated CD4+ memory T cells and activated NK cells (W=28 233,27 990,P

Abstract Background Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. Methods Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. Results Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a “ceRNA” for miR-4659a/b-3p to increase HBEGF and TGF-β/Smad expression, then promoted the development of GC. Conclusions Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-β/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

Abstract Cancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.