Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes toward α-Tetralones.

Carbonylative multifunctionalization of alkenes is an efficient approach to introduce multiple functional groups into one molecule from easily available materials. Herein, we developed an iron-catalyzed radical relay carbonylative cyclization of alkenes with acetamides. Various α-tetralones can be constructed in moderate yields from readily available substrates with an earth-abundant iron salt as the catalyst.

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.

Development and validation of a deep-learning model for the detection of non-displaced femoral neck fractures with anteroposterior and lateral hip radiographs.

Background: Hip fractures, including femoral neck fractures, are a significant cause of morbidity and mortality in the elderly population and are typically diagnosed using plain radiography. However, diagnosing non-displaced femoral neck fractures can be challenging due to their subtle appearance on hip radiographs. Previous deep-learning models have shown low accuracy in identifying these fractures on anteroposterior (AP) radiographs; however, no studies have used lateral radiographs. This study aimed to evaluate the potential of using deep-learning with both AP and lateral hip radiographs to automatically identify non-displaced femoral neck fractures. Methods: We conducted a retrospective analysis of patients with femoral neck fractures at The First Affiliated Hospital of Xiamen University. All the hip radiographs were reviewed, and cases of non-displaced femoral neck fractures were included in the study. Additionally, 439 participants with normal hip radiographs were also included in the study. A vision transformer (Vit) model was developed using 1,536 AP and lateral hip radiograph. The model's performance was compared to the performance of two groups of human observers: an expert group comprising orthopedic surgeons and radiologists, and a non-expert group, including emergency physicians and general practice doctors. We also carried out the external validation using two additional data sets to assess the generalizability of the model. Results: The Vit model showed exceptional performance in detecting non-displaced femoral neck fractures on paired AP and lateral hip radiographs, achieving a binary accuracy of 95.8% [95% confidence interval (CI): 94.9%, 96.8%] and an area under the curve (AUC) of 0.988. Compared to the human observers, the model had a higher accuracy of 96.7% (95% CI: 93.9%, 99.5%) on the paired AP and lateral hip radiographs, while the accuracy of the expert group was 90.5% (95% CI: 85.7%, 95.2%). Further, the model maintained good performance during the external validation, with an AUC of 0.959 on the paired AP and lateral views. Conclusions: Our Vit model showed expert-level performance in identifying non-displaced femoral neck fractures on paired AP and lateral hip radiographs. This model has the potential to enhance diagnosis accuracy and improve patient outcomes by reducing the need for additional examinations and preoperative time.

Genetically predicted triglycerides mediate the relationship between type 2 diabetes Mellitus and intervertebral disc degeneration.

BACKGROUND: To validate the causal relationship between type 2 diabetes mellitus (T2DM) and intervertebral disc degeneration (IVDD) and to identify and quantify the role of triglycerides (TGs) as potential mediators. METHODS: A two-sample Mendelian randomization (MR) analyses of T2DM (61,714 cases and 1178 controls) and IVDD (20,001 cases and 164,682 controls) was performed using genome-wide association studies (GWAS). Moreover, two-step MR was employed to quantify the proportionate impact of TG-mediated T2DM on IVDD. RESULTS: MR analysis showed that T2DM increased IVDD risk (OR: 1.0466, 95% CI 1.0049-1.0899, P = 0.0278). Reverse MR analyses demonstrated that IVDD does not affect T2DM risk (P = 0.1393). The proportion of T2DM mediated through TG was 11.4% (95% CI 5.5%-17.4%). CONCLUSION: This work further validates the causality between T2DM and IVDD, with a part of the effect mediated by TG, but the greatest impacts of T2DM on IVDD remain unknown. Further studies are needed to identify other potential mediators.

Ectopic gastric mucosa in the submucosa of the stomach: A case report.

Under normal circumstances, gastric mucosa only exists within the stomach. However, in certain situations, gastric mucosal tissue may undergo ectopia, commonly occurring in the esophagus and intestine, with rare occurrences within the stomach itself. A comprehensive literature review was performed to understand the distinct characteristics of ectopic gastric mucosa (EGM) in the stomach and investigate a rare incident of this disease, providing an in-depth analysis of the clinical, histopathologic, and differential diagnostic findings. The case was a 47-year-old man with acid reflux, heartburn, abdominal distension, and diarrhea (5-10 times daily) for >10 years. A gastroscope indicated a submucosal protuberance lesion in the gastric body that felt hard with biopsy forceps. A well-defined nodule under the mucosal muscle was revealed microscopically, composed of epithelial elements and no atypia. Immunohistochemical staining demonstrated similar EGM expression patterns compared with normal gastric mucosa. The present case report highlights the importance of accurate EGM diagnosis and understanding.

Cobalt-Catalyzed Carbonylative Synthesis of 4-Oxobutanoates from Formamide and Ethylene.

The direct concurrent installation of amide and ester groups across olefin motifs represents a powerful and promising functionalization tool in organic chemistry. Herein, a ligand-free cobalt-catalyzed four-component radical relay carbonylative difunctionalization of ethylene for the synthesis of 4-oxobutanoates has been developed. Valuable C4 building blocks were produced in a highly atom-economical fashion.

An unusual presentation of ossified spinal meningioma: case report and literature review.

Background: Spinal meningioma is a common intraspinal tumor, which mainly occurs in the thoracic spine. Ossified meningioma (OSM) is an extremely rare histological variant. Our article reports a rare patient with dorsal complete OSM and reviews this subject. Case presentation: A 68-year-old woman presented with a one-year history of progressive weakness in both lower limbs with gait disturbance. Physical examination revealed hypoesthesia with a sensory level below T10. Babinski and pathological signs on both sides were weakly positive. Magnetic resonance imaging (MRI) showed a mass at the T10 to T11 level causing severe compression of the spinal cord. Computed tomography (CT) showed complete ossification of the mass. 18F-Fluoro-deoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan combined with MRI revealed that the mass was an intradural extramedullary high-density ossified nodule. The patient underwent a gross total resection of the mass and pathologic examination indicated that the mass was a meningioma with diffused psammomatous bodies. Conclusion: We identified a rare case of dorsal complete OSM occurring in a 68-year-old woman. After complete surgical resection, although there were complications such as cerebral fluid leakage and fever, the patient finally recovered with a satisfactory result.

Emissions from international airport and its impact on air quality: A case study of beijing daxing international airport (PKX), China.

The Beijing Daxing International Airport is a newly opened airport, and a comprehensive emission inventory of air pollution sources has not yet been established. The lack of basic inventory data will cause difficulties in controlling the air quality (AQ) in and around the airport. Based on actual flight data, we established a comprehensive emission inventory (carbon monoxide (CO), nitrogen oxides (NOX), hydrocarbons (HC), sulfur dioxide (SO2), particulate matter (PM), and carbon dioxide (CO2)) at Beijing Daxing International Airport. Furthermore, we evaluated the impact of airport emissions on the AQ of the surrounding areas using the ADMS-Airport model. The results showed that Beijing Daxing International Airport emitted 1.15 E+03, 1.76 E+03, 1.38 E+02, 1.16 E+02, 3.53 E+01, and 3.75 E+05 t of CO, NOX, HC, SO2, PM, and CO2, respectively, from July 1, 2020, to June 30, 2021. Engine exhaust emissions (landing and takeoff [LTO] cycles) dominated all airport pollutant emissions except for PM from the power plant. Among all aircraft types, B738 emitted the most CO2, as it accounted for almost half of all the flights. The AQ simulations showed that the air pollutant diffusion range was concentrated within 15 km of the airport and the surrounding areas. The contribution of airport emissions to NOX concentrations was most apparent under the most unfavorable meteorological conditions. Based on the average pollutant concentration during the study period, the Gu'an Li Hu Primary School station was the most affected. In particular, NOX concentrations at this station were approximately 50% higher in winter than in summer. Currently, the airport's contribution to pollution in the surrounding areas is insignificant. However, with the continuous increase in the number of flights at the airport, its impact on the AQ in the surrounding areas must be addressed in the future.

Pan-cancer analysis of the intervertebral-disc-degeneration-related innate immunity gene NAIP.

BACKGROUND: Intervertebral disc degeneration (IDD) is a progressive chronic condition that commonly causes low back pain. Cancer is among the primary reasons for deaths worldwide. Our purpose was to identify the characteristic genes of IDD and explore the potential association between IDD and cancer. METHODS: Immune cell infiltration and differentially expressed analysis were conducted utilizing data from the GSE124272 database. Enrichment analysis of differentially expressed genes (DEGs) was performed to explore the possible mechanisms underlying IDD development. Moreover, weighted gene correlation network analysis (WGCNA) was applied to select IDD-related hub genes. The immune-related key genes were determined by intersecting DEGs, IDD-related hub genes, and immune genes. Subsequently, machine learning models based on these genes were built to identify and verify the characteristic genes. RNA sequencing and clinical data of 33 carcinoma categories were obtained from the Cancer Genome Atlas (TCGA). The association between NAIP expression and prognosis was calculated using the Kaplan-Meier analysis. To gain a deeper understanding of the impact of NAIP in tumor immunotherapy, the association between NAIP and immune infiltration and two immunotherapeutic biomarkers were explored. Ultimately, the association between NAIP and immunotherapeutic response was investigated utilizing two independent cohorts. RESULTS: NAIP was identified as an immune-related characteristic gene between IDD and normal intervertebral disc tissue. In certain carcinoma categories, NAIP expression levels were elevated (4/33) and significantly correlated to the respective tumor stage (4/21). Survival analysis revealed that the expression levels of NAIP have prognostic significance in different cancer types. Generally, NAIP presented a strong association with immune cell infiltration and modulators. NAIP may influence immunotherapy effects through tumor mutational burden and microsatellite instability. No remarkable association between NAIP and immunotherapy response was found in either cohort. CONCLUSION: Our study is the first to identify NAIP as an immune-related characteristic gene. Pan-cancer analysis revealed that NAIP could serve as a novel clinical prognostic marker and therapeutic target for a variety of carcinoma categories, reducing the risk of IDD in tumor patients.

Preclinical Models of Adrenocortical Cancer.

Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area.

Cobalt-Catalyzed Hydroxymethylation of Alkyl Halides with CO as the C1 Source.

Herein, we developed an effective strategy for the synthesis of one-carbon-extended alcohols through cobalt-catalyzed hydroxymethylation of alkyl halides with carbon monoxide as the C1 source and cheap and environmentally friendly PMHS as the hydride source. This procedure also features a ligand-free cobalt catalyst and a broad range of functional group tolerance.

CircADSS contributes to hepatocellular carcinoma development by regulating miR-431-5p/TOP2A.

CircRNAs participated in regulating hepatocellular carcinoma (HCC), and the regulation function of circRNA adenylosuccinate synthase (circADSS) on HCC development is not clear. RT-qPCR and western blot were performed to detect RNA expression. Cell proliferation was analysed by CCK-8 and EdU assay. Cell cycle distribution was analysed by flow cytometry assay. Cell migration and invasion were measured by transwell assay. Mechanism assays were employed to examine the interaction between miR-431-5p and circADSS, or TOP2A. Xenograft mouse model was constructed for in vivo assay. CircADSS and TOP2A expression were boosted, while miR-431-5p was limited in tumour tissues and cells. CircADSS silencing decreased HCC cell proliferation, cell cycle progression, migration, invasion, as well as EMT. MiR-431-5p inhibitors or ectopic TOP2A expression could restore the effect of circADSS knockdown on HCC progression. There was target relationship between miR-431-5p and circADSS, or TOP2A. Knockdown of circADSS suppressed tumour growth in vivo. CircADSS could regulate HCC cell malignancy by miR-431-5p/TOP2A axis.

Sevoflurane suppresses hepatocellular carcinoma cell progression via circ_0001649/miR-19a-3p/SGTB axis.

BACKGROUND: Sevoflurane is a widely used anesthetic agent and is reported to play an anti-tumor action in many cancers. However, the underlying mechanisms are largely unclear. METHODS: Hepatocellular carcinoma (HCC) cells were treated with sevoflurane for 12 or 24 h. HCC cell proliferation, migration, invasion, and apoptosis were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, and flow cytometry assay, respectively. The protein levels were determined by western blot. The expression of circular RNA (circ)_0001649, microRNA (miR)-19a-3p, and small glutamine rich tetratricopeptide repeat containing Beta (SGTB) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between miR-19a-3p and circ_0001649 or SGTB was predicted by Starbase and confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Sevoflurane inhibited HCC cell proliferation, migration, and invasion, but promoted apoptosis. Sevoflurane could affect the expression of circ_0001649 and knockdown of circ_0001649 reversed the effects of sevoflurane on HCC cell progression. Subsequently, miR-19a-3p was identified as a target of circ_0001649 and directly targeted SGTB. In addition, circ_0001649 suppressed the development of sevoflurane-induced HCC cells through miR-19a-3p/SGTB axis. CONCLUSION: Our study demonstrated that sevoflurane inhibited HCC cell development via circ_0001649/miR-19a-3p/SGTB axis.

Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma.

BACKGROUND: The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.

Circular RNA hsa_circ_0005397 promotes hepatocellular carcinoma progression by regulating the miR-326/PDK2 axis.

INTRODUCTION: Circular RNAs (circRNAs) are associated with the initiation and progression of cancer. However, the biological functions and underlying mechanism of hsa_circ_0005397 in hepatocellular carcinoma (HCC) have not been fully elucidated. METHODS: Hemotoxylin and eosin staining was used to assess histological changes. The expression levels of hsa_circ_0005397, miR-326 and pyruvate dehydrogenase kinase 2 (PDK2) were measured by a quantitative real-time polymerase chain reaction. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. Cell cycle distribution and apoptosis were detected by flow cytometry analysis. Caspase-3 activity was determined by a caspase-3 activity kit. Wound healing and transwell assays were used to evaluate cell migration and invasion. A western blot assay was performed to measure the expression of cyclin D1, p21, matrix metalloproteinase (MMP)2, MMP9, PDK2 and PCNA. The interaction between miR-326 and hsa_circ_0005397 or PDK2 was confirmed by dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Xenograft tumor models were established to confirm the role of hsa_circ_0005397 in vivo. RESULTS: Hsa_circ_0005397 and PDK2 were up-regulated, whereas miR-326 was down-regulated in HCC tissues and cells. Hsa_circ_0005397 knockdown inhibited cell proliferation and metastasis, and promoted apoptosis. miR-326 was a direct target of hsa_circ_0005397, and inhibition of miR-326 reversed the inhibitory effect of hsa_circ_0005397 silencing on HCC progression. Moreover, PDK2 was a direct target of miR-326 and PDK2 overexpression abated the anti-cancer roles of miR-326 in HCC. Additionally, hsa_circ_0005397 regulated PDK2 expression by sponging miR-326. Furthermore, hsa_circ_0005397 down-regulation suppressed tumor growth by up-regulating miR-326 and down-regulating PDK2. CONCLUSIONS: Hsa_circ_0005397 facilitates HCC progression by regulating the miR-326/PDK2 axis, providing a promising circRNA-targeted therapy for HCC.

Propofol Inhibits the Progression of Cervical Cancer by Regulating HOTAIR/miR-129-5p/RPL14 Axis.

BACKGROUND: Propofol has been proposed to function as a tumor suppressor in various human cancers. In this study, we aimed to investigate the anti-tumor effect of propofol on cervical cancer (CC). METHODS: Cell Counting Kit-8 (CCK-8) assay, colony formation assay, flow cytometry analysis, transwell assay and wound healing assay were conducted for cell viability, colony formation, apoptosis, invasion and migration, respectively. Western blot assay was used for protein levels. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for HOX antisense intergenic RNA (HOTAIR), miR-129-5p and RPL14 levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were executed to verify the interaction between miR-129-5p and HOTAIR or RPL14. Murine xenograft model assay was used for the role of propofol in tumor progression in vivo. RESULTS: Propofol treatment suppressed CC cell viability, colony formation, invasion and migration and facilitated apoptosis. Propofol treatment led to a marked reduction in HOTAIR level in CC cells. HOTAIR overexpression promoted cell colony formation, invasion and migration and repressed apoptosis in CC cells and propofol-treated CC cells. For mechanism analysis, HOTAIR positively regulated RPL14 expression via acting as the sponge of miR-129-5p. MiR-129-5p overexpression reversed the impacts of HOTAIR on the malignant behaviors of propofol-treated CC cells. Furthermore, miR-129-5p inhibition accelerated the progression of CC cells, while RPL14 interference rescued the effect. In addition, propofol treatment restrained tumor growth of CC in vivo. CONCLUSION: Propofol inhibited CC development by modulation of HOTAIR/miR-129-5p/RPL14 axis.

Chebyshev apodized fiber Bragg gratings.

In this paper, a new apodized fiber Bragg grating (FBG) structure, the Chebyshev apodization, is proposed. The Chebyshev polynomial distribution has been widely used for the optimal design of antennas and filters, but it has not been used for designing FBGs. Unlike the function of traditional Gaussian-apodized FBGs, the Chebyshev polynomial is a discrete function. We demonstrate a new methodology for designing Chebyshev-apodized FBGs: the grating region is divided by discrete n sections with uniform gratings, while the index change is used to express the Chebyshev polynomial. We analyze the Chebyshev-apodized FBGs by using coupled mode theory and the piecewise-uniform approach. The reflection spectrum and the dispersion of Chebyshev-apodized FBGs are calculated and compared with those of Gaussian FBGs. Moreover, a sidelobe suppression level (SSL), a parameter of the Chebyshev polynomial, along with the maximum ac-index change of FBGs are analyzed. Assume that the grating length is 20mm, SSL is 100 dB, the section number is 40, and the maximum ac-index change is 2 × 10-4. The reflection spectrum of Chebyshev apodized FBGs shows flattened sidelobes with an absolute SSL of -95.9 dB (corresponding to SSL=100 dB). The simulation results reveal that at the same full width at half maximum, the Chebyshev FBGs have lower sidelobe suppression than the Gaussian FBGs, but their dispersion is similar. We demonstrate the potential of using Chebyshev-apodized FBGs in optical filters, dispersion compensators, and sensors; Chebyshev apodization can be applied in the design of periodic dielectric waveguides.

Metabolic Reprogramming and Epithelial-Mesenchymal Plasticity: Opportunities and Challenges for Cancer Therapy.

Metabolic reprogramming and epithelial-mesenchymal plasticity are both hallmarks of the adaptation of cancer cells for tumor growth and progression. For metabolic changes, cancer cells alter metabolism by utilizing glucose, lipids, and amino acids to meet the requirement of rapid proliferation and to endure stressful environments. Dynamic changes between the epithelial and mesenchymal phenotypes through epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are critical steps for cancer invasion and metastatic colonization. Compared to the extensively studied metabolic reprogramming in tumorigenesis, the metabolic changes in metastasis are relatively unclear. Here, we review metabolic reprogramming, epithelial-mesenchymal plasticity, and their mutual influences on tumor cells. We also review the developing treatments for targeting cancer metabolism and the impact of metabolic targeting on EMT. In summary, understanding the metabolic adaption and phenotypic plasticity will be mandatory for developing new strategies to target metastatic and refractory cancers that are intractable to current treatments.

Blockade of PD-L1 Enhances Cancer Immunotherapy by Regulating Dendritic Cell Maturation and Macrophage Polarization.

The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine tumor model, we investigated whether anti-PD-L1 antibody increased the antigen-specific immune response and anti-tumor effects induced by the antigen-specific protein vaccine, as well as the possible mechanisms regarding activation of APCs. Anti-PD-L1 antibody combined with the PEK protein vaccine generated more potent E7-specific immunity (including the number and cytotoxic activity of E7-specific cytotoxic CD8+ T lymphocytes) and anti-tumor effects than protein vaccine alone. Anti-PD-L1 antibody enhanced the maturation of dendritic cells and the proportion of M1-like macrophages in tumor-draining lymph nodes and tumors in tumor-bearing mice treated with combinatorial therapy. PD-L1 blockade overturned the immunosuppressive status of the tumor microenvironment and then enhanced the E7 tumor-specific antigen-specific immunity and anti-tumor effects generated by an E7-specific protein vaccine through modulation of APCs in an E7-expressing small tumor model. Tumor-specific antigen (like HPV E7 antigen)-specific immunotherapy combined with APC-targeting modality by PD-L1 blockade has a high translational potential in E7-specific cancer therapy.

mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment.

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.