Combination of prostate volume and apparent diffusion coefficient can stratify patients with a PI-RADS score of 3 to reduce unnecessary prostate biopsies.

BACKGROUND: Nowadays, there are many patients who undergo unnecessary prostate biopsies after receiving a prostate imaging reporting and data system (PI-RADS) score of 3. Our purpose is to identify cutoff values of the prostate volume (PV) and minimum apparent diffusion coefficient (ADCmin) to stratify those patients to reduce unnecessary prostate biopsies. METHODS: Data from 224 qualified patients who received prostate biopsies from January 2019 to June 2023 were collected. The Mann-Whitney U test was used to compare non-normal distributed continuous variables, which were recorded as median (interquartile ranges). The correlation coefficients were calculated using Spearman's rank correlation analysis. Categorical variables are recorded by numbers (percentages) and compared by χ2 test. Both univariate and multivariate logistic regression analysis were used to determine the independent predictors. The receiver-operating characteristic curve and the area under the curve (AUC) were used to evaluate the diagnostic performance of clinical variables. RESULTS: Out of a total of 224 patients, 36 patients (16.07%) were diagnosed with clinically significant prostate cancer (csPCa), whereas 72 patients (32.14%) were diagnosed with any grade prostate cancer. The result of multivariate analysis demonstrated that the PV (p < 0.001, odds ratio [OR]: 0.952, 95% confidence interval [95% CI]: 0.927-0.978) and ADCmin (p < 0.01, OR: 0.993, 95% CI: 0.989-0.998) were the independent factors for predicting csPCa. The AUC values of the PV and ADCmin were 0.779 (95% CI: 0.718-0.831) and 0.799 (95% CI: 0.740-0.849), respectively, for diagnosing csPCa. After stratifying patients by PV and ADCmin, 24 patients (47.06%) with "PV < 55 mL and ADCmin < 685 µm2/s" were diagnosed with csPCa. However, only one patient (1.25%) with PV ≥ 55 mL and ADCmin ≥ 685 µm2/s were diagnosed with csPCa. CONCLUSIONS: In this study, we found the combination of PV and ADCmin can stratify patients with a PI-RADS score of 3 to reduce unnecessary prostate biopsies. These patients with "PV ≥ 55 mL and ADCmin ≥ 685 µm2/s" may safely avoid prostate biopsies.

SESN1 functions as a new tumor suppressor gene via Toll-like receptor signaling pathway in neuroblastoma.

AIMS: Neuroblastoma (NB) is the most common extracranial solid tumor in children, with a 5-year survival rate of <50% in high-risk patients. MYCN amplification is an important factor that influences the survival rate of high-risk patients. Our results indicated MYCN regulates the expression of SESN1. Therefore, this study aimed to investigate the role and mechanisms of SESN1 in NB. METHODS: siRNAs or overexpression plasmids were used to change MYCN, SESN1, or MyD88's expression. The role of SESN1 in NB cell proliferation, migration, and invasion was elucidated. Xenograft mice models were built to evaluate SESN1's effect in vivo. The correlation between SESN1 expression and clinicopathological data of patients with NB was analyzed. RNA-Seq was done to explore SESN1's downstream targets. RESULTS: SESN1 was regulated by MYCN in NB cells. Knockdown SESN1 promoted NB cell proliferation, cell migration, and cell invasion, and overexpressing SESN1 had opposite functions. Knockdown SESN1 promoted tumor growth and shortened tumor-bearing mice survival time. Low expression of SESN1 had a positive correlation with poor prognosis in patients with NB. RNA-Seq showed that Toll-like receptor (TLR) signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway in cancer were potential downstream targets of SESN1. Knockdown MyD88 or TLRs inhibitor HCQ reversed the effect of knockdown SESN1 in NB cells. High expression of SESN1 was significantly associated with a higher immune score and indicated an active immune microenvironment for patients with NB. CONCLUSIONS: SESN1 functions as a new tumor suppressor gene via TLR signaling pathway in NB.

Bio-integrated scaffold facilitates large bone regeneration dominated by endochondral ossification.

Repair of large bone defects caused by severe trauma, non-union fractures, or tumor resection remains challenging because of limited regenerative ability. Typically, these defects heal through mixed routines, including intramembranous ossification (IMO) and endochondral ossification (ECO), with ECO considered more efficient. Current strategies to promote large bone healing via ECO are unstable and require high-dose growth factors or complex cell therapy that cause side effects and raise expense while providing only limited benefit. Herein, we report a bio-integrated scaffold capable of initiating an early hypoxia microenvironment with controllable release of low-dose recombinant bone morphogenetic protein-2 (rhBMP-2), aiming to induce ECO-dominated repair. Specifically, we apply a mesoporous structure to accelerate iron chelation, this promoting early chondrogenesis via deferoxamine (DFO)-induced hypoxia-inducible factor-1α (HIF-1α). Through the delicate segmentation of click-crosslinked PEGylated Poly (glycerol sebacate) (PEGS) layers, we achieve programmed release of low-dose rhBMP-2, which can facilitate cartilage-to-bone transformation while reducing side effect risks. We demonstrate this system can strengthen the ECO healing and convert mixed or mixed or IMO-guided routes to ECO-dominated approach in large-size models with clinical relevance. Collectively, these findings demonstrate a biomaterial-based strategy for driving ECO-dominated healing, paving a promising pave towards its clinical use in addressing large bone defects.

Targeting monoamine oxidase A: a strategy for inhibiting tumor growth with both immune checkpoint inhibitors and immune modulators.

Monoamine oxidase A (MAOA) is a membrane-bound mitochondrial enzyme present in almost all vertebrate tissues that catalyzes the degradation of biogenic and dietary-derived monoamines. MAOA is known for regulating neurotransmitter metabolism and has been implicated in antitumor immune responses. In this review, we retrospect that MAOA inhibits the activities of various types of tumor-associated immune cells (such as CD8+ T cells and tumor-associated macrophages) by regulating their intracellular monoamines and metabolites. Developing novel MAOA inhibitor drugs and exploring multidrug combination strategies may enhance the efficacy of immune governance. Thus, MAOA may act as a novel immune checkpoint or immunomodulator by influencing the efficacy and effectiveness of immunotherapy. In conclusion, MAOA is a promising immune target that merits further in-depth exploration in preclinical and clinical settings.

Efficient 3D imaging and pathological analysis of the human lymphoma tumor microenvironment using light-sheet immunofluorescence microscopy.

Rationale: The composition and spatial structure of the lymphoma tumor microenvironment (TME) provide key pathological insights for tumor survival and growth, invasion and metastasis, and resistance to immunotherapy. However, the 3D lymphoma TME has not been well studied owing to the limitations of current imaging techniques. In this work, we take full advantage of a series of new techniques to enable the first 3D TME study in intact lymphoma tissue. Methods: Diverse cell subtypes in lymphoma tissues were tagged using a multiplex immunofluorescence labeling technique. To optically clarify the entire tissue, immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+), clear, unobstructed brain imaging cocktails and computational analysis (CUBIC) and stabilization to harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD) were comprehensively compared with the ultimate dimensional imaging of solvent-cleared organs (uDISCO) approach selected for clearing lymphoma tissues. A Bessel-beam light-sheet fluorescence microscope (B-LSFM) was developed to three-dimensionally image the clarified tissues at high speed and high resolution. A customized MATLAB program was used to quantify the number and colocalization of the cell subtypes based on the acquired multichannel 3D images. By combining these cutting-edge methods, we successfully carried out high-efficiency 3D visualization and high-content cellular analyses of the lymphoma TME. Results: Several antibodies, including CD3, CD8, CD20, CD68, CD163, CD14, CD15, FOXP3 and Ki67, were screened for labeling the TME in lymphoma tumors. The 3D imaging results of the TME from three types of lymphoma, reactive lymphocytic hyperplasia (RLN), diffuse large B-cell lymphoma (DLBCL), and angioimmunoblastic T-cell lymphoma (AITL), were quantitatively analyzed, and their cell number, localization, and spatial correlation were comprehensively revealed. Conclusion: We present an advanced imaging-based method for efficient 3D visualization and high-content cellular analysis of the lymphoma TME, rendering it a valuable tool for tumor pathological diagnosis and other clinical research.

Extracellular Vesicular Analysis of Glypican 1 mRNA and Protein for Pancreatic Cancer Diagnosis and Prognosis.

Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes-rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles-rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early-stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late-stage PDAC patients undergoing chemotherapy, lower GPC1 tMV-mProtein and Exo-mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.

Optimized Liposomal Delivery of Bortezomib for Advancing Treatment of Multiple Myeloma.

Bortezomib (BTZ), a boronic acid-derived proteasome inhibitor, is commonly employed in treating multiple myeloma (MM). However, the applications of BTZ are limited due to its poor stability and low bioavailability. Herein, we develop an optimized liposomal formulation of BTZ (L-BTZ) by employing a remote-loading strategy. This formulation uses Tiron, a divalent anionic catechol derivative, as the internal complexing agent. Compared to earlier BTZ-related formulations, this alternative formulation showed significantly greater stability due to the Tiron-BTZ complex's higher pH stability and negative charges, compared to the meglumine-BTZ complex. Significantly, the plasma AUC of L-BTZ was found to be 30 times greater than that of free BTZ, suggesting an extended blood circulation duration. In subsequent therapeutic evaluations using two murine xenograft tumor models of MM, the NCI-H929 and OPM2 models showed tumor growth inhibition (TGI) values of 37% and 57%, respectively. In contrast, free BTZ demonstrated TGI values of 17% and 11% in these models. Further, L-BTZ presented enhanced antitumor efficacy in the Hepa1-6 HCC syngeneic model, indicating its potential broader applicability as an antineoplastic agent. These findings suggest that the optimized L-BTZ formulation offers a significant advancement in BTZ delivery, holding substantial promise for clinical investigation in not merely MM, but other cancer types.

Engineering a tunable micropattern-array assay to sort single extracellular vesicles and particles to detect RNA and protein in situ.

The molecular heterogeneity of extracellular vesicles (EVs) and the co-isolation of physically similar particles, such as lipoproteins (LPs), confounds and limits the sensitivity of EV bulk biomarker characterization. Herein, we present a single-EV and particle (siEVP) protein and RNA assay (siEVP PRA) to simultaneously detect mRNAs, miRNAs, and proteins in subpopulations of EVs and LPs. The siEVP PRA immobilizes and sorts particles via positive immunoselection onto micropatterns and focuses biomolecular signals in situ. By detecting EVPs at a single-particle resolution, the siEVP PRA outperformed the sensitivities of bulk-analysis benchmark assays for RNA and protein. To assess the specificity of RNA detection in complex biofluids, EVs from various glioma cell lines were processed with small RNA sequencing, whereby two mRNAs and two miRNAs associated with glioblastoma multiforme (GBM) were chosen for cross-validation. Despite the presence of single-EV-LP co-isolates in serum, the siEVP PRA detected GBM-associated vesicular RNA profiles in GBM patient siEVPs. The siEVP PRA effectively examines intravesicular, intervesicular, and interparticle heterogeneity with diagnostic promise.

Key role of eg* band broadening in nickel-based oxyhydroxides on coupled oxygen evolution mechanism.

A coupled oxygen evolution mechanism (COM) during oxygen evolution reaction (OER) has been reported in nickel oxyhydroxides (NiOOH)-based materials by realizing eg* band (3d electron states with eg symmetry) broadening and light irradiation. However, the link between the eg* band broadening extent and COM-based OER activities remains unclear. Here, Ni1-xFexOOH (x = 0, 0.05, 0,2) are prepared to investigate the underlying mechanism governing COM-based activities. It is revealed that in low potential region, realizing stronger eg* band broadening could facilitate the *OH deprotonation. Meanwhile, in high potential region where the photon utilization is the rate-determining step, a stronger eg* band broadening would widen the non-overlapping region between dz2 and a1g* orbitals, thereby enhancing photon utilization efficiency. Consequently, a stronger eg* band broadening could effectuate more efficient OER activities. Moreover, we demonstrate the universality of this concept by extending it to reconstruction-derived X-NiOOH (X = NiS2, NiSe2, Ni4P5) with varying extent of eg* band broadening. Such an understanding of the COM would provide valuable guidance for the future development of highly efficient OER electrocatalysts.

Exosomal mRNAs for Angiogenic-Osteogenic Coupled Bone Repair.

Regenerative medicine in tissue engineering often relies on stem cells and specific growth factors at a supraphysiological dose. These approaches are costly and may cause severe side effects. Herein, therapeutic small extracellular vesicles (t-sEVs) endogenously loaded with a cocktail of human vascular endothelial growth factor A (VEGF-A) and human bone morphogenetic protein 2 (BMP-2) mRNAs within a customized injectable PEGylated poly (glycerol sebacate) acrylate (PEGS-A) hydrogel for bone regeneration in rats with challenging femur critical-size defects are introduced. Abundant t-sEVs are produced by a facile cellular nanoelectroporation system based on a commercially available track-etched membrane (TM-nanoEP) to deliver plasmid DNAs to human adipose-derived mesenchymal stem cells (hAdMSCs). Upregulated microRNAs associated with the therapeutic mRNAs are enriched in t-sEVs for enhanced angiogenic-osteogenic regeneration. Localized and controlled release of t-sEVs within the PEGS-A hydrogel leads to the retention of therapeutics in the defect site for highly efficient bone regeneration with minimal low accumulation in other organs.

Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer.

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.

T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere (T2T) version - T2T-CHM13 - reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. Here, to provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we assembled the genome of a male Han Chinese individual, T2T-YAO, which includes T2T assemblies of all the 22 + X + M and 22 + Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼ 330-Mb exclusive sequences, ∼ 3100 unique genes, and tens of thousands of nucleotide and structural variations as compared with CHM13, highlighting the necessity of a population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

Monoamine oxidase A (MAOA): A promising target for prostate cancer therapy.

Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Previous studies have shown that MAOA is clinically associated with prostate cancer (PCa) progression and plays a key role in almost each stage of PCa, including castrate-resistant prostate cancer, neuroendocrine prostate cancer, metastasis, drug resistance, stemness, and perineural invasion. Moreover, MAOA expression is upregulated not only in cancer cells but also in stromal cells, intratumoral T cells, and tumor-associated macrophages; thus, targeting MAOA can be a multi-pronged approach to disrupt tumor promoting interactions between PCa cells and tumor microenvironment. Furthermore, targeting MAOA can disrupt the crosstalk between MAOA and the androgen receptor (AR) to restore enzalutamide sensitivity, blocks glucocorticoid receptor (GR)- and AR-dependent PCa cell growth, and is a potential strategy for immune checkpoint inhibition, thereby alleviating immune suppression and enhancing T cell immunity-based cancer immunotherapy. MAOA is a promising target for PCa therapy, which deserves further exploration in preclinical and clinical settings.

The efficacy of targeted therapy combined with radiotherapy and temozolomide-based chemotherapy in the treatment of glioma: A systemic review and meta-analysis of phase II/III randomized controlled trials.

Background: Glioma is the most common intracranial tumor, accounting for about half of the primary intracranial tumors, with the characteristics of hidden onset and high mortality. Even after surgery, radiotherapy and chemotherapy, the prognosis of glioma is not ideal. Targeted therapy has developed rapidly in the treatment of other malignant tumors, which is also an important direction in the research and development of new therapies for glioma. So far, targeting combined with radiotherapy and chemotherapy have been used as the treatment of glioma in many clinical trials, but the role of targeted combined radiotherapy and chemotherapy in the treatment of glioma is still controversial. The purpose of this study was to evaluate the efficacy of targeted therapy combined with radiotherapy and temozolomide (TMZ)-based chemotherapy in the treatment of glioma. Methods: Phase II or phase III clinical trials involving targeted therapy combined with radiotherapy and chemotherapy and temozolomide-based radiotherapy and chemotherapy for gliomas were searched using PubMed, Embase and Web of Science databases, and a comprehensive meta-analysis was conducted. The primary outcome was overall survival time (OS) and progression-free survival time (PFS), and the secondary outcome was adverse reaction. The time-to-event data is summarized as hazard ratio (HR), and the binary results are summarized as odds ratio (OR). Two researchers conducted literature screening, data extraction and quality evaluation according to inclusion and exclusion criteria. Stata16.0 software was used for analysis, random effect model was used for data merging, and forest map was used for display. Results: A total of 11 eligible literatures and 12 prospective randomized controlled clinical trials of 1284 cases were included in the meta-analysis. The results showed that compared with radiotherapy and chemotherapy alone, targeted drugs combined with temozolomide-based radiotherapy and chemotherapy could significantly improve OS in phase II trial, but there was no improvement in Phase III trial, and PFS of newly diagnosed glioma patients was improved (HR=0.82(0.71-0.94) 95%CI, p =0.005). The PFS of the third phase of the experiment also improved. Compared with radiotherapy and chemotherapy alone, there was no statistically significant increase in adverse events in targeted combined radiotherapy and chemotherapy group. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022326012.

The role of ferroptosis in prostate cancer: a novel therapeutic strategy.

The incidence of prostate cancer is the second most among male cancers after lung cancer. Prostate cancer develops rapidly and is inclined to metastasize, and castration-resistant prostate cancer (CRPC) can be formed in the later stage, which brings great challenges to the prognosis and treatment. At present, the main treatment of prostate cancer is generally divided into four methods: surgery, chemotherapy, radiotherapy and endocrine therapy. However, the efficacy of these methods fails to satisfy the demands of patient prognosis. Ferroptosis is a newly discovered iron-dependent process, characterized by lipid peroxidation. Ferroptosis is associated with many diseases, especially tumor growth. In recent years, inhibiting tumor growth and overcoming tumor drug resistance by inducing ferroptosis has become a hot research topic. Previous studies have shown that induction of ferroptosis may be a new treatment for prostate cancer. We review the research progress of ferroptosis in prostate cancer in order to provide highly effective therapies for patients with prostate cancer.

Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.

Gain-of-function (GOF) mutations in CXCR4 cause WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, characterized by infections, leukocyte retention in bone marrow (BM), and blood leukopenias. B lymphopenia is evident at early progenitor stages, yet why do CXCR4 GOF mutations that cause B (and T) lymphopenia remain obscure? Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity. We identify lymphotoxin beta receptor (LTßR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTßR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTßR blocking also increased production of IL-7 and B cell activating factor (BAFF) in secondary lymphoid organs (SLOs), increasing B and T cell numbers in the periphery. These studies revealed that LTßR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size.

An immunogold single extracellular vesicular RNA and protein (Au SERP) biochip to predict responses to immunotherapy in non-small cell lung cancer patients.

Conventional PD-L1 immunohistochemical tissue biopsies only predict 20%-40% of non-small cell lung cancer (NSCLC) patients that will respond positively to anti-PD-1/PD-L1 immunotherapy. Herein, we present an immunogold biochip to quantify single extracellular vesicular RNA and protein (Au SERP) as a non-invasive alternative. With only 20 µl of purified serum, PD-1/PD-L1 proteins on the surface of extracellular vesicles (EVs) and EV PD-1/PD-L1 messenger RNA (mRNA) cargo were detected at a single-vesicle resolution and exceeded the sensitivities of their bulk-analysis conventional counterparts, ELISA and qRT-PCR, by 1000 times. By testing a cohort of 27 non-responding and 27 responding NSCLC patients, Au SERP indicated that the single-EV mRNA biomarkers surpass the single-EV protein biomarkers in predicting patient responses to immunotherapy. Dual single-EV PD-1/PD-L1 mRNA detection differentiated responders from non-responders with an accuracy of 72.2% and achieved an NSCLC diagnosis accuracy of 93.2%, suggesting the potential for Au SERP to provide enhanced immunotherapy predictions and cancer diagnoses within the clinical setting.

Gel Property of Soy Protein Emulsion Gel: Impact of Combined Microwave Pretreatment and Covalent Binding of Polyphenols by Alkaline Method.

This study investigated the effects of microwave modification, alkali polyphenol (ferulic acid) covalently combined modification, and microwave-alkali polyphenol covalently combined modification on the gel properties of soy protein emulsions. The results showed that the properties of soy protein emulsions were improved significantly by the three modification methods. After three kinds of modification, the viscoelasticity of soy protein emulsion gel increased, and a gel system with stronger elasticity was formed. The texture, water-holding, and hydration properties of the emulsion gel increased significantly. The SEM and ClSM results showed that the modified soy protein emulsion gel had a more compact and uniform porous structure, and the oil droplets could be better embedded in the network structure of the gel. Among the three modification methods, the microwave-alkali method polyphenol covalently combining the compound modification effect was best, and the microwave modification effect was least effective compared to the other two methods. Our obtained results suggested that for gel property modification of soy protein emulsion gels, microwave pretreatment combined with the covalent binding of polyphenols by an alkaline method is an effective method.

Combination Neoantigen-Based Dendritic Cell Vaccination and Adoptive T-Cell Transfer Induces Antitumor Responses Against Recurrence of Hepatocellular Carcinoma.

A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.