Identification of HIST1H2BH as the hub gene associated with multiple myeloma using integrated bioinformatics analysis.

OBJECTIVES: Identifying the specific biomarkers and molecular signatures of MM might provide novel evidence for MM prognosis and targeted therapy. METHODS: Bioinformatic analyses were performed through GEO and TCGA datasets. The differential expression of HIST1H2BH in MM sample was validated by the qRT-PCR. And the CCK-8 assay was performed to detect the proliferation activity of HIST1H2BH on MM cell lines. RESULTS: A total of 793 DEGs were identified between bone marrow plasma cells from newly diagnosed myeloma and normal donors in GSE6477. Among them, four vital genes (HIST1H2AC, HIST1H2BH, CCND1 and TCF7L2) modeling were constructed. The increased HIST1H2BH expression was correlated with worse survival of MM based on TCGA datasets. The transcriptional expression of HIST1H2BH was significantly up-regulated in primary MM patients. And knockdown HIST1H2BH decreased the proliferation of MM cell lines. CONCLUSIONS: We have identified up-regulated HIST1H2BH in MM patients associated with poor prognosis using integrated bioinformatical methods.

Efficacy and toxicity of drugs targeting KRASG12C mutation in non-small cell lung cancer: a meta-analysis.

OBJECTIVE: To systematically analyze the efficacy and toxicity of drugs targeting KRASG12C mutation in non-small cell lung cancer (NSCLC). METHODS: The candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases up to 1 June 2023. Data on efficacy, prognosis, and adverse events (AEs) were extracted and calculated by meta-analysis. RESULTS: Six eligible prospective studies were included in this meta-analysis, including 563 patients with advanced or metastatic NSCLC. For patients with NSCLC, the objective response rate (ORR) of drugs targeting KRASG12C mutation was 37% (95%CI 31-43), median duration of response (DOR) was 8.89 months (95%CI 7.96-9.83), and median progression-free survival (PFS) was 6.40 months (95%CI 5.86-6.93). The overall incidence of AEs was 88% (95%CI 79-96) and the incidence of grade ≥3 AEs was 44% (95%CI 24-64). The most common AEs were diarrhea, nausea, fatigue, and vomiting. The most common grade ≥3 AEs were Alaninetransaminase (ALT) or Aspartatetransaminase (AST) increased and diarrhea. CONCLUSION: Sotorasib, Adagrasib, and Garsorasib as the drugs of choice for patients with KRASG12C mutation NSCLC, have definite efficacy and acceptable safety, especially for patients with advanced or metastatic disease and within posterior line therapy.

Long-term effect of Helicobacter pylori eradication on colorectal cancer incidences.

Background: There is evidence supporting the association between Helicobacter pylori infection and colorectal cancer (CRC), but whether H. pylori eradication reduces the risk of CRC is still unknown. Objectives: To compare the incidence of CRC in subjects who had received H. pylori eradication therapy with general population. Design: A population-based retrospective cohort study. Methods: This study included all H. pylori-infected subjects who had received their first course of clarithromycin-containing triple therapy in 2003-2015 in Hong Kong. We compared the observed incidences of CRC in this H. pylori eradicated cohort with the expected incidences in the age- and sex-matched general population. The standardized incidence ratio (SIR) with 95% confidence interval (CI) was computed. Results: Among 96,572 H. pylori-eradicated subjects with a median follow-up of 9.7 years, 1417 (1.5%) developed CRC. Primary analysis showed no significant difference in the observed and expected incidences of CRC (SIR: 1.03, 95% CI: 0.97-1.09). However, when stratified according to the follow-up period, higher incidence of CRC was only observed in the first 5 years after eradication (SIR: 1.47, 95% CI: 1.39-1.55), but it was lower (SIR: 0.85, 95% CI: 0.74-0.99) than general population after 11 years. When stratified by tumor location, the observed incidence was higher for colon (SIR: 1.20, 95% CI: 1.12-1.29) but lower for rectal cancer (SIR: 0.90, 95% CI: 0.81-0.999) among H. pylori-eradicated subjects. Conclusions: H. pylori-infected subjects appeared to have a higher incidence of CRC initially, which declined progressively to a level lower than general population 10 years after H. pylori eradication, particularly for rectal cancer.

Promising application of a novel biomaterial, light chain of silk fibroin combined with NT3, in repairment of rat sciatic nerve defect injury.

Autologous nerve transplantation is the gold standard for treating peripheral nerve defects, but it is associated with defects such as insufficient donor and secondary injury. Artificial nerve guidance conduits (NGCs) are now considered promising alternatives for bridging long nerve gaps, although exploring new biomaterials to construct NGCs remains challenging. Silk fibroin (SF) has good biocompatibility and can self-assemble in aqueous solutions. However, the lack of proximal neurotrophic factors after nerve injury is a major concern, leading to incomplete nerve regeneration. In this study, NT-3, a neurotrophin that promotes neuronal survival and differentiation, was bound to the light chain of silk fibroin (FIBL) in two ways: one was directly bound to FIBL (FIBL-NT3) and the other was a polypeptides-linker (FIBL-Linker-NT3). The design aimed to take advantage of silk fiber's character of self-assembly of heavy-light chains and test whether a flexible linker with NT3 molecule is easy to be a NT3 dimer, the active form. In vitro studies indicated that FIBL-Linker-NT3 combined with SF membranes promoted axon growth in adult rat dorsal root ganglion (DRG) neurons. Then we tested if FIBL-Linker-NT3 could self-assemble with the SF heavy chain (SFH). DTT (Dithiothreitol) was used to break the disulfide bonds between the SF light and heavy chains, and the light-chain protein was removed via dialysis. SFH was assembled using FIBL-Linker-NT3, as evidenced by the western blotting results that showed a high molecular band corresponding to SFH-FIBL-Linker-NT3. Chitosan scaffolds have been identified to provide a suitable microenvironment, so a chitosan/SF-FIBL-Linker-NT3 conduit was also constructed. Nerve transplantation of this conduit was evaluated in vivo in a rat sciatic nerve defect model. Immunohistochemical assays showed that the chitosan/SF-FIBL-Linker-NT3 group was superior to the chitosan/PBS, SF, PBS + FIBL-Linker-NT3 groups in nerve regeneration. In addition, the chitosan/SF-FIBL-Linker-NT3 conduit-transplanted group exhibited better recovery in terms of neurite length, sciatic functional index value, sensitivity to heat, time on the rotarod, wet weight ratio, cross-sectional area, compound muscle action potential, number of myelin layers, and myelin thickness in the nerve. Taking together, our study identified that FIBL-Linker-NT3 could promote axonal growth and regeneration in vivo and in vitro and is a promising candidate biomaterial for artificial NGCs.

ICG-loaded and 125I-labeled theranostic nanosystem for multimodality imaging-navigated phototherapy of breast cancer.

Multimodality imaging-navigated precise phototherapy has been well-established as a promising strategy for enhancing the diagnostic and therapeutic efficiency of cancer in preclinical trials. However, proper theranostic agents with adequate biosafety and biological efficacy as well as simple components and preparations are still in great demand to promote the clinical translation of this regimen. Here, we developed a multifunctional nanosystem based on the self-assembly of FDA-approved indocyanine green (ICG) and 125I-labeled glycopeptides, which were composed of FDA-approved natural polysaccharide sodium alginate and endogenous tyrosine, for fluorescence imaging/single photon emission computed tomography (FLI/SPECT)-guided synergistic photothermal/photodynamic therapy (PTT/PDT) of breast cancer. The as-prepared ICG@ADY(125I) NPs possessed a stable nanostructure and radiolabel, an ICG-equivalent ROS and hyperthermia generation property, and a preferable photo/photothermal stability and biocompatibility, favoring its tumor homing, multimodality imaging, and phototherapy with high biosafety. Consequently, ICG@ADY(125I) NPs smoothly accumulated in tumors by virtue of their long blood circulation (t1/2 = 15.76 ± 1.34 h) and the EPR effect, thereby presenting highly sensitive FLI/SPECT images to realize cancer diagnosis. Guided by multimodality imaging, accurate PTT/PDT was performed using NIR laser irradiation, achieving a high tumor inhibition rate (81.8%) against 4T1 breast cancer models without appreciable side effects. Altogether, this theranostic nanosystem may have huge potential for the clinical diagnosis and treatment of breast cancer.

FXR deficiency in hepatocytes disrupts the bile acid homeostasis and inhibits autophagy to promote liver injury in Schistosoma japonicum-infected mice.

BACKGROUND: Schistosomiasis, with 250 million people affected, is characterized by its serious hepatic inflammatory response and fibrosis formation, which could lead to dangerous complications, such as portal hypertension, splenomegaly and even ascites. But until now, the pathogenesis of schistosomiasis remains largely unknown. Farnesoid X Receptor (FXR), a bile acid-activated nuclear transcription factor mainly expresses in hepatocytes in the liver, can regulate liver diseases by controlling bile acid metabolism. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that the expression of FXR was decreased in the liver of infected mice as shown by western blot and RT-qPCR assays. Furthermore, hepatocyte-specific FXR-deficient mice (FXRflox/floxAlbCre, FXR-HKO) were generated and infected with ~16 cercariae of S. japonicum for five weeks. We found that FXR deficiency in hepatocytes promoted the progression of liver injury, aggravated weight loss and death caused by infection, and promoted inflammatory cytokines production, such as IL-6, IL-1ß, TNF-α, IL-4, IL-10, and IL-13. Surprisingly, hepatic granulomas and fibrosis were not affected. In addition, using UPLC-MS/MS spectrometry, it was found that S. japonicum infection resulted in elevated bile acids in the liver of mice, which was more obvious in FXR-deficient mice. Meanwhile, autophagy was induced in littermate control mice due to the infection, but it was significantly decreased in FXR-HKO mice. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that FXR deficiency in hepatocytes disrupts bile acid homeostasis and inhibits autophagy, which may aggravate the damages of hepatocytes caused by S. japonicum infection. It highlights that FXR in hepatocytes plays a regulatory role in the progression of schistosomiasis.

Supramolecular Nitric Oxide Depot for Hypoxic Tumor Vessel Normalization and Radiosensitization.

In cancer radiotherapy, the lack of fixed DNA damage by oxygen in hypoxic microenvironment of solid tumors often leads to severe radioresistance. Nitric oxide (NO) is a potent radiosensitizer that acts in two ways. It can directly react with the radical DNA thus fixing the damage. It also normalizes the abnormal tumor vessels, thereby increasing blood perfusion and oxygen supply. To achieve these functions, the dosage and duration of NO treatment need to be carefully controlled, otherwise it will lead to the exact opposite outcomes. However, a delivery method that fulfills both requirements is still lacking. A NO depot is designed for the control of NO releasing both over quantity and duration for hypoxic tumor vessel normalization and radiosensitization. In B16-tumor-bearing mice, the depot can provide low dosage NO continuously and release large amount of NO immediately before irradiation for a short period of time. These two modes of treatment work in synergy to reverse the radioresistance of B16 tumors more efficiently than releasing at single dosage.

Sappanwood-derived polyphenolic antidote of amyloidal toxins achieved detoxification via inhibition/reversion of amyloidal fibrillation.

The formidable virulence of methicillin-resistant staphylococcus aureus (MRSA) have thrown great challenges to biomedicine, which mainly derives from their autocrine phenol-soluble modulins (PSMs) toxins, especially the most toxic member termed phenol-soluble modulins α3 (PSMα3). PSMα3 cytotoxicity is attributed to its amyloidal fibrillation and subsequent formation of cross-α sheet fibrils. Inspired by the multiple biological activity of Sappanwood, herein, we adopted brazilin, a natural polyphenolic compound originated from Caesalpinia sappan, as a potential antidote of PSMα3 toxins, and attempted to prove that the regulation of PSMα3 fibrillation was an effective alexipharmic way for MRSA infections. In vitro results revealed that brazilin suppressed PSMα3 fibrillation and disassembled preformed amyloidal fibrils in a dose-dependent manner, in which molar ratio (brazilin: PSMα3) of efficient inhibition and disassembly were both 1:1. These desired regulations dominated by brazilin benefited from its bonding to core fibrils-forming residues of PSMα3 monomers urged by hydrogen bonding and pi-pi stacking, and such binding modes facilitated brazilin-mediated inhibition or disruption of interactions between neighboring PSMα3 monomers. In this context, these inhibited and disassembled PSMα3 assemblies could not easily insert into cell membrane and subsequent penetration, and thus alleviating the membrane disruption, cytoplasmic leakage, and reactive oxygen species (ROS) generation in normal cells. As such, brazilin dramatically decreased the cytotoxicity borne by toxic PSMα3 fibrils. In addition, in vivo experiments affirmed that brazilin relieved the toxicity of PSMα3 toxins and thus promoted the skin wound healing of mice. This study provides a new antidote of PSMα3 toxins, and also confirms the feasibility of the assembly-regulation strategy in development of antidotes against supramolecular fibrillation-dependent toxins.

Evaluation of Safety of Treatment With Anti-Epidermal Growth Factor Receptor Antibody Drug Conjugate MRG003 in Patients With Advanced Solid Tumors: A Phase 1 Nonrandomized Clinical Trial.

Importance: The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy. Objective: To evaluate the safety and maximum tolerated dose of MRG003 in a phase 1a study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study. Design, Setting, and Participants: This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase 1a dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase 1a without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021. Interventions: An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase 1a. During phase 1b, patients were administered the recommended dose identified in phase 1a. Main Outcomes and Measures: The primary end points were dose-limiting toxic effects in phase 1a and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1. Results: Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase 1a and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase 1a, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively. Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN. Trial Registration: Clinicaltrials.gov Identifier: NCT04868344.

In situ injectable nano-complexed hydrogel based on chitosan/dextran for combining tumor therapy via hypoxia alleviation and TAMs polarity regulation.

The tumor microenvironment (TME) is characterized by low pH, hypoxia, and infiltrated tumor-associated macrophages (TAMs). Therefore, regulation of TAMs polarization into anti-tumor M1 phenotype and meanwhile alleviation of the hypoxia in TME are expected to improve anti-tumor therapeutic efficacy. To this end, a novel in situ injectable nano-complexed hydrogel was developed in this study for combining tumor therapy. Thereunto, hyaluronic acid modified transfersomes loaded with chlorogenic acid functioned to reverse M2 type into M1 type via CD44 mediated internalization, the nanomedicine was entrapped in Schiff-based crosslinked injectable hydrogel (fabricated with carboxymethyl chitosan and oxidized dextran) whose linkage was labile to the acidic TME for controlled drug release. Moreover, catalase was integrated in the hydrogel enabling to convert hydrogen peroxide in TME into dissolved oxygen and alleviate tumor hypoxia. The multifunctional nano-complexed injectable hydrogel was verified to efficiently inhibit tumor growth through synergetic effects of hypoxia alleviation and TAMs polarity regulation.

Ternary Complex Coacervate of PEG/TA/Gelatin as Reinforced Bioadhesive for Skin Wound Repair.

Bioadhesives have attracted more attention in surgery due to their easy operability and abilities of promoting wound closure and tissue healing. However, it is still a great challenge to develop a robust and biocompatible bioadhesive through a facile preparation method. Herein, a ternary complex coacervate comprised of tannic acid (TA), polyethylene glycol (PEG), and gelatin (TPG) is proposed as a novel bioadhesive, which is fabricated by simple physical blending method. The adhesion capacity of TPG was reinforced through programming the cross-linking network of TPG matrix and tailoring the interfacial interactions between matrix and tissue. Curing parameters (pH, temperature, and period) and gelatin content in TPG have crucial impacts on the final comprehensive adhesion performance. The adhesion strength of the optimized formulation, fabricated with 10% (m/m) gelatin (TPG10), was over 3 folds of TPG0 (without gelatin inclusion) after 24 h curing at pH 6 and 37 °C. The mechanism of the reinforced comprehensive adhesion was also investigated, suggesting TA provided tough interfacial adhesion, covalent cross-link of TA-gelatin improved mechanical properties, and the hydrogen bonds mediated dynamic cross-link between TA and PEG enabled the bulk matrix to dissipate energy upon deformation. Furthermore, the additional antibacterial activity, biocompatibility, and suitable degradability endowed TPG10 with desirable wound closure and tissue repairing efficacy on rat skin wound model. Such low-cost, readily prepared, and function-efficient bioadhesive could provide a versatile platform for tissue repair and regeneration.

MicroRNA-151 regulates the growth, drug sensitivity and epithelial mesenchymal transition of human glioma cells by targeting profilin 2.

The microRNA-151 (miR-151) has been reported to be involved in the growth, development, and tumorigenesis of different types of human cancers. This study was designed to unravel the role and therapeutic potential of miR-151 in glioma. The results showed glioma was found to be associated with significant (P<0.05) downregulation of miR-151. Low expression of miR-151 was also associated with poor survival of the glioma patients. Overexpression of miR-151 resulted in a significant (P<0.05) decline of glioma cell proliferation and colony formation. The sensitivity of the glioma cells to adriamycin also increased significantly (P<0.05) upon miR-151 overexpression. Additionally, overexpression of miR-151 also suppressed the migration and invasion of the human glioma cells. This was also associated with alteration in the expression of epithelial mesenchymal transition proteins. The expression of E-cadherin was increased while as that of N-cadherin, vimentin, and Snail was considerably decreased upon miR-151 overexpression. Bioinformatic analysis and ducal luciferase assay showed miR-151 targets profilin 2 (PFN2) in human glioma cells. The expression of PFN2 was found to be significantly (P<0.05) upregulated in human glioma tissues cells and cell lines. Nonetheless, the PFN2 expression was considerably suppressed upon miR-151 overexpression. Knockdown of PFN2 resulted in decrease of glioma cells proliferation. In contrary, overexpression of PFN2 could avoid the tumor-suppressive effects of miR-151. Taken together, present study points towards the tumor-suppressive effects of miR-151 and prospective therapeutic implications in human glioma.

Mitochondrion-targeted supramolecular "nano-boat" simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy.

Rationale: Tumor energy metabolism has been a well-appreciated target of cancer therapy; however, the metabolism change of cancer cells between oxidative phosphorylation and glycolysis poses a challenge to the above. In this study, we constructed an innovative mitochondrion-targeted supramolecular "nano-boat" based on peptide self-assembly for tumor combined chemo-radiotherapy by simultaneously inhibiting the dual energy metabolism. Methods: A lipophilic self-assembled peptide and a positively charged cyclen were integrated to fabricate a brand new mitochondrion-targeted nano-platform for the first time. The indices of mitochondrial dysfunction including mitochondrial membrane potential, apoptosis proteins expression and ultrastructure change were evaluated using a JC-1 probe, western blotting and biological transmission electron microscopy, respectively. Energy metabolism assays were conducted on a Seahorse XF24 system by detecting the oxygen consumption rate and the glycolytic proton efflux rate. The radio-sensitization effect was investigated by colony formation, the comet assay, and γ-H2AX staining. Results: The supramolecular "nano-boat" could selectively kill cancer cells by much higher enrichment and reactive oxygen species generation than those in normal cells. In the cancer cells treated with the supramolecular "nano-boat", the dysfunctional morphological changes of the mitochondrial ultrastructure including swelling and pyknosis were evidently observed, and the endogenous mitochondrial apoptosis pathway was effectively triggered by abundant of cytochrome C leaking out. Concurrently, the dual metabolic pathways of glycolysis and oxidative phosphorylation were severely inhibited. More importantly, the supramolecular "nano-boat" displayed an excellent radio-sensitization effect with a sensitization enhancement ratio value as high as 2.58, and hence, in vivo efficiently combining radiotherapy yielded an enhanced chemo-radiotherapy effect. Conclusion: Our study demonstrated that the rationally designed peptide-based "nano-boat" could efficiently induce cancer cell apoptosis by the energy metabolism inhibition involving multiple pathways, which may provide the motivation for designing novel and universal mitochondria-targeted drug delivery systems for cancer therapy.

[Research on anti-tumor natural product diosgenin].

Diosgenin is widely distributed in many plants, such as Polygonatum sibiricum, Paris polyphylla, Dioscorea oppositifolia, Trigonella foenum-graecum, Costus speciosus, Tacca chantrieri, which has good anti-tumor activity and preferable effects on preventing atherosclerosis, protecting the heart, treating diabetes, etc. This review combed through the anti-tumor mechanisms of diosgenin encompassing lung, breast, gallbladder, liver, oral cavity, stomach, bladder, bone marrow, etc. Besides, it was discovered that diosgenin mainly exerts its effect by inhibiting tumor cell migration, suppressing tumor cell proliferation and growth, and inducing cell apoptosis. However, problems like low yield and bioavailability frequently exist in natural diosgenin. This review introduced methods such as structural modification, dosage form optimization and combination medication to improve the yield and anti-tumor activity of diosgenin. Via the summary of this paper, it is expected to provide theoretical basis for the rational exploitation and utilization of diosgenin.

Binding Peptide-Guided Immobilization of Lipases with Significantly Improved Catalytic Performance Using Escherichia coli BL21(DE3) Biofilms as a Platform.

Developing novel immobilization methods to maximize the catalytic performance of enzymes has been a permanent pursuit of scientific researchers. Engineered Escherichia coli biofilms have attracted great concern as surface display platforms for enzyme immobilization. However, current biological conjugation methods, such as the SpyTag/SpyCatcher tagging pair, that immobilize enzymes onto E. coli biofilms seriously hamper enzymatic performance. Through phage display screening of lipase-binding peptides (LBPs) and co-expression of CsgB (nucleation protein of curli nanofibers) and LBP2-modified CsgA (CsgALBP2, major structural subunit of curli nanofibers) proteins, we developed E. coli BL21::ΔCsgA-CsgB-CsgALBP2 (LBP2-functionalized) biofilms as surface display platforms to maximize the catalytic performance of lipase (Lip181). After immobilization onto LBP2-functionalized biofilm materials, Lip181 showed increased thermostability, pH, and storage stability. Surprisingly, the relative activity of immobilized Lip181 increased from 8.43 to 11.33 U/mg through this immobilization strategy. Furthermore, the highest loading of lipase on LBP2-functionalized biofilm materials reached up to 27.90 mg/g of wet biofilm materials, equivalent to 210.49 mg/g of dry biofilm materials, revealing their potential as a surface with high enzyme loading capacity. Additionally, immobilized Lip181 was used to hydrolyze phthalic acid esters, and the hydrolysis rate against dibutyl phthalate was up to 100%. Thus, LBP2-mediated immobilization of lipases was demonstrated to be far more advantageous than the traditional SpyTag/SpyCatcher strategy in maximizing enzymatic performance, thereby providing a better alternative for enzyme immobilization onto E. coli biofilms.

Selectively enhancing radiosensitivity of cancer cells via in situ enzyme-instructed peptide self-assembly.

The radiotherapy modulators used in clinic have disadvantages of high toxicity and low selectivity. For the first time, we used the in situ enzyme-instructed self-assembly (EISA) of a peptide derivative (Nap-GDFDFpYSV) to selectively enhance the sensitivity of cancer cells with high alkaline phosphatase (ALP) expression to ionizing radiation (IR). Compared with the in vitro pre-assembled control formed by the same molecule, assemblies formed by in situ EISA in cells greatly sensitized the ALP-high-expressing cancer cells to γ-rays, with a remarkable sensitizer enhancement ratio. Our results indicated that the enhancement was a result of fixing DNA damage, arresting cell cycles and inducing cell apoptosis. Interestingly, in vitro pre-formed assemblies mainly localized in the lysosomes after incubating with cells, while the assemblies formed via in situ EISA scattered in the cell cytosol. The accumulation of these molecules in cells could not be inhibited by endocytosis inhibitors. We believed that this molecule entered cancer cells by diffusion and then in situ self-assembled to form nanofibers under the catalysis of endogenous ALP. This study provides a successful example to utilize intracellular in situ EISA of small molecules to develop selective tumor radiosensitizers.

A coassembled peptide hydrogel boosts the radiosensitization of cisplatin.

We constructed a novel supramolecular hydrogel by carrying out a coassembly of cisplatin and short naproxen-capped peptides. This procedure boosted the radiosensitization effect of cisplatin by increasing the number of Pt-DNA adducts, arresting the cell cycle, and inhibiting cyclooxygenase-2.

ANTP-SmacN7 fusion peptide-induced radiosensitization in A549 cells and its potential mechanisms.

BACKGROUND: Radioresistance in tumors limits the curative effect of the radiotherapy. Mimetic compounds of second mitochondria-derived activator of caspase (Smac) are potential new tumor radiation-sensitizing drugs because they can increase radiation-induced tumor cell apoptosis. Here, we observed the radiosensitization effect of a new Smac mimetic Antennapedia protein (ANTP)-SmacN7 fusion peptide in A549 cells and investigated the underlying mechanisms behind the effects of this protein on tumor cells. METHODS: The ANTP-SmacN7 fusion peptide was synthesized and linked with fluorescein isothiocyanate to observe the protein's ability to penetrate cells. A549 cells were divided into the control, radiation-only, ANTP-SmacN7-only and ANTP-SmacN7 + radiation groups. The cells were exposed to 0, 2, 4 and 6 Gy, with 20 µmol/L of ANTP-SmacN7. The radiation-sensitizing effects of the ANTP-SmacN7 fusion proteins were observed via clonogenic assay. Apoptosis was detected using flow cytometry. A comet assay was used to assess DNA damage. The levels and degrees of cytochrome-c, PARP, H2AX, caspase-8, caspase-3, and caspase-9 activation were detected via western blot assay. The radiation sensitization of the fusion peptide, expression of γ-H2AX and C-PARP were compared after adding the caspase inhibitor, Z-VAD. RESULTS: ANTP-SmacN7 fusion proteins entered the cells and promoted A549 cell radiosensitization. Treatment with ANTP-SmacN7 + radiation significantly reduced the A549 cell clone-forming rate, increased the cytochrome-c, cleaved caspase-8, cleaved caspase-3 and cleaved caspase-9 expression levels, promoted caspase activation, and increased the rate of radiation-induced apoptosis. The ANTP-SmacN7 fusion peptide significantly increased radiation-induced double-stranded DNA rupture in the A549 cells and increased DNA damage. Adding Z-VAD reduced the fusion peptide's proapoptotic effect but not the level of double-stranded DNA breakage. CONCLUSIONS: The ANTP-SmacN7 fusion peptide exerted a remarkable radiosensitization effect on A549 cells. This protein may reduce tumor cell radioresistance by inducing caspase activation and may be a potential new Smac mimetic that can be applied in radiosensitization therapy.

A mathematical model for predicting the changes of non-small cell lung cancer based on tumor mass during radiotherapy.

This study aims to build a feasible mathematical model to analyze the mass evolution of NSCLC during standard fractionated radiotherapy. Seventy-three cases of NSCLC who were received radiotherapy with prescription dose of 2 Gy × 30 fx were selected retrospectively and divided into adenocarcinoma (ADC) group and squamous cell carcinoma (SCC) group according to the pathological type. A total of six sets of CT/CBCT images were collected. The tumor masses were measured according to each set of images. We build a mathematical model (Linear Quadratic_Repopulation&Reoxygenation& Dissolution model, LQ_RRD model), which was used to fit the first five sets of measured mass into a smooth curve. By adjusting the model parameters (λ, ν and µ), the optimal fitting results can be obtained. In order to verify the accuracy of model prediction, we measured the mass of the review images (MV, measured values), and found out the estimate point of the corresponding time (EV, estimated value) on the fitting curve. The difference and correlation between MV and EV were compared. It was found that the model could substantially simulate the tumor mass changes during radiotherapy, and it had a good fit to the clinical data (%RMSE-Median = 5.52, %RMSE-Range = [3.19, 10.73]). Comparing the differences of model parameters between ADC and SCC group, there was no significant difference in λ (t = 1.622, p  = 0.109), but the difference was significant in ν and µ (z = -7.270, p  = 0.000 and t = -10.205, p  = 0.000). Moreover, linear correlation analysis showed that there was a linear correlation between MV and EV no matter mass or volume (r = 0.960, p  = 0.000 versus r = 0.926, p  = 0.000). Nevertheless, the deviation between MV and EV of volume was larger than that of mass (z = -1.897, p  = 0.058 versus z = -3.387, p  = 0.001), and the deviation was more pronounced in larger tumors. We suggest that this mathematical model is more suitable to predict the tumor mass than volume for NSCLC during radiotherapy.