Activating UCHL1 through the CRISPR activation system promotes cartilage differentiation mediated by HIF-1α/SOX9.

Developing strategies to enhance cartilage differentiation in mesenchymal stem cells and preserve the extracellular matrix is crucial for successful cartilage tissue reconstruction. Hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in maintaining the extracellular matrix and chondrocyte phenotype, thus serving as a key regulator in chondral tissue engineering strategies. Recent studies have shown that Ubiquitin C-terminal hydrolase L1 (UCHL1) is involved in the deubiquitylation of HIF-1α. However, the regulatory role of UCHL1 in chondrogenic differentiation has not been investigated. In the present study, we initially validated the promotive effect of UCHL1 expression on chondrogenesis in adipose-derived stem cells (ADSCs). Subsequently, a hybrid baculovirus system was designed and employed to utilize three CRISPR activation (CRISPRa) systems, employing dead Cas9 (dCas9) from three distinct bacterial sources to target UCHL1. Then UCHL1 and HIF-1α inhibitor and siRNA targeting SRY-box transcription factor 9 (SOX9) were used to block UCHL1, HIF-1α and SOX9, respectively. Cartilage differentiation and chondrogenesis were measured by qRT-PCR, immunofluorescence and histological staining. We observed that the CRISPRa system derived from Staphylococcus aureus exhibited superior efficiency in activating UCHL1 compared to the commonly used the CRISPRa system derived from Streptococcus pyogenes. Furthermore, the duration of activation was extended by utilizing the Cre/loxP-based hybrid baculovirus. Moreover, our findings show that UCHL1 enhances SOX9 expression by regulating the stability and localization of HIF-1α, which promotes cartilage production in ADSCs. These findings suggest that activating UCHL1 using the CRISPRa system holds significant potential for applications in cartilage regeneration.

Guidelines for permanent iodine-125 seed interstitial brachytherapy for pancreatic cancer (2023 edition): The Chinese expert consensus workshop report.

ABSTRACT: The incidence of pancreatic cancer is increasing worldwide. Approximately, 60% of patients with pancreatic cancer have distant metastases at the time of diagnosis, of which only 10% can be removed using standard resection. Further, patients derive limited benefits from chemotherapy or radiotherapy. As such, alternative methods to achieve local control have emerged, including permanent iodine-125 seed interstitial brachytherapy. In 2023, the Chinese College of Interventionalists, affiliated with the Chinese Medical Doctor Association, organized a group of multi-disciplinary experts to compose guidelines for this treatment modality. The aim of this conference was to standardize the procedure for permanent iodine-125 seed interstitial brachytherapy, including indications, contraindications, pre-procedural preparation, procedural operations, complications, efficacy evaluation, and follow-up.

The Expression of Circ-Astn1 Inhibits High Glucose Induced Endothelial Progenitor Cell Dysfunction by Activating Autophagy.

BACKGROUND: Diabetes mellitus (DM) and complications such as chronic kidney disease and cardiovascular symptoms pose a substantial public health burden. Increasing studies have shown that circular RNAs (circRNAs) regulate many gene expressions that are essential in diverse pathological and biological procedures. However, the roles of particular circRNAs in DM are unclear. METHODS: In the current investigation, endothelial progenitor cells (EPCs) were used to search for abnormal expression of circRNAs by using high-throughput sequencing under high glucose (HG) conditions. The regulatory mechanisms and targets were then studied through bioinformatics analysis, luciferase reporter analysis, angiogenic differentiation experiments, flow cytometry detection of apoptosis and RT-qPCR analysis. RESULTS: The circ-Astn1 expression in EPCs decreased after HG treatment. Overexpression or circ-Astn1 suppressed HG induced endothelial cell damage. MicroRNA (miR)-138-5p and SIRT5 were found to be the downstream targets of circ-Astn1 through luciferase reporter analysis. SIRT5 downregulation or miR-138-5p overexpression reversed circ-Astn1's protective effect against HG induced endothelial cell dysfunction, including apoptosis and abnormal vascular differentiation. Furthermore, circ-Astn1 overexpression promoted autophagy activation by increasing SIRT5 expression under HG conditions. Our findings suggest that circ-Astn1 mediated promotion of SIRT5 facilitates autophagy by sponging miR-138-5p. CONLUSION: Together, our findings show that the overexpression of circ-Astn1 suppresses HG induced endothelial cell damage by targeting miR-138-5p/SIRT5 axis.

Dressing and undressing MOF nanophotosensitizers to manipulate phototoxicity for precise therapy of tumors.

Photodynamic therapy (PDT) is a clinically approved treatment for tumors, and it relies on the phototoxicity of photosensitizers by producing reactive oxygen species (ROS) to destroy cancer cells under light irradiation. However, such phototoxicity is a double-edged sword, which is also harmful to normal tissues. To manipulate phototoxicity and improve the therapy effect, herein we have proposed a dressing-undressing strategy for de-activating and re-activating therapy functions of photosensitizer nanoparticles. One kind of metal organic framework (PCN-224), which is composed of Zr(IV) cation and tetrakis (4-carboxyphenyl) porphyrin (TCPP), has been prepared as a model of photosensitizer, and it has size of ∼70 nm. These PCN-224 nanoparticles are subsequently coated with a mesoporous organic silica (MOS) shell containing tetrasulfide bonds (-S-S-S-S-), realizing the dressing of PCN-224. MOS shell has the thickness of ∼20 nm and thus can block 1O2 (diffusion distance: <10 nm), deactivating the phototoxicity and preventing the damage to skin and eyes. Furthermore, PCN-224@MOS can be used to load chemotherapy drug (DOX·HCl). When PCN-224@MOS-DOX are mixed with glutathione (GSH), MOS shell with -S-S-S-S- bonds can be reduced by GSH and then be decomposed, which results in the undressing and then confers the exposure of PCN-224 with good PDT function as well as the release of DOX. When PCN-224@MOS-DOX dispersion is injected into the mice and accumulated in the tumor, endogenous GSH also confers the undressing of PCN-224@MOS-DOX, realizing the in-situ activation of PDT and chemotherapy for tumor. Therefore, the present study not only demonstrates a general dressing-undressing strategy for manipulating phototoxicity of photosensitizers, but also provide some insights for precise therapy of tumors without side-effects. STATEMENT OF SIGNIFICANCE: Photosensitizers can generate reactive oxygen species (ROS) under light radiation to destroy cancer cells. However, this phototoxicity is a double-edged sword and also harmful to normal tissues such as the skin and eyes. To control phototoxicity and improve therapeutic efficacy, we prepared a PCN-224@MOS-DOX nanoplatform and proposed a dressing and undressing strategy to deactivate and reactivate the therapeutic function of the photosensitizer nanoparticles. The MOS shell can block the diffusion of 1O2, eliminate phototoxicity, and prevent damage to the skin and eyes. When injected into mice and accumulated in tumors, PCN-224@MOS-DOX dispersions are endowed with an endogenous GSH-driven undressing effect, achieving in situ activation of PDT and tumor chemotherapy.

How immune breakthroughs could slow disease progression and improve prognosis in COVID-19 patients: a retrospective study.

Background: Previous infections and vaccinations have produced preexisting immunity, which differs from primary infection in the organism immune response and may lead to different disease severities and prognoses when reinfected. Objectives: The purpose of this retrospective cohort study was to investigate the impact of immune breakthroughs on disease progression and prognosis in patients with COVID-19. Methods: A retrospective cohort study was conducted on 1513 COVID-19 patients in Chengdu Public Health Clinical Medical Center from January 2020 to November 2022. All patients were divided into the no immunity group (primary infection and unvaccinated, n=1102) and the immune breakthrough group (previous infection or vaccination, n=411). The immune breakthrough group was further divided into the natural immunity subgroup (n=73), the acquired immunity subgroup (n=322) and the mixed immunity subgroup (n=16). The differences in clinical and outcome data and T lymphocyte subsets and antibody levels between two groups or between three subgroups were compared by ANOVA, t test and chi-square test, and the relationship between T lymphocyte subsets and antibody levels and the disease progression and prognosis of COVID-19 patients was assessed by univariate analysis and logistic regression analysis. Results: The total critical rate and the total mortality rate were 2.11% and 0.53%, respectively. The immune breakthrough rate was 27.16%. In the no immunity group, the critical rate and the mortality rate were all higher, and the coronavirus negative conversion time was longer than those in the immune breakthrough group. The differences in the critical rate and the coronavirus negative conversion time between the two groups were all statistically significant (3.72% vs. 0.24%, 14.17 vs. 11.90 days, all p<0.001). In addition, in the no immunity group, although lymphocyte counts and T subsets at admission were higher, all of them decreased consistently and significantly and were significantly lower than those in the immune breakthrough group at the same time from the first week to the fourth week after admission (all p<0.01). The total antibody levels and specific Immunoglobulin G (IgG) levels increased gradually and were always significantly lower than those in the immune breakthrough group at the same time from admission to the fourth week after admission (all p<0.001). Moreover, in the natural immunity subgroup, lymphocyte counts and T subsets at admission were the highest, and total antibody levels and specific IgG levels at admission were the lowest. Then, all of them decreased significantly and were the lowest among the three subgroups at the same time from admission to one month after admission (total antibody: from 546.07 to 158.89, IgG: from 6.00 to 3.95) (all p<0.001). Those in the mixed immunity subgroup were followed by those in the acquired immunity subgroup. While lymphocyte counts and T subsets in these two subgroups and total antibody levels (from 830.84 to 1008.21) and specific IgG levels (from 6.23 to 7.51) in the acquired immunity subgroup increased gradually, total antibody levels (from 1100.82 to 908.58) and specific IgG levels (from 7.14 to 6.58) in the mixed immunity subgroup decreased gradually. Furthermore, T lymphocyte subsets and antibody levels were negatively related to disease severity, prognosis and coronavirus negative conversion time. The total antibody, specific IgM and IgG levels showed good utility for predicting critical COVID-19 patients and dead COVID-19 patients. Conclusion: Among patients with COVID-19 patients, immune breakthroughs resulting from previous infection or vaccination, could decelerate disease progression and enhance prognosis by expediting host cellular and humoral immunity to accelerate virus clearance, especially in individuals who have been vaccinated and previously infected. Clinical trial registry: Chinese Clinical Trial Register ChiCTR2000034563.

FTO Knockdown-Mediated Maturation of miR-383-5p Inhibits Malignant Advancement of Pancreatic Cancer by Targeting ITGA3.

m6A demethylase FTO is confirmed to be involved in pancreatic cancer progression. FTO regulates miRNA processing. To investigate the regulatory effect of FTO on miR-383-5p and its role in pancreatic cancer. The expression of miR-383-5p, ITGA3, and FTO was predicted using bioinformatic analysis in tissues and was measured using qPCR in cells. Cell biological functions were investigated using MTT assay, Transwell assay, sphere formation assay, and qPCR. The targeting relationship between miR-383-5p and ITGA3 was evaluated using the dual-luciferase reporter assay. The effect of FTO on miR-383-5p processing was evaluated using RIP and MeRIP assay. FTO expression was upregulated in pancreatic cancer and silencing of FTO promoted the processing of miR-383-5p in an m6A-dependent manner. m6A-modified miRNA processing was recognized by IGF2BP1. Downregulation of miR-383-5p reversed FTO knockdown-induced inhibition of cellular processes. The FTO/miR-383-5p/ITGA3 axis facilitated cell viability, metastasis, and stemness in pancreatic cancer.

Effect of Aluminium Substitution on Physical Adsorption of Chloride and Sulphate Ions in Cement-Based Materials.

When aluminium-rich phase minerals are added to Portland cement, Al atoms will enter the C-S-H and Al, then a substitution reaction will occur, forming a hydrated silica-calcium aluminate (C-A-S-H), which changes the molecular structure of the cement material. Due to limitations in experimental methods, the research on the bonding effect between corroded ions and Al-substituted structures is still unclear. Here, the mechanism of an Al substitution reaction affecting the adsorption of chloride and sulphate ions was studied using simulation. The C-A-S-H model of aluminium random substitution was built, evaluating the binding effects among the C-A-S-H, and sulphate and chloride ions. The results demonstrated that the C-A-S-H structure generated by the Al substitution reaction increased the physical adsorption capacity of the chloride and sulphate ions. The adsorption capacity of the sulphate ions was 13.26% higher than that before the Al substitution, and the adsorption capacity of chloride ions was 21.32% higher than that before the Al substitution. The addition of high aluminium phase minerals caused the interfacial flocculants C-A-S-H and C-S-H to connect and intertwine in the the interface transition zone (ITZ) structure. The addition of high-alumina phase minerals improves the microstructure of concrete hydration products, improving the physical and mechanical properties and durability of concrete. After the addition of 20% lithium slag, the sulphate ion erosion content and the chloride ion erosion content of the concrete decreased by 13.65% and 15.72%, respectively. This paper provides a deeper understanding of the effect of high-alumina phase admixtures on concrete at the micro-scale.

UCHL1 alleviates apoptosis in chondrocytes via upregulation of HIF­1α­mediated mitophagy.

Stem cell­based tissue engineering has shown significant potential for rapid restoration of injured cartilage tissues. Stem cells frequently undergo apoptosis because of the prevalence of oxidative stress and inflammation in the microenvironment at the sites of injury. Our previous study demonstrated that stabilization of hypoxia­inducible factor 1α (HIF­1α) is key to resisting apoptosis in chondrocytes. Recently, it was reported that Ubiquitin C­terminal hydrolase L1 (UCHL1) can stabilize HIF­1α by abrogating the ubiquitination process. However, the effect of UCHL1 on apoptosis in chondrocytes remains unclear. Herein, adipose­derived stem cells were differentiated into chondrocytes. Next, the CRISPR activation (CRISPRa) system, LDN­57444 (LDM; a specific inhibitor for UCHL1), KC7F2 (a specific inhibitor for HIF­1α), and 3­methyladenine (a specific inhibitor for mitophagy) were used to activate or block UCHL1, HIF­1α, and mitophagy. Mitophagy, apoptosis, and mitochondrial function in chondrocytes were detected using immunofluorescence, TUNEL staining, and flow cytometry. Moreover, the oxygen consumption rate of chondrocytes was measured using the Seahorse XF 96 Extracellular Flux Analyzer. UCHL1 expression was increased in hypoxia, which in turn regulated mitophagy and apoptosis in the chondrocytes. Further studies revealed that UCHL1 mediated hypoxia­regulated mitophagy in the chondrocytes. The CRISPRa module was utilized to activate UCHL1 effectively for 7 days; endogenous activation of UCHL1 accelerated mitophagy, inhibited apoptosis, and maintained mitochondrial function in the chondrocytes, which was mediated by HIF­1α. Taken together, UCHL1 could block apoptosis in chondrocytes via upregulation of HIF­1α-mediated mitophagy and maintain mitochondrial function. These results indicate the potential of UCHL1 activation using the CRISPRa system for the regeneration of cartilage tissue.

Phytic acid-Cu2+ framework/Cu2-xS nanocomposites with heat-shock protein down-modulation ability for enhanced multimodal combination therapy.

Mild-temperature photothermal therapy (mPTT) has shown some advantages over traditional photothermal therapy, such as reducing the damage to surrounding healthy tissues and minimizing side effects. Nevertheless, cancer cells can easily repair damage caused by mild hyperthermia due to heat shock proteins (HSPs). Thus, it is imperative to maximize the mPTT efficiency by down-regulating HSPs overexpression and combining other cancer treatments. Herein, we report the synthesis of phytic acid (PA)-Cu2+ framework/copper sulfide (Cu2-xS) nanocomposites (abbreviated as PA-Cu/Cu2-xS NPs) as the novel therapeutic platform that can down-regulate HSPs overexpression for enhanced multimodal mPTT/chemodynamic therapy (CDT)/chemotherapy. PA-Cu/Cu2-xS NPs were prepared through self-assembly and in-situ vulcanization strategy, resulting in irregular-shaped particles with an approximate size of 100 nm. PA-Cu/Cu2-xS NPs display a plasmon effect from Cu2-xS, which enhances near-infrared (NIR) absorption and possesses excellent photothermal conversion efficiency (41.7%). Moreover, PA-Cu/Cu2-xS NPs exhibit Fenton-like reaction activity resulting from the Cu ions for CDT, and the reaction activity can be further improved 1.3 times due to mild hyperthermia during mPTT. Furthermore, the generated hydroxyl radical (•OH) can effectively decrease HSPs level to enhance mPTT. PA-Cu/Cu2-xS NPs can also serve as a drug delivery system, and they are capable of loading doxorubicin (DOX) with a loading ability (20.7%). Combining mPTT/CDT/chemotherapy exhibits significant inhibition of tumor growth. This approach can serve as a basis for designing more exquisite platforms that combine mPTT with other therapies to achieve more effective cancer treatment.

Nanoparticles of Cerium-Doped Zeolitic Imidazolate Framework-8 Promote Soft Tissue Integration by Reprogramming the Metabolic Pathways of Macrophages.

Soft tissue integration around the abutment of implants is the basis of long-term retention of implants. Macrophages are an important component involved in the repair of soft tissue due to their crucial role in improving the biological structure of connective tissues by regulating the fiber synthesis, adhesion, and contraction of gingival fibroblasts. Recent studies have illustrated that cerium-doped zeolitic imidazolate framework-8 (Ce@ZIF-8) nanoparticles (NPs) can attenuate periodontitis via both antibacterial and anti-inflammatory effects. However, the effect of Ce@ZIF-8 NPs on soft tissue integration around the abutment is unknown. Herein, we first prepared Ce@ZIF-8 NPs by a one-pot synthesis. Then, we probed the regulatory effect of Ce@ZIF-8 NPs on macrophage polarization, and further experiments were performed to study the changes of fiber synthesis as well as adhesion and contraction of fibroblasts in the M2 macrophage environment stimulated by Ce@ZIF-8 NPs. Strikingly, Ce@ZIF-8 NPs can be internalized by M1 macrophages through macropinocytosis and caveolae-mediated endocytosis in addition to phagocytosis. By catalyzing hydrogen peroxide to produce oxygen, the mitochondrial function was remedied, while hypoxia inducible factor-1α was restrained. Then, macrophages were shifted from the M1 to M2 phenotype via this metabolic reprogramming pathway, provoking soft tissue integration. These results provide innovative insights into facilitating soft tissue integration around implants.

Radiomic advances in the transarterial chemoembolization related therapy for hepatocellular carcinoma.

Radiomics is a hot topic in the research on customized oncology treatment, efficacy evaluation, and tumor prognosis prediction. To achieve the goal of mining the heterogeneity information within the tumor tissue, the image features concealed within the tumoral images are turned into quantifiable data features. This article primarily describes the research progress of radiomics and clinical-radiomics combined model in the prediction of efficacy, the choice of treatment modality, and survival in transarterial chemoembolization (TACE) and TACE combination therapy for hepatocellular carcinoma.

Construction of PEGylated chlorin e6@CuS-Pt theranostic nanoplatforms for nanozymes-enhanced photodynamic-photothermal therapy.

Multifunctional nanoagents with photodynamic therapy (PDT) and photothermal therapy (PTT) functions have shown great promise for cancer treatment, while the design and synthesis of efficient nanoagents remain a challenge. To realize nanozyme-enhanced PDT-PTT combined therapy, herein we have synthesized the Ce6@CuS-Pt/PEG nanoplatforms as a model of efficient nanoagents. Hollow CuS nanospheres with an average diameter of âˆ¼ 200 nm are first synthesized through vulcanization using Cu2O as the precursor. Subsequently, CuS nanospheres are surface-decorated with Pt nanoparticles (NPs) as nanozyme via an in-situ reduction route, followed by modifying the DSPE-PEG5000 and loading the photosensitizer Chlorin e6 (Ce6). The obtained Ce6@CuS-Pt/PEG NPs exhibit high photothermal conversion efficiency (43.08%), good singlet oxygen (1O2) generation ability, and good physiological stability. In addition, Ce6@CuS-Pt/PEG NPs show good catalytic performance due to the presence of Pt nanozyme, which can effectively convert H2O2 to O2 and significantly enhance the production of cytotoxic 1O2. When Ce6@CuS-Pt/PEG NPs dispersion is injected into mice, the tumors can be wholly suppressed owing to nanozyme-enhanced PDT-PTT combined therapy, providing better therapeutic effects compared to single-mode phototherapy. Thus, the present Ce6@CuS-Pt/PEG NPs can act as an efficient multifunctional nanoplatform for tumor therapy.

Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment.

Probiotic supplements were shown to improve cognitive function in Alzheimer's disease (AD) patients. However, it is still unclear whether this applies to older individuals with mild cognitive impairment (MCI). We aimed to explore the effects of probiotic supplementation on multiple neural behaviors in older adults with MCI. Forty-two MCI patients (age > 60 years) were randomly divided into two groups and consumed either probiotics (n=21) or placebo (n=21) for 12 weeks. Various scale scores, gut microbiota measures and serological indicators were recorded pre- and posttreatment. After 12 weeks of intervention, cognitive function and sleep quality were improved in the probiotic group compared with those in the control group, and the underlying mechanisms were associated with changes in the intestinal microbiota. In conclusion, our study demonstrated that probiotic treatment enhanced cognitive function and sleep quality in older MCI patients, thus providing important insights into the clinical prevention and treatment of MCI.

Switching from membrane disrupting to membrane crossing, an effective strategy in designing antibacterial polypeptide.

Drug-resistant bacterial infections have caused serious threats to human health and call for effective antibacterial agents that have low propensity to induce antimicrobial resistance. Host defense peptide-mimicking peptides are actively explored, among which poly-ß-l-lysine displays potent antibacterial activity but high cytotoxicity due to the helical structure and strong membrane disruption effect. Here, we report an effective strategy to optimize antimicrobial peptides by switching membrane disrupting to membrane penetrating and intracellular targeting by breaking the helical structure using racemic residues. Introducing ß-homo-glycine into poly-ß-lysine effectively reduces the toxicity of resulting poly-ß-peptides and affords the optimal poly-ß-peptide, ßLys50HG50, which shows potent antibacterial activity against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) and MRSA persister cells, excellent biosafety, no antimicrobial resistance, and strong therapeutic potential in both local and systemic MRSA infections. The optimal poly-ß-peptide demonstrates strong therapeutic potential and implies the success of our approach as a generalizable strategy in designing promising antibacterial polypeptides.

The polycaprolactone/silk fibroin/carbonate hydroxyapatite electrospun scaffold promotes bone reconstruction by regulating the polarization of macrophages.

Macrophages are known to modulate the osteogenic environment of bone regeneration elicited by biological bone grafts. Alteration in certain chemical components tends to affect macrophages polarization. Comparatively to hydroxyapatite (HAp), carbonate hydroxyapatite (CHA) consists of 7.4 (wt%) carbonate ions and more closely resembles the mineral content of bone. It remains unknown whether CHA scaffolds or HA scaffolds have better osteogenic properties. In this study, we fabricated PCL/SF scaffold, PCL/SF/HAp scaffold and PCL/SF/CHA scaffold using the electrospinning technique. Despite comparable mechanical properties, the PCL/SF/CHA scaffold exhibited better osteogenic properties than the PCL/SF/HAp scaffold. Although no significant differences were observed between the two scaffolds for promoting osteoblast differentiation in vitro, the PCL/SF/CHA group appeared to be more effective at promoting bone regeneration in cranial defects in vivo. The PCL/SF/CHA scaffold was found to promote macrophage polarization toward M2 via activating the JAK/STAT5 pathway which caused a pro-osteogenic microenvironment to facilitate osteoblast differentiation. The results of this study indicated a higher potential of CHA to substitute HAp in the production of bone scaffolds for better bone regeneration.

Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.

Most of tumors are located in deep-depth of animals, and the therapy of deep-seated tumors remains a severe challenge due to the performance reduction of promising technologies including phototherapy. To solve the problem, herein we have developed a hafnium-hemoporfin frameworks (HfHFs) as multifunctional theranostic nanoplatforms for synergetic sonodynamic therapy (SDT) and radiation therapy (RT) of deep-seated tumors. HfHFs are constructed by a sonication-assisted assembly route with hematoporphyrin monomethyl ether (HMME) sonosensitizer molecules as bridging linkers and Hf4+ as metal nodes. The resulting HfHFs sample is composed of spherical nanoparticles with size of 90-130 nm, and then surface-modified with DSPE-PEG to improve the water-dispersity. Under ultrasound (US) irradiation, HMME ligands in HfHFs can be motivated to produce singlet oxygen (1O2) due to sonodynamic effect. When the HfHFs sample is exposed by X-ray, the high atomic-number Hf4+ in the HfHFs can effectively absorb X-ray to increase RT effect by producing hydroxyl radicals (•OH). When HfHFs dispersion is intravenously injected in the tumor-bearing mice, the tumor can be monitored by CT imaging. Moreover, the deep-seated tumors coated by tissue barriers can be suppressed effectively by the synergistic SDT and RT, which is better than that of SDT or RT alone. Therefore, HfHFs can be employed as a novel nanoagent for the SDT-RT of deep-seated tumors.

Multifunctional hemoporfin-Cu9S8-MnO2 for magnetic resonance imaging-guided catalytically-assisted photothermal-sonodynamic therapies.

Integrated theranostic nanoplatforms with multi-model imaging and therapeutic functions are attracting great attention in cancer treatments, while the design and preparation of such nanoplatforms remain an open challenge. Herein, we report hemoporfin@Cu9S8@MnO2 nanoparticles (H@Cu9S8@MnO2 NPs) as multifunctional nanoplatforms for magnetic resonance imaging-guided catalytically-assisted photothermal-sonodynamic therapies of tumors. Cu9S8 hollow spherical nanoparticles were firstly prepared by in-situ vulcanization of Cu2O, and the growth of MnO2 shell was realized by the reduction of manganese permanganate, where the hollow structure of Cu9S8 could be used to load hemoporfin sonosensitizer. Cu9S8@MnO2 nanoparticles with diameters of âˆ¼ 130 nm exhibit increased photoabsorption in near-infrared (NIR) region (680-1100 nm) due to the plasmonic effect of Cu9S8, and the photothermal conversion efficiency is determined to be 32.5% under 1064 nm laser irradiation. Furthermore, MnO2 shells can mimic catalase to trigger the decomposition of endogenous H2O2 into O2 with a significant O2 elevation (14.7 mg L-1) within 8 min and then promote the production of 1O2 via sonodynamic effect of hemoporfin. Meanwhile, MnO2 shells provide the T1-weight magnetic resonance (MR) imaging function. When H@Cu9S8@MnO2 NPs solution is administered to the mice, the tumor growth can be effectively inhibited due to catalytically-assisted synergetic photothermal-sonodynamic therapies which have superior therapeutic effect compared to mono-model therapy alone. Thus, H@Cu9S8@MnO2 NPs present a promising strategy for the development of integrated theranostic nanoplatforms with multi-model imaging and therapy functions.

GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.

PURPOSE: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role. METHODS: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer. RESULTS: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM. CONCLUSION: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

Microbial Metabolite Inspired ß-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of ß-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL-1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.

Multifunctional Doxorubicin@Hollow-Cu9S8 nanoplatforms for Photothermally-Augmented Chemodynamic-Chemo therapy.

Multimodal therapy has attracted increasing interests in tumor treatment due to its high anti-cancer efficacy, and the key is to develop multifunctional nanoagents. The classic multifunctional nanoagents are made up of expensive and complex components, leading to limited practical applications. To solve these problems, we have developed the polyethylene glycol (PEG) coated hollow Cu9S8 nanoparticles (H-Cu9S8/PEG NPs), whose H-Cu9S8 component exhibits the photothermal effect for near-infrared (NIR) photothermal therapy (PTT), the Fenton-like catalytic activity for chemodynamic therapy (CDT), and the drug-loading capacity for chemotherapy. The H-Cu9S8/PEG NPs with a diameter of âˆ¼ 100 nm have been synthesized by sulfurizing cuprous oxide (Cu2O) nanoparticles through "Kirkendall effect", and they exhibit high photothermal conversion efficiency of 40.9%. Meanwhile, the H-Cu9S8/PEG NPs are capable of a Fenton-like reaction, which can be augmented by 2 times under the NIR irradiation. The hollow structure gives the H-Cu9S8/PEG high doxorubicin (DOX) loading capacity (21.1%), and then the DOX release can be further improved by pH and photothermal effect. When the DOX@H-Cu9S8/PEG dispersions are injected into the tumor-bearing mice, the tumor growth can be efficiently inhibited due to the synergistic effect of photothermally-augmented CDT-chemo therapy. Therefore, the DOX@H-Cu9S8/PEG can serve as a multifunctional nanoplatform for photothermally-augmented CDT-chemo treatment of malignant tumors.