Precise pancreatic cancer therapy through targeted degradation of mutant p53 protein by cerium oxide nanoparticles.

BACKGROUND: In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells. RESULTS: We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model. CONCLUSIONS: Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.

Synthesis and Biological Evaluation of Novel Allobetulon/Allobetulin-Nucleoside Conjugates as AntitumorAgents.

Allobetulin is structurally similar tobetulinic acid, inducing the apoptosis of cancer cells with low toxicity. However, both of them exhibited weak antiproliferation against several tumor cell lines. Therefore, the new series of allobetulon/allobetulin-nucleoside conjugates 9a-10i were designed and synthesized for potency improvement. Compounds 9b, 9e, 10a, and 10d showed promising antiproliferative activity toward six tested cell lines, compared to zidovudine, cisplatin, and oxaliplatin based on their antitumor activity results. Among them, compound 10d exhibited much more potent antiproliferative activity against SMMC-7721, HepG2, MNK-45, SW620, and A549 human cancer cell lines than cisplatin and oxaliplatin. In the preliminary study for the mechanism of action, compound 10d induced cell apoptosis and autophagy in SMMC cells, resulting in antiproliferation and G0/G1 cell cycle arrest by regulating protein expression levels of Bax, Bcl-2, and LC3. Consequently, the nucleoside-conjugated allobetulin (10d) evidenced that nucleoside substitution was a viable strategy to improve allobetulin/allobetulon's antitumor activity based on our present study.

Photoresponsive PAMAM-Assembled Nanocarrier Loaded with Autophagy Inhibitor for Synergistic Cancer Therapy.

As one of the most promising drug-delivery carriers due to its small size, easy surface modifiability, and hydrophobic interior, cationic poly(amidoamine) (PAMAM) per se, demonstrated by previous reports and the authors' present study, indicate potential anticancer capability, however, which are restricted by autophagy elicitation. Besides, its side-toxicity profile, having also been extensively documented, limits its translation into the clinic. Herein, the authors design a photoresponsive PAMAM-assembled nanoparticle loaded with the autophagy inhibitor (chloroquine, CQ), which exhibits light responsiveness for precisely controlling drug release and superior dark biosafety. Upon light irradiation, the nanoparticle can dissociate into charged small PAMAM for a significant antitumor effect. Meanwhile, the released CQ can inhibit pro-survival autophagy induced by PAMAM to achieve an excellent synergistic anticancer efficacy in vitro and in vivo. The authors' study provided a vision of utilizing PAMAM as self-carried anticancer therapeutics in combination with an autophagy inhibitor and proposing a cancer therapy with high antitumor efficacy and low side effects to normal tissues.

Slower Removing Ligands of Metal Organic Frameworks Enables Higher Electrocatalytic Performance of Derived Nanomaterials.

The widely used route of high-temperature pyrolysis for transformation of Prussian blue analogs (PBAs) to functional nanomaterials leads to the fast removal of CN- ligands, and thus the formation of large metal aggregates and the loss of porous structures inside PBAs. Here, a controllable pyrolysis route at low temperature is reported for retaining the confined effect of CN- ligands to metal cations during the whole pyrolysis process, thereby preparing high-surface-area cubes comprising disordered bimetallic oxides (i.e., Co3 O4 and Fe2 O3 ) nanoparticles. The disordered structure of Co3 O4 enables the exposure of abundant oxygen vacancies. Notably, for the first time, it is found that the in situ generated CoOOH during the oxygen evolution reaction (OER) can inherit the oxygen vacancies of pristine Co3 O4 (i.e., before OER), and such CoOOH with abundant oxygen vacancies adsorbs two - OH in the following Co3+ to Co4+ for markedly promoting OER. However, during the similar step, the ordered Co3 O4 with less oxygen vacancies only involves one - OH, resulting in the additional overpotentials for adsorbing - OH. Consequently, with high surface area and disordered Co3 O4 , the as-synthesized electrocatalysts have a low potential of 237 mV at 10 mA cm-2 , surpassing most of reported electrocatalysts.

Nonmetal Doping as a Robust Route for Boosting the Hydrogen Evolution of Metal-Based Electrocatalysts.

Recently, nonmetal doping has exhibited its great potential for boosting the hydrogen evolution reaction (HER) of transition-metal (TM)-based electrocatalysts. To this end, this work overviews the recent achievements made on the design and development of the nonmetal-doped TM-based electrocatalysts and their performance for the HER. It is also shown that by rationally doping nonmetal elements, the electronic structures of TM-based electrocatalysts can be effectively tuned and in turn the Gibbs free energy of the TM for adsorption of H* intermediates (ΔGH* ) optimized, consequently enhancing the intrinsic activity of TM-based electrocatalysts. Notably, we highlight that concurrently doping two nonmetal elements can continuously and precisely regulate the electronic structures of the TM, thereby maximizing the activity for HER. Moreover, nonmetal doping also accounts for enhancing the physical properties of the TM (i.e. surface area). Therefore, nonmetal doping is a robust strategy for simultaneous regulation of the chemical and physical features of the TM.

A prospective randomized controlled trial comparing two different treatments of intrauterine adhesions.

RESEARCH QUESTION: Intrauterine adhesions (IUA) are primarily caused by trauma to the endometrium, and hysteroscopy is presently the main treatment for IUA. However, high rates of post-operative adhesion re-formation remain a problem. In this study, the combination of an intrauterine device (IUD) with a Foley catheter and the balloon uterine stent were investigated to evaluate their efficacy in preventing adhesion re-formation and the subsequent reproductive outcomes in patients with moderate to severe adhesions. DESIGN: A prospective randomized controlled study was conducted in a university-affiliated hospital. A total of 171 women with Asherman's syndrome were initially recruited between August 2016 and December 2017 and were randomized to undergo either balloon uterine stent insertion or placement of a contraceptive IUD plus a Foley catheter after hysteroscopic adhesiolysis. Reduction of adhesion scores, incidence of adhesion re-formation, changes in menstrual flow and reproductive outcomes were analysed. RESULTS: A total of 118 participants were eligible for analysis. The American Fertility Society (AFS) scores were not significantly different between groups before hysteroscopic adhesiolysis. At the second-look hysteroscopy, the AFS scores and adhesion recurrence rates were significantly higher in the balloon uterine stent group compared with the combination group (P < 0.01 and P = 0.024, respectively). There were no statistically significant differences in pregnancy and live birth rates between the two groups. CONCLUSIONS: The combination of an IUD and a Foley balloon catheter had better efficacy in preventing adhesion re-formation than the balloon uterine stent alone; however, it did not produce better reproductive outcomes.

Facile Synthesis of Sub-Nanometric Copper Clusters by Double Confinement Enables Selective Reduction of Carbon Dioxide to Methane.

Previous density-functional theory (DFT) calculations show that sub-nanometric Cu clusters (i.e., 13 atoms) favorably generate CH4 from the CO2 reduction reaction (CO2 RR), but experimental evidence is lacking. Herein, a facile impregnation-calcination route towards Cu clusters, having a diameter of about 1.0 nm with about 10 atoms, was developed by double confinement of carbon defects and micropores. These Cu clusters enable high selectivity for the CO2 RR with a maximum Faraday efficiency of 81.7 % for CH4 . Calculations and experimental results show that the Cu clusters enhance the adsorption of *H and *CO intermediates, thus promoting generation of CH4 rather than H2 and CO. The strong interactions between the Cu clusters and defective carbon optimize the electronic structure of the Cu clusters for selectivity and stability towards generation of CH4 . Provided here is the first experimental evidence that sub-nanometric Cu clusters facilitate the production of CH4 from the CO2 RR.

Nomogram Predicting Overall Survival in Operable Cervical Cancer Patients.

OBJECTIVE: Nomograms are widely used as predictive tools to predict oncological outcomes intuitively and precisely. The aim of our study was to develop a nomogram for predicting overall survival (OS) of patients with early stage cervical cancer. METHODS: In this retrospective study, the clinical, pathological, and hematological data and prognosis of 795 cervical cancer patients were investigated. We identified and incorporated independent significant prognostic factors for OS to develop a nomogram. The predictive accuracy and discriminative ability were measured by concordance index. RESULTS: By univariable analysis and subsequent multivariable analysis, we identified body mass index, albumin, platelet, leukocyte, tumor differentiation, and the status of the pelvic lymph node (PLN) (all P < 0.05) as independent prognostic factors. The concordance index of the nomogram integrating these 6 variables was 0.74. The calibration curves for probability of 3- and 5-year OS also demonstrated ideal agreement between nomogram prediction and actual observation. CONCLUSIONS: We developed a novel nomogram that can provide prediction of OS for patients with early stage cervical cancer individually. Furthermore, studies are required to validate whether it can be applied to other cohorts.

[Reporting quality and effect size comparison in randomized controlled trials of bo's abdominal acupuncture using CONSORT statement and STRICTA].

OBJECTIVE: To evaluate the reporting quality of randomized controlled trials (RCT) that compared Bo's abdominal acupuncture with conventional body acupuncture, and compare the efficacy and safety between them by performing a Meta-analysis. METHODS: All RCTs comparing Bo's abdominal acupuncture with conventional body acupuncture were included. English and Chinese databases were searched from their respective inceptions to March 2014. The reporting quality was assessed according to the "Consolidated Standards of Reporting Trials" (CONSORT) checklist for parallel RCTs and the revised "Standards for Reporting Interventions in Clinical Trials of Acupuncture" (STRICTA). A Meta-analysis was conducted to synthesize the effect sizes, and publication bias was evaluated by the Egger linear regression test using Stata. RESULTS: Ninety-seven studies were included, of which most lacked adequate reporting information, and 80.4% showed that the efficacy of abdominal acupuncture is superior to conventional body acupuncture, especially for the following diseases: lumbar disc herniation, cervical spondylosis, omarthritis and cervical vertigo, except simple obesity. Effect-sizes were controversial when evaluating different outcomes. CONCLUSION: The international standard CONORT statement and STRICTA guidelines should be strictly applied when reporting acupuncture RCTs in the future. Abdominal acupuncture appears to be more effective compared with conventional body acupuncture for some diseases. However, fur-her high quality blind RCTs using validated out-ome indexes and standard reporting are warranted.

Photodynamic Modulation of Endoplasmic Reticulum and Mitochondria Network Boosted Cancer Immunotherapy.

Immunogenic cell death (ICD) represents a promising approach for enhancing tumor therapy efficacy by inducing antitumor immune response. However, current ICD inducers often have insufficient endoplasmic reticulum (ER) enrichment and ineffectiveness in tumor immune escape caused by ER-mitochondria interaction. In this study, a kind of photoactivatable probe, THTTPy-PTSA, which enables sequential targeting of the ER and mitochondria is developed. THTTPy-PTSA incorporates p-Toluenesulfonamide (PTSA) for ER targeting, and upon light irradiation, the tetrahydropyridine group undergoes a photo oxidative dehydrogenation reaction, transforming into a pyridinium group that acts as a mitochondria-targeting moiety. The results demonstrate that THTTPy-PTSA exhibits exceptional subcellular translocation from the ER to mitochondria upon light irradiation treatment, subsequently triggers a stronger ER stress response through a cascade-amplification effect. Importantly, the augmented ER stress leads to substantial therapeutic efficacy in a 4T1 tumor model by eliciting the release of numerous damage-associated molecular patterns, thereby inducing evident and widespread ICD, consequently enhancing the antitumor immune efficacy. Collectively, the findings emphasize the pivotal role of photodynamic modulation of the ER-mitochondria network, facilitated by THTTPy-PTSA with precise spatial and temporal regulation, in effectively bolstering the antitumor immune response. This innovative approach presents a promising alternative for addressing the challenges associated with cancer immunotherapy.

Enzyme/pH Dual-Responsive Engineered Nanoparticles for Improved Tumor Immuno-Chemotherapy.

Combining immune checkpoint blockade (ICB) therapy with chemotherapy can enhance the efficacy of ICB and expand its indications. However, the limited tumor specificity of chemotherapy drugs results in severe adverse reactions. Additionally, the low tissue penetration and immune-related adverse events associated with monoclonal antibodies restrict their widespread application. To address challenges faced by traditional combination therapies, we design a dual-responsive engineered nanoparticle based on ferritin (denoted as CMFn@OXA), achieving tumor-targeted delivery and controlled release of the anti-PD-L1 peptide CLP002 and oxaliplatin (OXA). Our results demonstrate that CMFn@OXA not only exhibits tumor-specific accumulation but also responds to matrix metalloproteinase-2/9 (MMP-2/9), facilitating the controlled release of CLP002 to block PD-1/PD-L1 interaction. Simultaneously, it ensures the precise delivery of the OXA to tumor cells and its subsequent release within the acidic environment of lysosomes, thereby fostering a synergistic therapeutic effect. Compared to traditional combination therapies, CMFn@OXA demonstrates superior performance in inhibiting tumor growth, extending the survival of tumor-bearing mice, and exhibiting excellent biocompatibility. Collectively, our results highlight CMFn@OXA as a novel and promising strategy in the field of cancer immunotherapy.

Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors.

In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.

Identification of necroptosis-related genes as prognostic indicators for lower-grade glioma.

The purpose of this research is to develop a predictive model based on necroptosis-related genes to predict the prognosis and survival of lower grade gliomas (LGGs) efficiently. To achieve this goal, we searched for differentially expressed necrotizing apoptosis-related genes using the TCGA and CGGA databases. To construct a prognostic model, LASSO Cox and COX regression analyses were conducted on the differentially expressed genes. In this study, three genes were used to develop a prognostic model of necrotizing apoptosis, and all samples were split into high- and low-risk groups. We observed that patients with a high-risk score had a worse overall survival rate (OS) than those with a low-risk score. In the TCGA and CGGA cohorts, the nomogram plot showed a high capacity to predict overall survival of LGG patients. GSEA analysis revealed that the high-risk group was enriched for inflammatory responses, tumor-related pathways, and pathological processes. Additionally, the high-risk score was associated with invading immune cell expression. In conclusion, our predictive model based on necroptosis-related genes in LGG was shown to be effective in the diagnosis and could predict the prognosis of LGG. In addition, we identified possible targets related to necroptosis-related genes for glioma therapy in this study.

2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway.

Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85ß protein expression contributes to tamoxifen resistance, and reveal p85ß protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high performance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.

Quantitative 1H NMR with global spectral deconvolution approach for the determination of gamma-aminobutyric acid in Chinese yam (Dioscorea polystachya Turczaninow).

We developed a quantitative proton nuclear magnetic resonance (qNMR) with global spectral deconvolution (GSD) method to determine the gamma-aminobutyric acid content in Chinese yam with the proton signal at δH 2.30. Trimethylsilyl-2,2,3,3-tetradeuteropropionic acid sodium salt was set as the internal standard. The method was validated and showed admissible stability, repeatability, and precision. Compared to the traditional high-performance liquid chromatography method, this method did not involve tedious pre-treatment and expensive standard. Compared to ordinary qNMR, GSD algorithm could effectively remove the effect of noise, baseline distortions and signal overlapping. Overall, qNMR with GSD method is a rapid, simple and reliable method to quantitatively determine functional metabolites even overlapped with other compounds in herbs or foods.

Bacteria-based multiplex system eradicates recurrent infections with drug-resistant bacteria via photothermal killing and protective immunity elicitation.

BACKGROUND: The high mortality associated with drug-resistant bacterial infections is an intractable clinical problem resulting from the low susceptibility of these bacteria to antibiotics and the high incidence of recurrent infections. METHODS: Herein, a photosynthetic bacteria-based multiplex system (Rp@Al) composed of natural Rhodopseudomonas palustris (Rp) and Food and Drug Administration-approved aluminum (Al) adjuvant, was developed to combat drug-resistant bacterial infections and prevent their recurrence. We examined its photothermal performance and in vitro and in vivo antibacterial ability; revealed its protective immunomodulatory effect; verified its preventative effect on recurrent infections; and demonstrated the system's safety. RESULTS: Rp@Al exhibits excellent photothermal properties with an effective elimination of methicillin-resistant Staphylococcus aureus (MRSA). In addition, Rp@Al enhances dendritic cell activation and further triggers a T helper 1 (TH1)/TH2 immune response, resulting in pathogen-specific immunological memory against recurrent MRSA infection. Upon second infection, Rp@Al-treated mice show significantly lower bacterial burden, faster abscess recovery, and higher survival under near-lethal infection doses than control mice. CONCLUSIONS: This innovative multiplex system, with superior photothermal and immunomodulatory effects, presents great potential for the treatment and prevention of drug-resistant bacterial infections.

A smartphone-integrated portable platform based on polychromatic ratiometric fluorescent paper sensors for visual quantitative determination of norfloxacin.

The emergence of "superbugs" due to antibiotics overuse poses a significant threat to human health and security. The development of sensitive and effective antibiotics detection is undoubtedly a prerequisite for addressing antibiotics overuse-associated issues. However, current techniques for monitoring antibiotics typically require costly equipment and well-trained professionals. Hence, we developed herein a rapid, instrument-free, and on-site detection method for antibiotic residues such as norfloxacin (NOR) based on a ratiometric sensing platform utilizing "on-off-on" response properties of polychromatic fluorescence for direct visual quantitative NOR analysis. Specifically, this platform integrated iron ions (Fe3+)-chelated blue carbon dots (BCDs) for signal sensing and red carbon dots (RCDs) as an internal reference. The sensor mechanism is selective quenching of BCDs' blue fluorescence by Fe3+ via an inner filter effect with unaffected RCDs' red fluorescence. Further NOR addition led to competitive binding with BCDs due to Fe3+ shedding from the BCDs' surface for a recovered blue fluorescence signal. Notably, the ratiometric fluorescence sensor demonstrated rapid and highly sensitive NOR detection in a concentration range of 1-70 µM with an impressive detection limit of 6.84 nM. The ratiometric fluorescence sensing platform was constructed by integrating smartphone and paper-based strategies, which exhibited exceptional sensitivity, selectivity, and rapid response for portable, instrument-free, visual quantification of NOR in real samples.

An ultrasound-based radiomics model for survival prediction in patients with endometrial cancer.

PURPOSE: To establish a nomogram integrating radiomics features based on ultrasound images and clinical parameters for predicting the prognosis of patients with endometrial cancer (EC). MATERIALS AND METHODS: A total of 175 eligible patients with ECs were enrolled in our study between January 2011 and April 2018. They were divided into a training cohort (n = 122) and a validation cohort (n = 53). Least absolute shrinkage and selection operator (LASSO) regression were applied for selection of key features, and a radiomics score (rad-score) was calculated. Patients were stratified into high risk and low-risk groups according to the rad-score. Univariate and multivariable COX regression analysis was used to select independent clinical parameters for disease-free survival (DFS). A combined model based on radiomics features and clinical parameters was ultimately established, and the performance was quantified with respect to discrimination and calibration. RESULTS: Nine features were selected from 1130 features using LASSO regression in the training cohort, which yielded an area under the curve (AUC) of 0.823 and 0.792 to predict DFS in the training and validation cohorts, respectively. Patients with a higher rad-score were significantly associated with worse DFS. The combined nomogram, which was composed of clinically significant variables and radiomics features, showed a calibration and favorable performance for DFS prediction (AUC 0.893 and 0.885 in the training and validation cohorts, respectively). CONCLUSION: The combined nomogram could be used as a tool in predicting DFS and may assist individualized decision making and clinical treatment.

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system.

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.