Construction of Smart DNA-Based Drug Delivery Systems for Cancer Therapy.

Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.

Hypomethylating agents (HMAs) show benefit in AML rather than in intermediate/high-risk MDS based on genetic mutations in epigenetic modification (EMMs): from a retrospective study.

Since HMAs were recommended for treatments in AML and MDS, we wondered whether HMAs could provide similar benefit to AML and intermediate/high-risk MDS under the direction of next-generation sequencing. Here we retrospectively analyzed the prognosis of 176 AML and 128 intermediate/high-risk MDS patients treated with HMAs or non-HMA regimens. For AML, HMAs regimen was related to better CR rate compared with non-HMA regimen in elder cohort, while the situation was the opposite in younger cohort. In consolidation phase, EMM (+) patients could benefit from HMAs regimen. Relapsed AML patients receiving HMAs regimen rather than non-HMA regimen had better post-relapse survival. Multivariate analysis identified HMA regimen as an independent prognostic factor for OS in EMM (+) cohort. For intermediate/high-risk MDS patients not undergoing HSCT, however, HMA regimen showed no survival advantage in EMM (+) cohort and was conversely associated with shorter survival in EMM (-) cohort compared with non-HMA regimen. And among those undergoing HSCT, HMA prior to HSCT predicted poor prognosis compared with upfront HSCT regardless of the existence of EMMs. Therefore, HMAs had better therapeutic value in AML rather than in intermediate/high-risk MDS based on EMMs.

R2-ISS staging combined with circulating plasma cells improves risk stratification for newly diagnosed multiple myeloma: a single-center real-world study.

We aimed to evaluate if circulating plasma cells (CPC) detected by flow cytometry could add prognostic value of R2-ISS staging. We collected the electronic medical records of 336 newly diagnosed MM patients (NDMM) in our hospital from January 2017 to June 2023. The median overall survival (OS) for patients and R2-ISS stage I-IV were not reached (NR), NR, 58 months and 53 months, respectively. There was no significant difference in OS between patients with stage I and patients with stage II (P = 0.309) or between patients with stage III and patients with stage IV (P = 0.391). All the cases were re-classified according to R2-ISS stage and CPC numbers ≥ 0.05% (CPC high) or<0.05% (CPC low) into four new risk groups: Group 1: R2-ISS stage I + R2-ISS stage II and CPC low, Group 2: R2-ISS stage II and CPC high + R2-ISS stage III and CPC low, Group 3: R2-ISS stage III and CPC high + R2-ISS stage IV and CPC low, Group 4: R2-ISS stage IV and CPC high. The median OS were NR, NR, 57 months and 32 months. OS of Group 1 was significantly longer than that of Group 2 (P = 0.033). OS in Group 2 was significantly longer than that of Group 3 (P = 0.007). OS in Group 3 was significantly longer than that of Group 4 (P = 0.041). R2-ISS staging combined with CPC can improve risk stratification for NDMM patients.

Risk-benefit ratio of percutaneous kyphoplasty and percutaneous vertebroplasty in patients with newly diagnosed multiple myeloma with vertebral fracture: a single-center retrospective study.

The indications for percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) are painful vertebral compression fractures. Our study is to assess the risk-benefit ratio of PKP/PVP surgery in the patients with newly diagnosed multiple myeloma (NDMM) without receiving antimyeloma therapy. The clinical data of 426 consecutive patients with NDMM admitted to our center from February 2012 to April 2022 were retrospectively analyzed. The baseline data, postoperative pain relief, the proportion of recurrent vertebral fractures, and survival time were compared between the PKP/PVP surgical group and the nonsurgical group in the NDMM patients. Of the 426 patients with NDMM, 206 patients had vertebral fractures (206/426, 48.4%). Of these, 32 (32/206, 15.5%) underwent PKP/PVP surgery for misdiagnosis of simple osteoporosis prior to diagnosis of MM (surgical group), and the other 174 (174/206, 84.5%) did not undergo surgical treatment prior to definitive diagnosis of MM (non-surgical group). The median age of patients in the surgical and nonsurgical groups was 66 and 62 years, respectively (p = 0.01). The proportion of patients with advanced ISS and RISS stages was higher in the surgical group (ISS stage II + III 96.9% vs. 71.8%, p = 0.03; RISS stage III 96.9% vs. 71%, p = 0.01). Postoperatively, 10 patients (31.3%) never experienced pain relief and 20 patients (62.5%) experienced short-term pain relief with a median duration of relief of 2.6 months (0.2-24.1 months). Postoperative fractures of vertebrae other than the surgical site occurred in 24 patients (75%) in the surgical group, with a median time of 4.4 months postoperatively (0.4-86.8 months). Vertebral fractures other than the fracture site at the first visit occurred in 5 patients (2.9%) in the nonoperative group at the time of diagnosis of MM, with a median time of 11.9 months after the first visit (3.5-12.6 months). The incidence of secondary fractures was significantly higher in the surgical group than in the nonsurgical group (75% vs. 2.9%, p = 0.001). The time interval between the first visit and definitive diagnosis of MM was longer in the surgical group than in the nonsurgical group (6.1 months vs. 1.6 months, p = 0.01). At a median follow-up of 32 months (0.3-123 months), median overall survival (OS) was significantly shorter in the surgical group than in the nonsurgical group (48.2 months vs. 66 months, p = 0.04). Application of PKP/PVP surgery for pain relief in NDMM patients without antimyeloma therapy has a limited effect and a high risk of new vertebral fractures after surgery. Therefore, patients with NDMM may need to have their disease controlled with antimyeloma therapy prior to any consideration for PKP/PVP surgery.

Exploiting immunostimulatory mechanisms of immunogenic cell death to develop membrane-encapsulated nanoparticles as a potent tumor vaccine.

Vaccine is one of the most promising strategies for cancer immunotherapy; however, there are no therapeutic cancer vaccine achieving significant clinical efficacy till now. The main limiting factors include the immune suppression and escape mechanisms developed by tumor and not enough capacity of vaccines to induce a vigorous anti-tumor immunity. This study aimed to develop a strategy of membrane-based biomimetic nanovaccine and investigate the immunological outcomes of utilizing the unique immunostimulatory mechanisms derived of immunogenic cell death (ICD) and of fulfilling a simultaneous nanoscale delivery of a highlighted tumor antigen and broad membrane-associated tumor antigens in the vaccine design. TC-1 tumor cells were treated in vitro with a mixture of mitoxantrone and curcumin for ICD induction, and then chitosan (CS)-coated polylactic co-glycolic acid (PLGA) nanoparticles loaded with HPV16 E744-62 peptides were decorated with the prepared ICD tumor cell membrane (IM); further, the IM-decorated nanoparticles along with adenosine triphosphate (ATP) were embedded with sodium alginate (ALG) hydrogel, And then, the immunological features and therapeutic potency were evaluated in vitro and in vivo. The nanovaccine significantly stimulated the migration, antigen uptake, and maturation of DCs in vitro, improved antigen lysosome escape, and promoted the retention at injection site and accumulation in LNs of the tumor antigen in vivo. In a subcutaneously grafted TC-1 tumor model, the therapeutic immunization of nanovaccine elicited a dramatical antitumor immunity. This study provides a strategy for the development of tumor vaccines.

Effects of sous vide cooking combined with ultrasound pretreatment on physicochemical properties and microbial communities of Russian sturgeon meat (Acipenser gueldenstaedti).

BACKGROUND: The production of Russian sturgeon is expanding rapidly in China but it is necessary to adopt measures to extend the shelf life of sturgeon meat. Previous studies found that sous vide cooking (SVC) at 60 °C increased the protein and lipid oxidation. The addition of antioxidant substances reduced the acceptance of the product. The effect of combination SVC and ultrasound pretreatment was therefore investigated. RESULTS: Results showed that SVC at 50 °C combined with ultrasound effectively restrained the growth of total viable counts (TVC) in samples. Meanwhile, the main dominant genera changed from Pseudomonas to Carnobacterium and the number of microbial species decreased. The odor profile of Russian sturgeon meat was more stable and the lipoxygenase (LOX) activity decreased more rapidly after treating with SVC and ultrasound. Importantly, more stable protein aggregates were formed in samples treated by SVC 50 °C together with ultrasound pretreatment, so the protein and lipid oxidation were slowed during storage. Higher springiness values were obtained and the color of sturgeon meat was lighter under these conditions. CONCLUSION: The combination of SVC 50 °C and ultrasound pretreatment effectively inhibited the microbial growth of Russian sturgeon meat at lower oxidation levels. These findings theoretically support the preservation and development of sturgeon meat, and the application of SVC technology. © 2022 Society of Chemical Industry.

MR-KPA: medication recommendation by combining knowledge-enhanced pre-training with a deep adversarial network.

BACKGROUND: Medication recommendation based on electronic medical record (EMR) is a research hot spot in smart healthcare. For developing computational medication recommendation methods based on EMR, an important challenge is the lack of a large number of longitudinal EMR data with time correlation. Faced with this challenge, this paper proposes a new EMR-based medication recommendation model called MR-KPA, which combines knowledge-enhanced pre-training with the deep adversarial network to improve medication recommendation from both feature representation and the fine-tuning process. Firstly, a knowledge-enhanced pre-training visit model is proposed to realize domain knowledge-based external feature fusion and pre-training-based internal feature mining for improving the feature representation. Secondly, a medication recommendation model based on the deep adversarial network is developed to optimize the fine-tuning process of pre-training visit model and alleviate over-fitting of model caused by the task gap between pre-training and recommendation. RESULT: The experimental results on EMRs from medical and health institutions in Hainan Province, China show that the proposed MR-KPA model can effectively improve the accuracy of medication recommendation on small-scale longitudinal EMR data compared with existing representative methods. CONCLUSION: The advantages of the proposed MR-KPA are mainly attributed to knowledge enhancement based on ontology embedding, the pre-training visit model and adversarial training. Each of these three optimizations is very effective for improving the capability of medication recommendation on small-scale longitudinal EMR data, and the pre-training visit model has the most significant improvement effect. These three optimizations are also complementary, and their integration makes the proposed MR-KPA model achieve the best recommendation effect.

COF-DNA Bicolor Nanoprobes for Imaging Tumor-Associated mRNAs in Living Cells.

Developing probes for the simultaneous detection of multiple tumor-associated mRNAs is beneficial for the precise diagnosis and early therapy of cancer. In this work, we prepared two COF-DNA bicolor probes at room temperature and freezing conditions and evaluated their performances in simultaneous imaging of intracellular tumor-associated mRNAs. By loading dye-labeled survivin- and TK1-mRNA recognition sequences on porphyrin COF NPs, nucleic acid-specific "off-on" nanoprobes were obtained. The nanoprobe prepared by the freezing method exhibits higher ssDNA loading density and better fluorescence quenching efficiency. Moreover, its signal-to-noise ratio is significantly higher than that prepared at room temperature, and the target recognition effect was unaffected. Significantly, the freezing-method-prepared nanoprobe has higher signal intensities in target-overexpressed cells compared to the room-temperature-prepared probe, while their signals in cells with low target expression are similar. Thus, the freezing-method-prepared nanoprobe is a promising tool for improved cancer diagnostic imaging. This work can offer new insights into the exploration of high-performance COF-based nanoprobes for multiple biomarker detection.

Characterization of the SWEET Gene Family in Longan (Dimocarpus longan) and the Role of DlSWEET1 in Cold Tolerance.

Sugars will eventually be exported transporters (SWEET), a group of relatively novel sugar transporters, that play important roles in phloem loading, seed and fruit development, pollen development, and stress response in plants. Longan (Dimocarpus longan), a subtropic fruit tree with high economic value, is sensitive to cold. However, whether the SWEET gene family plays a role in conferring cold tolerance upon longan remains unknown. Here, a total of 20 longan SWEET (DlSWEET) genes were identified, and their phylogenetic relationships, gene structures, cis-acting elements, and tissue-specific expression patterns were systematically analyzed. This family is divided into four clades. Gene structures and motifs analyses indicated that the majority of DlSWEETs in each clade shared similar exon-intron organization and conserved motifs. Tissue-specific gene expression suggested diverse possible functions for DlSWEET genes. Cis-elements analysis and quantitative real-time PCR (qRT-PCR) analysis revealed that DlSWEET1 responded to cold stress. Notably, the overexpression of DlSWEET1 improved cold tolerance in transgenic Arabidopsis, suggesting that DlSWEET1 might play a positive role in D. longan's responses to cold stress. Together, these results contribute to a better understanding of SWEET genes, which could serve as a foundation for the further functional identification of these genes.

Polyoxometalate-Based Nanomaterials Toward Efficient Cancer Diagnosis and Therapy.

As an emerging class of inorganic metal oxides, organically functionalized polyoxometalates (POMs) or POM-based nanohybrids have been demonstrated promising potential for the inhibition of various cancer types by the virtue of their diversity in structures and significantly reduced toxicity. This contribution summarizes the latest achievement of POM-based nanomaterials in cancer diagnosis and various therapeutics to put forward our fundamental viewpoints on the design principles of modified POMs based on their application. In addition, major challenges and perspectives in this field are also discussed. We expect that this review will provide a valuable and systematic reference for the further development of POM-based nanomaterials.

Epigenetic silencing of miR564 contributes to the leukemogenesis of t(8;21) acute myeloid leukemia.

The AML1-ETO oncoprotein, which results from t(8;21) translocation, is considered an initial event of t(8;21) acute myeloid leukemia (AML). However, the precise mechanisms of the oncogenic activity of AML1-ETO is yet to be fully determined. The present study demonstrates that AML1-ETO triggers the heterochromatic silencing of microRNA-564 (miR564) by binding at the AML1 binding site along the miR564 promoter region and recruiting chromatin-remodeling enzymes. Suppression of miR564 enhances the oncogenic activity of the AML1-ETO oncoprotein by directly inhibiting the expression of CCND1 and the DNMT3A genes. Ectopic expression of miR564 can induce retardation of G1/S transition, reperform differentiation, promote apoptosis, as well as inhibit the proliferation and colony formation of AML1-ETO+ leukemia cells in vitro. Enhanced miR564 levels can significantly inhibit the tumor proliferation of t(8;21)AML in vivo. We first identify an unexpected and important epigenetic circuitry of AML1-ETO/miR564/CCND1/DNMT3A that contributes to the leukemogenesis in vitro/vivo of AML1-ETO+ leukemia, indicating that miR564 enhancement could provide a potential therapeutic method for AML1-ETO+ leukemia.

Acute myeloid leukemia immune escape by epigenetic CD48 silencing.

Acute myeloid leukemia (AML) is a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions and epigenetic modification. The mechanism of AML immune evasion is not clearly understood. Here we show that CD48 high expression is a favorable prognosis factor that is down-regulated in AML patients, which can help AML evade from NK cell recognition and killing. Furthermore, we demonstrate that CD48 expression is regulated by methylation and that a hypomethylating agent can increase the CD48 expression, which increases the NK cells killing in vitro. Finally, we show that CD48 high expression can reverse the AML immune evasion and activate NK cells function in vivo. The present study suggests that a combination the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.

Self-Assembling Nonconjugated Poly(amide-imide) into Thermoresponsive Nanovesicles with Unexpected Red Fluorescence for Bioimaging.

Nonconjugated red fluorescent polymers have been increasingly studied to improve the biocompatibility and penetration depth over conventional fluorescent materials. However, the accessibility of such polymers remains challenging due to the scarcity of nonconjugated fluorophores and lacking relevant mechanism of red-shifted fluorescence. Herein, we discovered that the combination of hydrogen bonding and π-π stacking interactions provides nonconjugated poly(amide-imide) with a large bathochromic shift (>100 nm) from blue-green fluorescence to red emission. The amphiphilic PEGylated poly(amide-imide) derived from in situ PEGylation self-assembled into nanovesicles in water, which isolated the aminosuccinimide fluorophore from the solvents and suppressed the hydrogen bonds formation between aminosuccinimide fluorophores and water. Therefore, the fluorescence of PEGylated poly(amide-imide) in water was soundly retained. Furthermore, the strong hydrogen bonding and hydrophobic interactions with water provided PEGylated poly(amide-imide) with a reversible thermoresponsiveness and presented a concentration-dependent behavior. Finally, accompanied by the excellent biostability and photostability, PEGylated poly(amide-imide) exhibited as a good candidate for cell imaging.

Asymptotic Rate-Distortion Analysis of Symmetric Remote Gaussian Source Coding: Centralized Encoding vs. Distributed Encoding.

Consider a symmetric multivariate Gaussian source with ℓ components, which are corrupted by independent and identically distributed Gaussian noises; these noisy components are compressed at a certain rate, and the compressed version is leveraged to reconstruct the source subject to a mean squared error distortion constraint. The rate-distortion analysis is performed for two scenarios: centralized encoding (where the noisy source components are jointly compressed) and distributed encoding (where the noisy source components are separately compressed). It is shown, among other things, that the gap between the rate-distortion functions associated with these two scenarios admits a simple characterization in the large ℓ limit.

Nanomaterials for Disease Treatment by Modulating the Pyroptosis Pathway.

Pyroptosis differs significantly from apoptosis and cell necrosis as an alternative mode of programmed cell death. Its occurrence is mediated by the gasdermin protein, leading to characteristic outcomes including cell swelling, membrane perforation, and release of cell contents. Research underscores the role of pyroptosis in the etiology and progression of many diseases, making it a focus of research intervention as scientists explore ways to regulate pyroptosis pathways in disease management. Despite numerous reviews detailing the relationship between pyroptosis and disease mechanisms, few delve into recent advancements in nanomaterials as a mechanism for modulating the pyroptosis pathway to mitigate disease effects. Therefore, there is an urgent need to fill this gap and elucidate the path for the use of this promising technology in the field of disease treatment. This review article delves into recent developments in nanomaterials for disease management through pyroptosis modulation, details the mechanisms by which drugs interact with pyroptosis pathways, and highlights the promise that nanomaterial research holds in driving forward disease treatment.

Magneto-optical nanosystems for tumor multimodal imaging and therapy in-vivo.

Multimodal imaging, which combines the strengths of two or more imaging modalities to provide complementary anatomical and molecular information, has emerged as a robust technology for enhancing diagnostic sensitivity and accuracy, as well as improving treatment monitoring. Moreover, the application of multimodal imaging in guiding precision tumor treatment can prevent under- or over-treatment, thereby maximizing the benefits for tumor patients. In recent years, several intriguing magneto-optical nanosystems with both magnetic and optical properties have been developed, leading to significant breakthroughs in the field of multimodal imaging and image-guided tumor therapy. These advancements pave the way for precise tumor medicine. This review summarizes various types of magneto-optical nanosystems developed recently and describes their applications as probes for multimodal imaging and agents for image-guided therapeutic interventions. Finally, future research and development prospects of magneto-optical nanosystems are discussed along with an outlook on their further applications in the biomedical field.

Transition-Metal-Based Nanozymes: Synthesis, Mechanisms of Therapeutic Action, and Applications in Cancer Treatment.

Cancer, as one of the leading causes of death worldwide, drives the advancement of cutting-edge technologies for cancer treatment. Transition-metal-based nanozymes emerge as promising therapeutic nanodrugs that provide a reference for cancer therapy. In this review, we present recent breakthrough nanozymes for cancer treatment. First, we comprehensively outline the preparation strategies involved in creating transition-metal-based nanozymes, including hydrothermal method, solvothermal method, chemical reduction method, biomimetic mineralization method, and sol-gel method. Subsequently, we elucidate the catalytic mechanisms (catalase (CAT)-like activities), peroxidase (POD)-like activities), oxidase (OXD)-like activities) and superoxide dismutase (SOD)-like activities) of transition-metal-based nanozymes along with their activity regulation strategies such as morphology control, size manipulation, modulation, composition adjustment and surface modification under environmental stimulation. Furthermore, we elaborate on the diverse applications of transition-metal-based nanozymes in anticancer therapies encompassing radiotherapy (RT), chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), immunotherapy, and synergistic therapy. Finally, the challenges faced by transition-metal-based nanozymes are discussed alongside future research directions. The purpose of this review is to offer scientific guidance that will enhance the clinical applications of nanozymes based on transition metals.

A Simple and Rapid Quantitative Assay for Gossypol via Reactive Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry.

The development of simple and rapid analytical tools for gossypol (GSP) is important to the food industry and medical field. Here, we report a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method for the detection of GSP by using a reactive matrix 4-hydrazinoquinazoline (4-HQ). The two aldehyde groups of GSP react with the 4-HQ and therefore improve the detection sensitivity and selectivity of GSP. Moreover, GSP forms homogeneous crystals with the 4-HQ matrix, allowing the quantification of the GSP by the proposed method. With the optimized experimental conditions, GSP could be detected at concentrations as low as 0.1 µM and quantified in a wide linear range (1-500 µM). After a brief extraction with an organic solvent, the GSP contents in cottonseeds and cottonseed kernels from different provinces of China were determined successfully. The spiked recovery of GSP in cottonseed/cottonseed kernel samples was obtained as 97.88-105.80%, showing the reliability of the assay for GSP determination in real samples.

Activatable Probes for Ratiometric Imaging of Endogenous Biomarkers In Vivo.

Dynamic variations in the concentration and abnormal distribution of endogenous biomarkers are strongly associated with multiple physiological and pathological states. Therefore, it is crucial to design imaging systems capable of real-time detection of dynamic changes in biomarkers for the accurate diagnosis and effective treatment of diseases. Recently, ratiometric imaging has emerged as a widely used technique for sensing and imaging of biomarkers due to its advantage of circumventing the limitations inherent to conventional intensity-dependent signal readout methods while also providing built-in self-calibration for signal correction. Here, the recent progress of ratiometric probes and their applications in sensing and imaging of biomarkers are outlined. Ratiometric probes are classified according to their imaging mechanisms, and ratiometric photoacoustic imaging, ratiometric optical imaging including photoluminescence imaging and self-luminescence imaging, ratiometric magnetic resonance imaging, and dual-modal ratiometric imaging are discussed. The applications of ratiometric probes in the sensing and imaging of biomarkers such as pH, reactive oxygen species (ROS), reactive nitrogen species (RNS), glutathione (GSH), gas molecules, enzymes, metal ions, and hypoxia are discussed in detail. Additionally, this Review presents an overview of challenges faced in this field along with future research directions.