A computer-aided, heterodimer-based "triadic" carrier-free drug delivery platform to mitigate multidrug resistance in lung cancer and enhance efficiency.

Co-delivering multiple drugs or circumventing the drug efflux mechanism can significantly decrease multidrug resistance (MDR), a major cause of cancer treatment failure. In this study, we designed and fabricated a universal "three-in-one" self-delivery system for synergistic cancer therapy using a computer-aided strategy. First, we engineered two glutathione (GSH)-responsive heterodimers, ERL-SS-CPT (erlotinib [ERL] linked with camptothecin [CPT] via a disulfide bond [SS]) and CPT-SS-ERI (CPT conjugated with erianin [ERI]), which serve as both cargo and carrier material. Next, molecular dynamics simulations indicated that multiple noncovalent molecular forces, including π-π stacking, hydrogen bonds, hydrophobic interactions, and sulfur bonds, drive the self-assembly process of these heterodimers. We then explored the universality of the heterodimers and developed a "triadic" drug delivery platform comprising 40 variants. Subsequently, we conducted case studies on docetaxel (DTX)-loaded ERL-SS-CPT nanoparticles (denoted as DTX@ERL-SS-CPT NPs) and curcumin (CUR)-loaded ERL-SS-CPT NPs (identified as CUR@CPT-SS-ERI NPs) to comprehensively investigate their self-assembly mechanism, physicochemical properties, storage stability, GSH-responsive drug release, cellular uptake, apoptosis effects, biocompatibility, and cytotoxicity. Both NPs exhibited well-defined spherical structures, high drug loading rates, and excellent storage stability. DTX@ERL-SS-CPT NPs exhibited the strongest cytotoxicity in A549 cells, following the order of DTX@ERL-SS-CPT NPs > ERL-SS-CPT NPs > CPT > DTX > ERL. Conversely, DTX@ERL-SS-CPT NPs showed negligible cytotoxicity in normal human bronchial epithelium cell line (BEAS-2B), indicating good biocompatibility and safety. Similar observations were made for CUR@CPT-SS-ERI NPs regarding biocompatibility and cytotoxicity. Upon endocytosis and encountering intracellular overexpressed GSH, the disulfide-bond linker is cleaved, resulting in the release of the versatile NPs into three parts. The spherical NPs enhance water solubility, reduce the required dosage of free drugs, and increase cellular drug accumulation while suppressing P-glycoprotein (P-gp) expression, leading to apoptosis. This work provides a computer-aided universal strategy-a heterodimer-based "triadic" drug delivery platform-to enhance anticancer efficiency while reducing multidrug resistance.

DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids.

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here, we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3'-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3' overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.

Enhanced docetaxel therapeutic effect using dual targeted SRL-2 and TA1 aptamer conjugated micelles in inhibition Balb/c mice breast cancer model.

Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (ß-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (ß-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue < 0.001) which further confirmed by in vivo biodistribution and fluorescent TUNEL assay experiments. NPs treated groups demonstrated notable tumor growth inhibition in 4T1 tumor bearing Balb/c mice by only 1/10th of the DTX therapeutic dose (TD) as a drug model. In conclusion, cleverly designed nanostructures here demonstrated improved anticancer effects by enhancing tumor targeting, delivering chemotherapeutic agents more accurately, promoting drug release, reducing the therapeutic dosage, and lowering side effects of anticancer drugs.

E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

Overexpression of DTX1 inhibits D-GalN/TNF-α-induced pyroptosis and inflammation in hepatocytes by regulating NLRP3 ubiquitination.

Background: Acute liver injury (ALI) is characterized by massive hepatocyte death and has high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the pathophysiology of ALI and is involved in the inflammatory response mediated by NOD-like receptor protein 3 (NLRP3) inflammasome activation. Deltex 1 (DTX1) is a single transmembrane protein with ubiquitin E3 ligase activity and is closely involved in cell growth, differentiation, and apoptosis, as well as intracellular signal transduction. However, little is known about the influence of DTX1 on ALI. This study aimed to investigate the role of DTX1 in pyroptosis and inflammation induced by D-galactosamine (D-GalN) and tumor necrosis factoralpha (TNF-α) in human hepatocytes (LO2 cells) in vitro. Methods: Cell pyroptosis was measured by flow cytometry. The levels of DTX1, pyroptosis-associated proteins, and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Immunofluorescence staining, co-immunoprecipitation, ubiquitination, and luciferase reporter and chromatin immunoprecipitation assays were performed to detect the regulation between DTX1 and NLRP3 or hepatocyte nuclear factor 4 alpha (HNF4α). Analysis of variance was performed to compare groups. Results: We found that DTX1 was decreased in D-GalN/TNF-α-induced LO2 cells. DTX1 overexpression significantly inhibited D-GalN/TNF-α-induced cell pyroptosis and inflammation. DTX1 interacted with NLRP3 and induced NLRP3 ubiquitination and degradation. Furthermore, by targeting NLRP3, DTX1 knockdown significantly induced cell pyroptosis and inflammation. In addition, HNF4α promoted DTX1 transcription by binding with its promoter. Conclusion: Our study revealed that DTX1 suppressed D-GalN/TNF-α-induced hepatocyte pyroptosis and inflammation by regulating NLRP3 ubiquitination.

Human centered design of AI-powered Digital Therapeutics for stress prevention: Perspectives from multi-stakeholders' workshops about the SHIVA solution.

Background: AI-powered Digital Therapeutics (DTx) hold potential for enhancing stress prevention by promoting the scalability of P5 Medicine, which may offer users coping skills and improved self-management of mental wellbeing. However, adoption rates remain low, often due to insufficient user and stakeholder involvement during the design phases. Objective: This study explores the human-centered design potentials of SHIVA, a DTx integrating virtual reality and AI with the SelfHelp+ intervention, aiming to understand stakeholder views and expectations that could influence its adoption. Methods: Using the SHIVA example, we detail design opportunities involving AI techniques for stress prevention across modeling, personalization, monitoring, and simulation dimensions. Workshops with 12 stakeholders-including target users, digital health designers, and mental health experts-addressed four key adoption aspects through peer interviews: AI data processing, wearable device roles, deployment scenarios, and the model's transparency, explainability, and accuracy. Results: Stakeholders perceived AI-based data processing as beneficial for personalized treatment in a secure, privacy-preserving environment. While wearables were deemed essential, concerns about compulsory use and VR headset costs were noted. Initial human facilitation was favored to enhance engagement and prevent dropouts. Transparency, explainability, and accuracy were highlighted as crucial for the stress detection model. Conclusion: Stakeholders recognized AI-driven opportunities as crucial for SHIVA's adoption, facilitating personalized solutions tailored to user needs. Nonetheless, challenges persist in developing a transparent, explainable, and accurate stress detection model to ensure user engagement, adherence, and trust.

A Novel Encapsulation Approach to Enhance the Delivery and Antitumor Activity of Docetaxel in Breast Cancer Therapy.

Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC50) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1ß) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G1 phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel.

Back on track - digital health applications to treat back pain of rheumatic patients? Results of a qualitative interview study.

Non-specific low back pain (NLBP) is prevalent among patients with rheumatic conditions. Digital health applications (DiGAs) provide reimbursed, personalized home treatment for patients, promising to overcome limitations of traditional healthcare systems. However, the adoption and effectiveness of back pain-specific DiGAs in rheumatology are not well understood. This study aims to explore the experiences and perspectives of a diverse group of rheumatology stakeholders regarding the use of DiGAs for back pain management. Qualitative interviews and a focus group discussion were conducted with a wide range of stakeholders including rheumatic patients, rheumatologists, nurses and DiGA producers. The data were analysed using qualitative content analysis. The study included 15 interviews (10 rheumatic patients, 4 rheumatologists, 1 DiGA producer) and 1 focus group with mixed participants (n = 12). Most stakeholders valued the instant access to personalized and effective back pain treatment provided by DiGAs. Patients appreciated the flexibility and ease of use of DiGAs which can be used anywhere and anytime. Concerns were raised about insufficient guidance regarding correct execution of exercises, which was seen as potentially dangerous and unsettling for patients. Healthcare professionals (HCPs) highlighted barriers, such as the lack of reimbursement, time constraints, and inadequate DiGA-specific education as barriers to prescribing DiGAs. Additionally, poor patient onboarding often led to delays, increased skepticism, and premature discontinuation of therapy. Stakeholders emphasized the challenges of current care driven by a shortage of HCPs and generally supported usage of back pain DiGAs. Various barriers and solution approaches were identified to enhance the performance, usability, and implementation of DiGAs in rheumatology.

Comparison of Product Features and Clinical Trial Designs for the DTx Products with the Indication of Insomnia Authorized by Regulatory Authorities.

BACKGROUND: Digital therapeutics (DTx) have attracted attention as the substitutes or add-ons to conventional pharmacotherapy and the number of DTx products authorized with the regulatory reviews of the clinical evidence is increasing. Insomnia is one of the major targets of the DTx due to the benefit from cognitive behavioral interventions and several products have been launched in the market with regulatory reviews. However, common features of the products and the clinical evidence required by each regulatory agency have not been investigated. METHODS: In this study, we identified the DTx products with the primary indication of insomnia authorized with regulatory reviews of clinical evidence by literature and website searches, and investigated the common features of the products and of the study designs for the pivotal clinical trials. RESULTS: The total of 6 DTx products were identified. The components of cognitive behavioral therapy for insomnia (CBT-I) were identified as common features of the products. All the pivotal clinical trials were randomized, parallel-group, blind studies against insomnia patients. No products have been authorized in multiple countries regardless of the similarity of the features of the products and of the study designs for the pivotal clinical trials. CONCLUSIONS: Our study revealed that the components of CBT-I and gold standard design in pivotal clinical trials were adopted in all the DTx products for insomnia authorized with reviews of clinical evidence. At the same time, our findings suggest the needs of internationally harmonized regulatory review and authorization system to facilitate the early patient access to the promising DTx products.

Complementary App-Based Yoga Home Exercise Therapy for Patients With Axial Spondyloarthritis: Usability Study.

BACKGROUND: Axial spondyloarthritis (AS) is a chronic inflammatory rheumatic disease characterized by potentially disabling inflammation of the spine and adjacent joints. Regular exercise is a cornerstone of treatment. However, patients with AS currently have little support. YogiTherapy (MaD Lab) is an app developed to support patients with AS by providing instructions for yoga-based home exercise therapy. OBJECTIVE: This study aimed to evaluate the usability and acceptance of the newly designed YogiTherapy app for patients with AS. METHODS: Patients completed the User Version of the Mobile Application Rating Scale (uMARS) and net promoter score (NPS) questionnaires after the app introduction. Wilcoxon Mann-Whitney rank sum test, chi-square test for count data, and correlation analysis were conducted to examine the usability of the app, acceptance, and patient characteristics. RESULTS: A total of 65 patients with AS (33, 51% female; age: mean 43.3, SD 13.6 years) were included in the study from May 2022 to June 2023. Subsequently, the data were analyzed. Usability was rated moderate, with a mean uMARS of 3.35 (SD 0.47) points on a scale from 0 to 5. The highest-rated uMARS dimension was information (mean 3.88, SD 0.63), followed by functionality (mean 3.84, SD 0.87). Females reported a significantly higher uMARS total score than males (mean 3.47, SD 0.48 vs mean 3.23, SD 0.45; P=.03, Vargha and Delaney A [VDA] 0.66, 95% CI 0.53-0.77). The mean average of the NPS was 6.23 (SD 2.64) points (on a scale from 0 to 10), based on 43% (26/65 nonpromoters, 42% (25/65) indifferent, and 15% (9/65) promoters. A total of 7% (5/65) of those surveyed did not answer the question. When applying the NPS formula, the result is -26%. The NPS showed a positive correlation with the usage of mobile apps (r=0.39; P=.02). uMARS functionality was significantly higher rated by patients younger than 41 years (mean 4.17, SD 0.55 vs mean 3.54, SD 1; P<.001; VDA 0.69, 95% CI 0.56-0.80). Patients considering mobile apps as useful reported higher uMARS (r=0.38, P=.02). The uMARS app quality mean score was correlated with the frequency of using apps (r=-0.21, P<.001). CONCLUSIONS: The results revealed moderate acceptance and usability ratings, prompting further app improvement. Significant differences were observed between age and gender. Our results emphasize the need for further improvements in YogiTherapy.

p-STAT3-elevated E3 ubiquitin ligase DTX4 confers the stability of HBV cccDNA by ubiquitinating APOBEC3B in liver.

Background: Clinically, the persistence of HBV cccDNA is the major obstacle in anti-HBV therapy. However, the underlying mechanism of HBV cccDNA is poorly understood. The transcriptional factor STAT3 is able to activate HBV replication in liver. Approach & Results: RNA-Seq analysis demonstrated that cucurbitacin I targeting STAT3 was associated with virus replication in liver. HBV-infected human liver chimeric mouse model and HBV hydrodynamic injection mouse model were established. Then, we validated that cucurbitacin I effectively limited the stability of HBV cccDNA and HBV replication in cells, in which cucurbitacin I enhanced the sensitivity of pegylated interferon α (PEG-IFN α) against HBV via combination in vitro and in vivo. Mechanistically, we identified that cucurbitacin I increased the levels of APOBEC3B to control HBV cccDNA by inhibiting p-STAT3 in cells, resulting in the inhibition of HBV replication. Moreover, RNA-Seq data showed that E3 ubiquitin ligase DTX4 might be involved in the events. Then, we observed that HBV particles could upregulate DTX4 by increasing the levels of p-STAT3 in vitro and in vivo. The p-STAT3-elevated DTX4/male-specific lethal 2 (MSL2) independently and synergistically enhanced the stability of HBV cccDNA by facilitating the ubiquitination degradation of APOBEC3B in cells, leading to the HBV replication. Conclusions: p-STAT3-elevated DTX4 confers the stability of HBV cccDNA and HBV replication by facilitating the ubiquitination degradation of APOBEC3B. Cucurbitacin Ⅰ effectively enhances the sensitivity of PEG-IFN α in anti-HBV therapy by inhibiting the p-STAT3/DTX4/MSL2/APOBEC3B signalling. Our finding provides new insights into the mechanism of HBV cccDNA. The p-STAT3 and DTX4/MSL2 might serve as the therapeutical targets of HBV cccDNA.

The Revolution of Digital Therapeutics (DTx) in the Pharmaceutical Industry and Their Quality Impacts.

An increasing number of developments and trends are driving the expansion of the digital therapeutics (DTx) market in the pharmaceutical industry. Digital therapeutics are therapies intended to treat, diagnose, and prevent diseases by using patient-directed clinically assessed software applications, which can optimize the effectiveness and delivery of healthcare. These digital innovations became important as the world changed, particularly during the coronavirus pandemic. Nowadays pharma companies are getting more comfortable with the idea of digital therapies. The majority of pharmaceutical companies are examining how to incorporate pharmaceuticals and digital therapies into their treatment regimens, leveraging digital tools to enhance patient outcomes and streamline healthcare delivery. A thorough overview of the most recent technological advancements in the creation of digital therapies shows particular technologies that are essential to the market's future growth. Moreover, the evaluation of digital therapeutics by clinical trial and real-world data is outlined. The critical quality attributes of DTx products and the challenges, including data management issues and regulatory obstacles, which make the creation, approval, and marketing of customized medicines more difficult, are covered in this review article. Overall, pharma companies are venturing into the world of digital therapeutics while acknowledging the limitations of the emerging field.

Ubiquitylation of nucleic acids by DELTEX ubiquitin E3 ligase DTX3L.

The recent discovery of non-proteinaceous ubiquitylation substrates broadened our understanding of this modification beyond conventional protein targets. However, the existence of additional types of substrates remains elusive. Here, we present evidence that nucleic acids can also be directly ubiquitylated via ester bond formation. DTX3L, a member of the DELTEX family E3 ubiquitin ligases, ubiquitylates DNA and RNA in vitro and that this activity is shared with DTX3, but not with the other DELTEX family members DTX1, DTX2 and DTX4. DTX3L shows preference for the 3'-terminal adenosine over other nucleotides. In addition, we demonstrate that ubiquitylation of nucleic acids is reversible by DUBs such as USP2, JOSD1 and SARS-CoV-2 PLpro. Overall, our study proposes reversible ubiquitylation of nucleic acids in vitro and discusses its potential functional implications.

l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.

BACKGROUND: Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored. METHODS: Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. RESULTS: l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells. CONCLUSIONS: This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.

Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery.

Traumatic injury to the spinal cord can lead to significant, permanent disability. Mammalian spinal cords are not capable of regeneration; in contrast, adult zebrafish are capable of such regeneration, fully recovering motor function. Understanding the mechanisms underlying zebrafish neuroregeneration may provide useful information regarding endogenous regenerative potential and aid in the development of therapeutic strategies in humans. DELTEX proteins (DTXs) regulate a variety of cellular processes. However, their role in neural regeneration has not been described. We found that zebrafish dtx2, encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous dtx2 mutant fish motor function recovered quicker than that of the wild-type controls. The mutant fish displayed increased ependymo-radial glial cell proliferation and augmented motor neuron formation. Moreover, her gene expression, downstream of Notch signaling, increased in Dtx2 mutants. Notch signaling inactivation by dominant-negative Rbpj abolished the increased ependymo-radial glia proliferation caused by Dtx2 deficiency. These results indicate that ependymo-radial glial proliferation is induced by Dtx2 deficiency by activating Notch-Rbpj signaling to improve spinal cord regeneration and motor function recovery.

Digital Therapeutics in Hearing Healthcare: Evidence-Based Review.

Digital therapeutics (DTx) in hearing research have emerged as a new category of therapies providing evidence-based intervention via digital means, such as software, smartphone apps, or websites. However, although relatively new, they are not well-established. In this article, we review DTx technologies in hearing research fields, focusing on three categories: prevention and diagnosis, aid (assistance), and cure (digital medicine). We observe that most DTx systems require interactions with users (or patients) without the direct support of clinical professionals to obtain or collect medical evidence; this makes training (or education) features crucial to the therapy's success. In this view, this article discusses the education or training functions of the current DTx and their contribution and purposes. The impact of emerging artificial intelligence (AI) on DTx in hearing research is being explored, and the future of DTx concerning AI integration is being discussed. We believe that this work will contribute to a better understanding of the current and future DTx technological advancements and, in particular, shed light on the field of hearing research.

Feasibility and Acceptability Evaluation of a Digital Therapeutic Program for Improving Cancer Prevention: A Quasi-experimental Pre-post Interventional Pilot Study.

Previous studies have proved that healthy behaviors hinder the onset and progression of tumors. Digital therapeutics (DTx), playing a pivotal role in facilitating behavioral adjustments through educational interventions, lifestyle support, and symptom monitoring, contribute to the goal of tumor prevention. We aim to optimize the evaluation of the feasibility and acceptability of DTx for cancer prevention. This involves assessing AITI's daily activity rates and user feedback, and comparing changes in behavioral habits and differences in SF-36 before and after the intervention. In a 4-week trial with 57 participants engaging actively, we found both the average daily activity rate and 4-week retention rate at 35 (61.4%). The USE Questionnaire scores (validity, ease of use, acquisition, and satisfaction) ranged from 68.06 to 83.10, indicating AITI's user-friendliness and acceptability. Furthermore, positive habit changes were noted among participants in exercise and diet (p < 0.0001), suggesting the effectiveness of the DTx approach in modifying behavioral habits related to physical activity and nutrition. This pilot study underscores the potential of DTx in advancing cancer prevention. However, larger and longer studies are needed to comprehensively assess its impact.

Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability.

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.

Effect of Perioperative Docetaxel-induced Limb Edema on Health-related Quality of Life in Patients with Early-stage Breast Cancer: A Prospective Observational Study.

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.

Critical success factors for creating sustainable digital health applications: A systematic review of the German case.

Objective: The Covid-19 pandemic has accelerated the adoption of digital technologies to address social needs, leading to increased investments in digital healthcare applications. Germany implemented a special law called the "Digitales Versorgungsgesetz" (DVG-Digital Supply Act) in 2019, which enables the reimbursement of digital health applications, including digital therapeutics (DTx), through a fast-track process. The Federal Institute for Drugs and Medical Devices (BfArM), the German federal authority responsible for overseeing digital health applications, has implemented legislative adjustments since the law's introduction, which have increased requirements for these applications and potentially led to the removal of some from the directory as well as a slowdown in the addition of new ones. To counteract this trend, this work aimed to identify key success factors for digital health applications (DiGAs). Methods: This research identifies critical success factors through a structured literature review for developing sustainable digital health applications within the European healthcare systems, specifically DiGAs. The study aims to support the ongoing digital transformation in healthcare. Results: The identified success factors that significantly impact the sustainability of DiGAs include patient-centered design, application effectiveness, user-friendliness, and adherence to data protection and information security regulations using standardized approaches. These factors are crucial in preventing the failure of DiGA manufacturers in European countries. Conclusion: By considering and implementing these critical success factors, DiGA manufacturers can enhance their chances of long-term success and contribute to the digital transformation of the healthcare system in Europe.