Innovative Treatment Research Articles

Development and application of a sustainable approach for the determination of 95 pharmaceutical substances and metabolites in urban wastewater by means of ultra-high-performance liquid-chromatography-tandem mass spectrometry

ABSTRACT In the last few years, the interest in pharmaceutical drugs and their metabolites as environmental pollutants is gaining growing importance. Regular monitoring and timely actions are decisive to implement appropriate water resource management strategies and to evaluate the efficiency of traditional or innovative wastewater treatment plants (WWTPs). This study describes the development and validation of an analytical procedure using 10 mL sample volume followed by direct-injection in ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of 95 pharmaceutical drugs and 10 of their main metabolites in wastewater. Adequate sensitivity was recorded for all target analytes, with limits of detection below 5 ng/L for 60 out of 95 analytes and recoveries exceeding 80% for all the analytes under study. A total of 42 target analytes were detected in almost all sites, and limited differences were observed among several pharmaceutical drug arrays found at different sampling sites. In addition, an abatement yield higher than 50% was observed for only 12 of the 42 detected substances. The procedure, which combined direct injection and small sample volume collection, showed great potential and efficiency for the high-performance determination of pharmaceutical drugs in wastewater.

Construction of dual functional CuAl-LDHs nanocomposite loaded with IGF2BP3 siRNA for enhanced therapy of gastric cancer

Gastric cancer (GC) is a prevalent malignancy in China, necessitating innovative treatments. Recent advancements in nucleic acid drugs, particularly small interfering RNAs (siRNAs), have shown promise in therapeutic applications. Biodegradable layered double hydroxides (LDHs), as a class of typical two-dimensional (2D) materials, hold great prospects in biomedical and drug delivery systems. Building on our previous research, which identified the upregulated insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) promoted GC progression, we devised a strategy that leverages the unique properties of LDHs carriers with siRNA therapeutics. Herein, we synthesized CuAl-LDHs containing variable valence metal cations (Cu2+), capable of inducing a Fenton-like reaction in the tumor micro-acid environment (TME) of GC. Subsequently, we constructed si-IGF2BP3/CuAl-LDHs nanocomposites to protect and deliver si-IGF2BP3 via the CuAl-LDHs carrier. The obtained nanocomposites demonstrated significant efficacy in inhibiting GC cell proliferation by silencing the IGF2BP3 gene at both the mRNA and protein levels, accelerating oxidative stress in GC cells through a Fenton-like reaction, and achieving greater suppression of tumor volume than CuAl-LDHs alone. The remarkable anti-tumor effect was attributed to the CuAl-LDHs carrier’s superior siRNA immobilization and delivery capabilities, as well as the catalytic ability of Cu in CuAl-LDHs, facilitating the Fenton-like reaction within TME. Overall, this integrated GC therapy strategy employing LDHs nano-carriers may represent a significant advancement in developing next-generation therapeutic systems. It underscores the potential of LDHs as an effective platform for targeted GC therapy.

A Swine Burn Model for Investigating the Healing Process in Multiple Depth Burn Wounds.

Burn wound healing is a complex and long process. Despite extensive experience, plastic surgeons and specialized teams in burn centers still face significant challenges. Among these challenges, the extent of the burned soft tissue can evolve in the early phase, creating a delicate balance between conservative treatments and necrosing tissue removal. Thermal burns are the most common type, and burn depth varies depending on multiple parameters, such as temperature and exposure time. Burn depth also varies in time, and the secondary aggravation of the "shadow zone" remains a poorly understood phenomenon. In response to these challenges, several innovative treatments have been studied, and more are in the early development phase. Nanoparticles in modern wound dressings and artificial skin are examples of these modern therapies still under evaluation. Taken together, both burn diagnosis and burn treatments need substantial advancements, and research teams need a reliable and relevant model to test new tools and therapies. Among animal models, swine are the most relevant because of their strong similarities in skin structure with humans. More specifically, Yucatan minipigs show interesting features such as melanin pigmentation and slow growth, allowing for studying high phototypes and long-term healing. This article aims to describe a reliable and reproducible protocol to study multi-depth burn wounds in Yucatan minipigs, enabling long-term follow-up and providing a relevant model for diagnosis and therapeutic studies.

Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.

Ventricular arrhythmias are the leading cause of sudden cardiac death in patients after myocardial infarction (MI). Connexin43 (Cx43) is the most important gap junction channel-forming protein in cardiomyocytes. Dysfunction of Cx43 contributes to impaired myocardial conduction and the development of ventricular arrhythmias. Following an MI, Cx43 undergoes structural remodeling, including expression abnormalities, and redistribution. These alterations detrimentally affect intercellular communication and electrical conduction within the myocardium, thereby increasing the susceptibility to post-infarction ventricular arrhythmias. Emerging evidence suggests that post-translational modifications play essential roles in Cx43 regulation after MI. Therefore, Cx43-targeted management has the potential to be a promising protective strategy for the prevention and treatment of post infarction ventricular arrhythmias. In this article, we primarily reviewed the regulatory mechanisms of Cx43 mediated post-translational modifications on post-infarction ventricular arrhythmias. Furthermore, Cx43-targeted therapy have also been discussed, providing insights into an innovative treatment strategy for ventricular arrhythmias after MI.

Targeted DNA Methylation Editing Using an All-in-One System Establishes Paradoxical Activation of EBF3.

Cutaneous melanoma is rapidly on the rise globally, surpassing the growth rate of other cancers, with metastasis being the primary cause of death in melanoma patients. Consequently, understanding the mechanisms behind this metastatic process and exploring innovative treatments is of paramount importance. Recent research has shown promise in unravelling the role of epigenetic factors in melanoma progression to metastasis. While DNA hypermethylation at gene promoters typically suppresses gene expression, we have contributed to establishing the newly understood mechanism of paradoxical activation of genes via DNA methylation, where high methylation coincides with increased gene activity. This mechanism challenges the conventional paradigm that promoter methylation solely silences genes, suggesting that, for specific genes, it might actually activate them. Traditionally, altering DNA methylation in vitro has involved using global demethylating agents, which is insufficient for studying the mechanism and testing the direct consequence of gene methylation changes. To investigate promoter hypermethylation and its association with gene activation, we employed a novel approach utilising a CRISPR-SunTag All-in-one system. Here, we focused on editing the DNA methylation of a specific gene promoter segment (EBF3) in melanoma cells using the All-in-one system. Using bisulfite sequencing and qPCR with RNA-Seq, we successfully demonstrated highly effective methylation and demethylation of the EBF3 promoter, with subsequent gene expression changes, to establish and validate the paradoxical role of DNA methylation. Further, our study provides novel insights into the function of the EBF3 gene, which remains largely unknown. Overall, this study challenges the conventional view of methylation as solely a gene-silencing mechanism and demonstrates a potential function of EBF3 in IFN pathway signalling, potentially uncovering new insights into epigenetic drivers of malignancy and metastasis.

The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Proguanil Suppresses Breast Tumor Growth In Vitro and In Vivo by Inducing Apoptosis via Mitochondrial Dysfunction.

Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations.

Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells' Escape from the Bone Marrow Microenvironment.

Recent therapeutic advancements have markedly increased the survival rates of individuals with multiple myeloma (MM), doubling survival compared to pre-2000 estimates. This progress, driven by highly effective novel agents, suggests a growing population of MM survivors exceeding the 10-year mark post-diagnosis. However, contemporary clinical observations indicate potential trends toward more aggressive relapse phenotypes, characterized by extramedullary disease and dominant proliferative clones, despite these highly effective treatments. To build upon these advances, it is crucial to develop models of MM evolution, particularly focusing on understanding the biological mechanisms behind its development outside the bone marrow. This comprehensive understanding is essential to devising innovative treatment strategies. This review emphasizes the role of 3D models, specifically addressing the bone marrow microenvironment and development of extramedullary sites. It explores the current state-of-the-art in MM modelling, highlighting challenges in replicating the disease's complexity. Recognizing the unique demand for accurate models, the discussion underscores the potential impact of these advanced 3D models on understanding and combating this heterogeneous and still incurable disease.

Uncovering Structure-Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments.

The rapidly evolving psychedelic industry has garnered considerable attention due to 3,4-methylenedioxymethamphetamine-assisted psychotherapy's ground-breaking success in treating moderate-to-severe Post-traumatic Stress Disorder in two Phase 3 clinical trials. This has opened Pandora's box for the development of innovative therapeutic modalities. Of particular interest are the phenethylamines and their ability to inhibit monoamine transporters. In this study, we employed the quantitative structure-activity relationship methodology to develop three vigorous models for the reuptake of serotonin, dopamine, and norepinephrine through monoamine transporters. These models were thoroughly validated using various criteria, including fitting (R2DAT = 0.869, R2SERT = 0.828, and R2NET = 0.887), internal (Q2looDAT = 0.795, Q2looSERT = 0.784, and Q2looNET = 0.820), and external (RMSEextDAT = 0.373, R2extDAT = 0.831, RMSEextSERT = 0.200, R2extSERT = 0.955, RMSEextNET = 0.318, and R2extNET = 0.711) criteria.

Overview of Iron-Coated Dynamic Membrane for Water Treatment

The increasing global demand for clean and potable water has prompted the exploration of innovative water treatment technologies. Pre-deposited dynamic membrane systems, a novel approach in wastewater treatment, have gained attention due to their versatility and effectiveness. This mini-review focuses on the application of iron oxide-based dynamic membranes in water treatment processes. It discusses the impact, formation, properties, and various water treatment applications of iron oxide dynamic membranes, highlighting their potential to revolutionize the field of sustainable water treatment.

Antibacterial Defective‐ZIF‐8/PPY/BC‐Based Flexible Electronics as Stress‐Strain and NO2 Gas Sensors

AbstractIntelligent wearable sensors play a crucial role in the detection of toxic gases and monitoring physiological signals, thereby effectively ensuring environmental and personal health safety. Nonetheless, achieving the requirements for antibacterial properties, comfortable wear, and multifunctional detection remains a major challenge. In this study, a novel Def‐ZIF‐8/PPY/BC‐based flexible sensor is developed by in situ growth of zeolitic imidazolate frameworks‐8 (ZIF‐8) and polypyrrole (PPY) on bacterial cellulose (BC), followed by water immersion. The Def‐ZIF‐8/PPY/BC‐based flexible sensor demonstrates effective dual‐sensitivity responses to nitrogen dioxide (NO2) toxic gas and stress‐strain behaviors at room temperature. The structural characterization and theoretical calculations affirm that the innovative water treatment method successfully introduces defects into ZIF‐8, resulting in a significant 2.57‐fold improvement in response intensity to 80 ppm NO2. Stress‐strain sensing performance analysis reveals that the Def‐ZIF‐8/PPY/BC‐based flexible sensor exhibited high sensitivity (6.44 kPa−1), rapid response and recovery times (0.7/0.4 s), and exceptional cyclic stability (8000 cycles). Further, the inhibitory effect of ZIF‐8 on common bacterial strains contributes to the exceptional antibacterial properties (antibacterial rate exceeding 99%) of the Def‐ZIF‐8/PPY/BC based on the flexible sensor. This study offers a significant advancement in metal‐organic framework defect engineering and provides an effective strategy for developing multifunctional wearable sensors.

Advancements in NSCLC: From Pathophysiological Insights to Targeted Treatments.

With the global incidence of non-small cell lung cancer (NSCLC) on the rise, the development of innovative treatment strategies is increasingly vital. This review underscores the pivotal role of precision medicine in transforming NSCLC management, particularly through the integration of genomic and epigenomic insights to enhance treatment outcomes for patients. We focus on the identification of key gene mutations and examine the evolution and impact of targeted therapies. These therapies have shown encouraging results in improving survival rates and quality of life. Despite numerous gene mutations being identified in association with NSCLC, targeted treatments are available for only a select few. This paper offers an exhaustive analysis of the pathogenesis of NSCLC and reviews the latest advancements in targeted therapeutic approaches. It emphasizes the ongoing necessity for research and development in this domain. In addition, we discuss the current challenges faced in the clinical application of these therapies and the potential directions for future research, including the identification of novel targets and the development of new treatment modalities.

Willingness to pay for an mRNA-based anti-cancer treatment: results from a contingent valuation study in Israel.

mRNA technology is currently being investigated for a range of oncology indications. We assessed the willingness to pay (WTP) of the general population in Israel for a hypothetical novel mRNA-based treatment for oncology indications. We used a contingent valuation methodology to elicit WTP using a web-based questionnaire. A sample of adult participants were presented with a hypothetical scenario in which an mRNA-based intervention increased the likelihood of a cure for various cancer types from 20% to 40% (half of the sample), or 60% (the other half of the sample). 531 respondents completed the questionnaire. The mean, median and mode WTP for the proposed hypothetical treatment in both scenarios were ILS65,000 (± ILS114,000), ILS20,000 and ILS50,000, respectively (1USD = 3.4ILS). The WTP was skewed towards zero, and 9.6% of the respondents were not willing to pay any amount. WTP higher amounts was significantly associated with higher income (p < 0.01), self-reported good health (p < 0.05), supplementary health insurance (p < 0.05), Jews compared to other populations (p < 0.01), interest in technology (p < 0.001) and a tendency to adopt medical innovations (p < 0.001). No statistical difference between the 40% vs. the 60% potential cure scenarios was found. Logistic and OLS regressions indicated that age, religion, income, and interest in adopting medical innovations were the best predictors of respondents' WTP. Despite the scientific breakthroughs in oncology treatment over the last few decades, many types of cancer are still incurable. Given the expected development of innovative mRNA-based treatments for cancer, these results should inform policymakers, the pharmaceutical industry and other stakeholders on the future coverage and reimbursement of these technologies incorporating patients' and societal views. To date, WTP considerations have not been given much weight in prioritization of drug reimbursement processes, neither in Israel nor in other countries. As a pioneer in adoption of the mRNA technology, Israel can also lead the incorporation of WTP considerations in this field.

Microbiome Dynamics: A Paradigm Shift in Combatting Infectious Diseases.

Infectious diseases have long posed a significant threat to global health and require constant innovation in treatment approaches. However, recent groundbreaking research has shed light on a previously overlooked player in the pathogenesis of disease-the human microbiome. This review article addresses the intricate relationship between the microbiome and infectious diseases and unravels its role as a crucial mediator of host-pathogen interactions. We explore the remarkable potential of harnessing this dynamic ecosystem to develop innovative treatment strategies that could revolutionize the management of infectious diseases. By exploring the latest advances and emerging trends, this review aims to provide a new perspective on combating infectious diseases by targeting the microbiome.

Optimal intertemporal curative drug expenses: The case of hepatitis C in France

We study intertemporal tradeoffs that health authorities face when considering the control of an epidemic using innovative curative medical treatments. We set up a dynamically controlled susceptible–infected–recovered (SIR) model for an epidemic in which patients can be asymptomatic, and we analyze the optimality conditions of the sequence of cure expenses decided by health authorities at the onset of the drug innovation process. We show that analytical conclusions are ambiguous because of their dependence on parameter values. As an application, we focus on the case study of hepatitis C, the treatment for which underwent a major upheaval when curative drugs were introduced in 2014. We calibrate our controlled SIR model using French data and simulate optimal policies. We show that the optimal policy entails some front loading of the intertemporal budget. The analysis demonstrates how beneficial intertemporal budgeting can be compared to non-forward-looking constant budget allocation.

New and future treatment approaches for allergic conjunctivitis

In severe and recurrent ocular allergies conventional ophthalmic drugs can reach their limits, especially in chronic forms. The first novel immunomodulators and biologicals are already in clinical use and could provide relief. Based on the immunopathophysiological mechanisms of ocular allergies, possible targets for innovative treatment approaches are presented. An overview of promising new and future immunomodulators and biologicals and their modes of action is also given. Current reviews on ocular allergies and the treatment of systemic allergic diseases were screened. Case reports on the treatment of ocular allergy using immunomodulators and biologicals were analyzed. The clinical relevance and possible applications are presented. In chronic forms of ocular allergies, complex ocular surface inflammatory responses mediated via immunoglobulinE (IgE), mast cells, CD4-positive type 2 T‑helper cells and eosinophilic granulocytes are predominant. CyclosporineA 0.1% eyedrops have been approved in Europe since 2018 for children aged 4 years and older with severe vernal keratoconjunctivitis (VKC). In addition, case reports present promising data on the systemic off-label use of biologicals, such as dupilumab or omalizumab, in refractory VKC or atopic keratoconjunctivitis (AKC). Aprofound understanding of the immunopathophysiology of ocular allergies is necessary to detect further targets for future immunomodulators and biologicals. Currently, immunomodulatory therapy remains limited to cyclosporineA eyedrops. Other immunomodulatory agents, such as tacrolimus and biologicals can only be used off-label. Further studies on the controlled clinical use of these substances in the treatment of VKC or AKC are underway.

Innovative Anodic Treatment to Obtain Stable Metallic Silver Micropatches on TiO2 Nanotubes: Structural, Electrochemical, and Photochemical Properties.

Electrochemical modification of the Ti surface to obtain TiO2 nanotubes (NT-Ti) has been proposed to enhance osseointegration in medical applications. However, susceptibility to microbial adhesion, linked to biomaterial-associated infections, and the high TiO2 band gap energy, which allows light absorption almost exclusively in the ultraviolet (UV) region, limit its applications. Modifying the TiO2 semiconductor with metals such as Ag has been suggested both for antimicrobial purposes and for absorbing light in the visible region. The formation of NT-Ti with Ag micropatches (Ag-NT-Ti) is pursued with the objective of enhancing the stability of the deposits and preventing cytotoxic levels of Ag cellular uptake. The innovative process proposed here involves immersing NT-Ti in a AgNO3 solution as the initial step. Diverging from previously reported electrochemical methods, this process incorporates anodization within the TiO2 oxide formation region instead of cathodic reduction generally employed by other researchers. The final step encompasses an annealing treatment. The treatments result in the in situ Ag1+ reduction and formation of stable and active micropatches of metallic Ag on the NT-Ti surface. Scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), Raman, diffuse reflectance spectroscopy (DRS), wettability assessment, and electrochemical characterizations were conducted to evaluate the modified surfaces. The well-known properties of NT-Ti surfaces were enhanced, leading to improved photocatalytic activity across both visible and UV regions, significant stability against detachment, and controlled release of Ag1+ for promising antimicrobial effects.

Transferring an extremely premature infant to an extra-uterine life support system: a prospective view on the obstetric procedure.

To improve care for extremely premature infants, the development of an extrauterine environment for newborn development is being researched, known as Artificial Placenta and Artificial Womb (APAW) technology. APAW facilitates extended development in a liquid-filled incubator with oxygen and nutrient supply through an oxygenator connected to the umbilical vessels. This setup is intended to provide the optimal environment for further development, allowing further lung maturation by delaying gas exposure to oxygen. This innovative treatment necessitates interventions in obstetric procedures to transfer an infant from the native to an artificial womb, while preventing fetal-to-neonatal transition. In this narrative review we analyze relevant fetal physiology literature, provide an overview of insights from APAW studies, and identify considerations for the obstetric procedure from the native uterus to an APAW system. Lastly, this review provides suggestions to improve sterility, fetal and maternal well-being, and the prevention of neonatal transition.

Unveiling the Role of Endothelial Dysfunction: A Possible Key to Enhancing Catheter Ablation Success in Atrial Fibrillation.

Atrial fibrillation, a prevalent type of arrhythmia, is increasingly contributing to the economic burden on healthcare systems. The development of innovative treatments, notably catheter ablation, has demonstrated both impressive and promising outcomes. However, these treatments have not yet fully replaced pharmaceutical approaches, primarily due to the relatively high incidence of atrial fibrillation recurrence post-procedure. Recent insights into endothelial dysfunction have shed light on its role in both the onset and progression of atrial fibrillation. This emerging understanding suggests that endothelial function might significantly influence the effectiveness of catheter ablation. Consequently, a deeper exploration into endothelial dynamics could potentially elevate the status of catheter ablation, positioning it as a primary treatment option for atrial fibrillation.

Anti-CD38 targeted nanotrojan horses stimulated by acoustic waves as therapeutic nanotools selectively against Burkitt’s lymphoma cells

The horizon of nanomedicine research is moving toward the design of therapeutic tools able to be completely safe per se, and simultaneously be capable of becoming toxic when externally activated by stimuli of different nature. Among all the stimuli, ultrasounds come to the fore as an innovative approach to produce cytotoxicity on demand in presence of NPs, without invasiveness, with high biosafety and low cost. In this context, zinc oxide nanoparticles (NPs) are among the most promising metal oxide materials for theranostic application due to their optical and semi-conductor properties, high surface reactivity, and their response to ultrasound irradiation. Here, ZnO nanocrystals constitute the stimuli-responsive core with a customized biomimicking lipidic shielding, resembling the composition of natural extracellular vesicles. This core–shell hybrid structure provides high bio- and hemocompatibility towards healthy cells and is here proofed for the treatment of Burkitt’s Lymphoma. This is a very common haematological tumor, typically found in children, for which consolidated therapies are so far the combination of chemo-therapy drugs and targeted immunotherapy. In this work, the proposed safe-by-design antiCD38-targeted hybrid nanosystem exhibits an efficient selectivity toward cancerous cells, and an on-demand activation, leading to a significant killing efficacy due to the synergistic interaction between US and targeted hybrid NPs. Interestingly, this innovative treatment does not significantly affect healthy B lymphocytes nor a negative control cancer cell line, a CD38- acute myeloid leukemia, being thus highly specific and targeted. Different characterization and analyses confirmed indeed the effective formation of targeted hybrid ZnO NPs, their cellular internalization and the damages produced in Burkitt’s Lymphoma cells only with respect to the other cell lines. The presented work holds promises for future clinical applications, as well as translation to other tumor types.Graphical abstract