Challenges For Clinical Translation Research Articles

The Potential Pharmacological Effects of Natural Product Withaferin A in Cancer: Opportunities and Challenges for Clinical Translation.

Cancer is one of the biggest health concerns with a complex pathophysiology. Currently, available chemotherapeutic drugs are showing deleterious side effects, and tumors often show resistance to treatment. Hence, extensive research is required to develop new treatment strategies to fight against cancer. Natural resources from plants are at the forefront of hunting novel drugs to treat various types of cancers. Withaferin A (WA) is a naturally occurring withanolide, a biologically active component obtained from the plant Ashwagandha. Various in vitro and in vivo oncological studies have reported that Withaferin A (WA) has shown protection from cancer. WA shows its activity by inhibiting the growth and proliferation of malignant cells, apoptosis, and inhibiting angiogenesis, metastasis, and cancer stem cells (CSCs). In addition, WA also showed chemo- and radio-sensitizing properties. Besides the beneficiary pharmacological activities of WA, a few aspects like pharmacokinetic properties, safety, and toxicity studies are still lacking, hindering this potent natural product from entering clinical development. In this review, we have summarized the various pharmacological mechanisms shown by WA in in vitro and in vivo cancer studies and the challenges that must be overcome for this potential natural product's clinical translation to be effective.

Piezoelectric nanomaterials: latest applications in biomedicine and challenges in clinical translation.

Tweetable abstract Nano-sized piezoelectric materials allow for precise interaction with living systems to local deliver electrical cues. Recent innovations enhance their potential in tissue engineering and regenerative medicine.

Clinical translation of pluripotent stem cell-based therapies: successes and challenges.

The translational stem cell research field has progressed immensely in the past decade. Development and refinement of differentiation protocols now allows the generation of a range of cell types, such as pancreatic β-cells and dopaminergic neurons, from human pluripotent stem cells (hPSCs) in an efficient and good manufacturing practice-compliant fashion. This has led to the initiation of several clinical trials using hPSC-derived cells to replace lost or dysfunctional cells, demonstrating evidence of both safety and efficacy. Here, we highlight successes from some of the hPSC-based trials reporting early signs of efficacy and discuss common challenges in clinical translation of cell therapies.

Cell Membrane Camouflaged Biomimetic Nanoparticles as a Versatile Platform for Brain Diseases Treatment.

Although there are various advancements in biomedical in the past few decades, there are still challenges in the treatment of brain diseases. The main difficulties are the inability to deliver a therapeutic dose of the drug to the brain through the blood-brain barrier (BBB) and the serious side effects of the drug. Thus, it is essential to select biocompatible drug carriers and novel therapeutic tools to better enhance the effect of brain disease treatment. In recent years, biomimetic nanoparticles (BNPs) based on natural cell membranes, which have excellent biocompatibility and low immunogenicity, are widely used in the treatment of brain diseases to enable the drug to successfully cross the BBB and target brain lesions. BNPs can prolong the circulation time in vivo, are more conducive to drug aggregation in brain lesions. Cell membranes (CMs) from cancer cells (CCs), red blood cells (RBCs), white blood cells (WBCs), and so on are used as biomimetic coatings for nanoparticles (NPs) to achieve the ability to target, evade clearance, or stimulate the immune system. This review summarizes the application of different cell sources as BNPs coatings in the treatment of brain diseases and discusses the possibilities and challenges of clinical translation.

Unconditioned stimulus devaluation decreases the generalization of costly safety behaviors

Safety behaviors are often maladaptive in clinical anxiety as they typically persist without realistic threat and cause various impairments. In the laboratory, safety behaviors are modelled by responses to a conditioned stimulus (CS) that reduce the occurrence of an expected aversive unconditioned stimulus (US). Preliminary evidence suggests that US devaluation, a procedure that decreases US aversiveness, devalues the threat value of the CS and thus diminishes safety behaviors to the CS. This study (n = 78) aimed to extend this finding and examined whether US-devaluation can reduce the generalization of safety behaviors to various stimuli. After acquiring safety behaviors to CSs of different categories, the US predicted by one CS category was devalued. In test, participants showed a selective reduction in safety behaviors to novel stimuli of the devalued CS category, reflecting a decrease in generalization of safety behaviors. Trait anxiety was associated with persistent generalized safety behaviors to novel stimuli of the devalued category. We discuss how US devaluation may improve treatment outcome but also the challenges of clinical translation.

Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation.

The safety and efficacy of both cell and gene therapies have been demonstrated in numerous preclinical and clinical trials. Chimeric antigen receptor T (CAR-T) cell therapy, which leverages the technologies of both cell and gene therapies, has also shown great promise for treating various cancers. Advancements in pertinent fields have also highlighted challenges faced while manufacturing cell and gene therapy products. Potential problems and obstacles must be addressed to ease the clinical translation of individual therapies. Literature reviews of representative cell-based, gene-based, and cell-based gene therapies with regard to their general manufacturing processes, the challenges faced during manufacturing, and QC specifications are limited. We review the general manufacturing processes of cell and gene therapies, including those involving mesenchymal stem cells, viral vectors, and CAR-T cells. The complexities associated with the manufacturing processes and subsequent QC/validation processes may present challenges that could impede the clinical progression of the products. This article addresses these potential challenges. Further, we discuss the use of the manufacturing model and its impact on cell and gene therapy.

Integrating Artificial Intelligence for Academic Advanced Therapy Medicinal Products: Challenges and Opportunities

Cell and gene therapies represent promising new treatment options for many diseases, but also face challenges for clinical translation and delivery. Hospital-based GMP facilities enable rapid bench-to-bedside development and patient access but require significant adaptation to implement pharmaceutical manufacturing in healthcare infrastructures constrained by space, regulations, and resources. This article reviews key considerations, constraints, and solutions for establishing hospital facilities for advanced therapy medicinal products (ATMPs). Technologies like process analytical technology (PAT), continuous manufacturing, and artificial intelligence (AI) can aid these facilities through enhanced process monitoring, control, and automation. However, quality systems tailored for product quality rather than just compliance, and substantial investment in infrastructure, equipment, personnel, and multi-departmental coordination, remain crucial for successful hospital ATMP facilities and to drive new therapies from research to clinical impact.

PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance.

The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings. Using the ULCAN portal, we noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations. Our study emphasized the connection between PROX1 and α-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship. PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition.

Collation of fullerenes and carbon nanotubes with genistein for synergistic anti-Alzheimer's activity by amyloid-β deaggregation

This research study aimed to compare the therapeutic potential of two pharmacologically-active carbon-based nanocarriers, Fullerene (C60) and Multi-wall carbon nanotubes (MWCNTs), both loaded with genistein (GEN), for their synergistic action on amyloid-β (Aβ) plaques in Alzheimer's disease. Utilizing a 32 Factorial design with Design Expert® software, the researchers optimized the formulations. The optimized batch OPC60 and OP-MWCNT displayed particle sizes of 444.02 ± 1.23 nm and 236.91 ± 1.22 nm, respectively, with excellent encapsulation efficiencies of 86.13 ± 2.68 % and 85.13 ± 2.89 %. Both formulations exhibited favourable in-vitro release profiles in brain pH (7.2), with OPC60 and OP-MWCNTs releasing 83.25 ± 0.36 % and 87.38 ± 0.49 %, respectively. Ex-vivo and in-vivo brain distribution studies on male Wistar rats demonstrated successful controlled release of GEN in the brain through intranasal administration. The formulations permeated the nasal membrane mainly via receptor-mediated endocytosis, involving scavenger receptor class B type 1 (SR-B1). Pharmacokinetic analysis yielded parameters for OPC60, including AUC0-24 of 6688 μgh/L, Cmax of 321 ± 4.67 μg, Tmax of 24 h, and T1/2 of 6.7 h. For OP-MWCNTs, the parameters were AUC0-24 of 5942 μgh/L, Cmax of 339.41 ± 2.84 μg, Tmax of 24 h, and T1/2 of 9.4 h. Both formulations showed promising potential for reversing Alzheimer's disease and could serve as viable alternatives soon. Further research is warranted to understand the mechanisms underlying their therapeutic effects and address safety and clinical translation challenges for large-scale production and medical applications.

Advanced Nanomaterials in Medical 3D Printing.

3D printing is now recognized as a significant tool for medical research and clinical practice, leading to the emergence of medical 3D printing technology. It is essential to improve the properties of 3D-printed products to meet the demand for medical use. The core of generating qualified 3D printing products is to develop advanced materials and processes. Taking advantage of nanomaterials with tunable and distinct physical, chemical, and biological properties, integrating nanotechnology into 3D printing creates new opportunities for advancing medical 3D printing field. Recently, some attempts are made to improve medical 3D printing through nanotechnology, providing new insights into developing advanced medical 3D printing technology. With high-resolution 3D printing technology, nano-structures can be directly fabricated for medical applications. Incorporating nanomaterials into the 3D printing material system can improve the properties of the 3D-printed medical products. At the same time, nanomaterials can be used to expand novel medical 3D printing technologies. This review introduced the strategies and progresses of improving medical 3D printing through nanotechnology and discussed challenges in clinical translation.

Engineering a Novel Modular Adenoviral mRNA Delivery Platform Based on Tag/Catcher Bioconjugation.

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, the mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors integrating Tag/Catcher proteins at specific locales on the Ad capsid proteins, allowing us to anchor mRNA to the surface of engineered Ad viruses. In proof-of-concept studies, the Ad-mRNA platform successfully mediated mRNA delivery and could be optimized via the highly flexible modular design of both the Ad-mRNA and protein bioconjugation systems.

Bridging the Translational Gap in Heart Failure Research: Using Human iPSC-derived Cardiomyocytes to Accelerate Therapeutic Insights.

Heart failure (HF) remains a leading cause of death worldwide, with increasing prevalence and burden. Despite extensive research, a cure for HF remains elusive. Traditionally, the study of HF's pathogenesis and therapies has relied heavily on animal experimentation. However, these models have limitations in recapitulating the full spectrum of human HF, resulting in challenges for clinical translation. To address this translational gap, research employing human cells, especially cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs), offers a promising solution. These cells facilitate the study of human genetic and molecular mechanisms driving cardiomyocyte dysfunction and pave the way for research tailored to individual patients. Further, engineered heart tissues combine hiPSC-CMs, other cell types, and scaffold-based approaches to improve cardiomyocyte maturation. Their tridimensional architecture, complemented with mechanical, chemical, and electrical cues, offers a more physiologically relevant environment. This review explores the advantages and limitations of conventional and innovative methods used to study HF pathogenesis, with a primary focus on ischemic HF due to its relative ease of modeling and clinical relevance. We emphasize the importance of a collaborative approach that integrates insights obtained in animal and hiPSC-CMs-based models, along with rigorous clinical research, to dissect the mechanistic underpinnings of human HF. Such an approach could improve our understanding of this disease and lead to more effective treatments.

Organic Sonodynamic Materials for Combination Cancer Immunotherapy.

Sonodynamic therapy (SDT) is a promising non-invasive therapeutic modality to treat deep-seated tumors owing to the good tissue penetration ability and spatiotemporal controllability of ultrasound (US); however, the low sonodynamic activity and potential side effects greatly limit its clinical translation. Cancer immunotherapy that leverages the immune system to fight against cancer has great potential to synergize with SDT for the treatment of cancer with high efficiency and safety. In this review, the convergence of SDT with cancer immunotherapy to exert their merits and break through the limitations of combination cancer sono-immunotherapy are discussed. The focus is on the development and construction of organic materials with high sonodynamic activity and immunotherapeutic efficiency. These organic materials not only induce immunogenic cell death to improve tumor immunogenicity via SDT but also activate antitumor immunity via immuno-oncology drug-mediated immune pathway modulation. The combination of various immuno-oncology drugs with organic sonosensitizers is categorized and discussed along with the prospects and challenges for clinical translation.

Redox-Responsive Polymeric Nanoparticle for Nucleic Acid Delivery and Cancer Therapy: Progress, Opportunities, and Challenges.

Cancer development and progression of cancer are closely associated with the activation of oncogenes and loss of tumor suppressor genes. Nucleic acid drugs (e.g., siRNA, mRNA, and DNA) are widely used for cancer therapy due to their specific ability to regulate the expression of any cancer-associated genes. However, nucleic acid drugs are negatively charged biomacromolecules that are susceptible to serum nucleases and cannot cross cell membrane. Therefore, specific delivery tools are required to facilitate the intracellular delivery of nucleic acid drugs. In the past few decades, a variety of nanoparticles (NPs) are designed and developed for nucleic acid delivery and cancer therapy. In particular, the polymeric NPs in response to the abnormal redox status in cancer cells have garnered much more attention as their potential in redox-triggered nanostructure dissociation and rapid intracellular release of nucleic acid drugs. In this review, the important genes or signaling pathways regulating the abnormal redox status in cancer cells are briefly introduced and the recent development of redox-responsive NPs for nucleic acid delivery and cancer therapy is systemically summarized. The future development of NPs-mediated nucleic acid delivery and their challenges in clinical translation are also discussed.

Advancements in Biotechnology and Stem Cell Therapies for Breast Cancer Patients.

This comprehensive review article examines the integration of biotechnology and stem cell therapy in breast cancer diagnosis and treatment. It discusses the use of biotechnological tools such as liquid biopsies, genomic profiling, and imaging technologies for accurate diagnosis and monitoring of treatment response. Stem cell-based approaches, their role in modeling breast cancer progression, and their potential for breast reconstruction post-mastectomy are explored. The review highlights the importance of personalized treatment strategies that combine biotechnological tools and stem cell therapies. Ethical considerations, challenges in clinical translation, and regulatory frameworks are also addressed. The article concludes by emphasizing the potential of integrating biotechnology and stem cell therapy to improve breast cancer outcomes, highlighting the need for continued research and collaboration in this field.

Surface Modification of Metallic Nanoparticles for Targeting Drugs

This review focuses on the surface modification of metallic nanoparticles for targeted drug delivery. Metallic nanoparticles, owing to their unique size, stability, and payload capacity, have emerged as promising drug carriers. However, their application necessitates surface modification to enable precise targeting. Various strategies, such as polymer coating methods, the use of functional groups, and bio-conjugation with targeting ligands, are explored. The review also discusses the selection of ligands based on target receptors, active and passive targeting approaches, and stimuli-responsive targeting. It further delves into the challenges of translating these strategies to clinical settings, including scalability, toxicity, and regulatory hurdles. The surface modification of metallic nanoparticles is a promising avenue for targeted drug delivery. Various strategies, including polymer coating, functionalization with specific groups, and bioconjugation with targeting ligands, have been explored to enhance the therapeutic potential of these nanoparticles. The challenges in clinical translation, continuous advancements in nanoparticle synthesis, and surface modification techniques offer a positive outlook for the future of targeted metallic nanoparticle systems. Despite the promising potential of metallic nanoparticles in drug delivery, there are several challenges that need to be addressed for their successful clinical translation. These include scalable fabrication and functionalization of nanoparticles, toxicity concerns, and regulatory hurdles. However, continuous advancements in nanoparticle synthesis and surface modification techniques are expected to overcome these challenges in the near future.

Challenges of clinical translation from single‐cell sequencing to measures in clinical biochemistry of haematology: Definition of immune cell identities

AbstractPeripheral immune cells play important roles in the maintenance of systemic and microenvironmental hemostasis. Measurements of circulating blood cells by single‐cell RNA sequencing (scRNA‐seq) were proposed as one of the routine measures in the clinical biochemistry of haematology. Out of translational challenges, defining precise identities of cell subsets and states is more difficult, due to the complexity of immune cell development, location, regulation, function, and metabolism. It is also a challenge to precisely interpret the clinical significance and impact of each cell identity marker gene panel (ciMGPs). ciMGPs have the potential to advance the understanding of systemic responses to the disease, identify disease‐specific biomarkers and define cell heterogeneity. Recently, a large number of peripheral cell subsets and expanding/activating states have been identified and validated for use in the fast developments in clinical single‐cell biomedicine. Defining the specificity, measurability and repeatability of cell subsets/states is important for the translation of peripheral scRNA‐seq in clinical haematology and biochemistry. The development of standard operating procedures and the performance of clinical trials in large populations of various ages, diseases, and therapies will promote the clinical translation of ciMGPs to measures. Thus, defining cell subset/state identities will provide the multi‐dimensional and comprehensive readouts of systemic immune cells, the precision monitoring of immune dynamics, and a deeper understanding of the disease and response to therapy.

Noninvasive Assessment of Diabetic Kidney Disease With MRI: Hype or Hope?

Owing to the increasing prevalence of diabetic mellitus, diabetic kidney disease (DKD) is presently the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early identification and disease interception is of paramount clinical importance for DKD management. However, current diagnostic, disease monitoring and prognostic tools are not satisfactory, due to their low sensitivity, low specificity, or invasiveness. Magnetic resonance imaging (MRI) is noninvasive and offers a host of contrast mechanisms that are sensitive to pathophysiological changes and risk factors associated with DKD. MRI tissue characterization involves structural and functional information including renal morphology (kidney volume (TKV) and parenchyma thickness using T1- or T2-weighted MRI), renal microstructure (diffusion weighted imaging, DWI), renal tissue oxygenation (blood oxygenation level dependent MRI, BOLD), renal hemodynamics (arterial spin labeling and phase contrast MRI), fibrosis (DWI) and abdominal or perirenal fat fraction (Dixon MRI). Recent (pre)clinical studies demonstrated the feasibility and potential value of DKD evaluation with MRI. Recognizing this opportunity, this review outlines key concepts and current trends in renal MRI technology for furthering our understanding of the mechanisms underlying DKD and for supplementing clinical decision-making in DKD. Progress in preclinical MRI of DKD is surveyed, and challenges for clinical translation of renal MRI are discussed. Future directions of DKD assessment and renal tissue characterization with (multi)parametric MRI are explored. Opportunities for discovery and clinical break-through are discussed including biological validation of the MRI findings, large-scale population studies, standardization of DKD protocols, the synergistic connection with data science to advance comprehensive texture analysis, and the development of smart and automatic data analysis and data visualization tools to further the concepts of virtual biopsy and personalized DKD precision medicine. We hope that this review will convey this vision and inspire the reader to become pioneers in noninvasive assessment and management of DKD with MRI. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Revitalizing Cytokine-Based Cancer Immunotherapy through Advanced Delivery Systems.

Cytokines can coordinate robust immune responses, holding great promise as therapeutics against infections, autoimmune diseases, and cancers. In cancer treatment, numerous pro-inflammatory cytokines have displayed promising efficacy in preclinical studies. However, their clinical application is hindered by poor pharmacokinetics, significant toxicity and unsatisfactory anticancer efficacy. Thus, while IFN-α and IL-2 are approved for specific cancer treatments, other cytokines still remain subject of intense investigation. To accelerate the application of cytokines as cancer immunotherapeutics, strategies need to be directed to improve their safety and anticancer performance. In this regard, delivery systems could be used to generate innovative therapies by targeting the cytokines or nucleic acids, such as DNA and mRNA, encoding the cytokines to tumor tissues. This review centers on these innovative delivery strategies for cytokines, summarizing key approaches, such as gene delivery and protein delivery, and critically examining their potential and challenges for clinical translation.

Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases.

Ocular drug delivery is a challenging field due to the unique anatomical and physiological barriers of the eye. Biodegradable polymers have emerged as promising tools for efficient and controlled drug delivery in ocular diseases. This review provides an overview of biodegradable polymer-based drug-delivery systems for ocular diseases with emphasis on the potential for biodegradable polymers to overcome the limitations of conventional methods, allowing for sustained drug release, improved bioavailability, and targeted therapy. Natural and synthetic polymers are both discussed, highlighting their biodegradability and biocompatibility. Various formulation strategies, such as nanoparticles, hydrogels, and microemulsions, among others, are investigated, detailing preparation methods, drug encapsulation, and clinical applications. The focus is on anterior and posterior segment drug delivery, covering glaucoma, corneal disorders, ocular inflammation, retinal diseases, age-related macular degeneration, and diabetic retinopathy. Safety considerations, such as biocompatibility evaluations, in vivo toxicity studies, and clinical safety, are addressed. Future perspectives encompass advancements, regulatory considerations, and clinical translation challenges. In conclusion, biodegradable polymers offer potential for efficient and targeted ocular drug delivery, improving therapeutic outcomes while reducing side effects. Further research is needed to optimize formulation strategies and address regulatory requirements for successful clinical implementation.