Genetics of rheumatoid arthritis.

In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.

Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications.

Natural killer (NK) cells are important immune cells in the organism and are the third major type of lymphocytes besides T cells and B cells, which play an important function in cancer therapy. In addition to retaining the tumor cell killing function of natural killer cells, natural killer cell-derived exosomes cells also have the characteristics of high safety, wide source, easy to preserve and transport. At the same time, natural killer cell-derived exosomes are easy to modify, and the engineered exosomes can be used in combination with a variety of current cancer therapies, which not only enhances the therapeutic efficacy, but also significantly reduces the side effects. Therefore, this review summarizes the source, isolation and modification strategies of natural killer cell-derived exosomes and the combined application of natural killer cell-derived engineered exosomes with other antitumor therapies, which is expected to accelerate the clinical translation process of natural killer cell-derived engineered exosomes in cancer therapy.

Biomarkers of Parkinson's disease in perspective of early diagnosis and translation of neurotrophic therapies.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine neurons and aberrant deposits of alpha-synuclein (α-syn) in the brain. The symptomatic treatment is started after the onset of motor manifestations in a late stage of the disease. Preclinical studies with neurotrophic factors (NTFs) show promising results of disease-modifying neuroprotective or even neurorestorative effects. Four NTFs have entered phase I-II clinical trials with inconclusive outcomes. This is not surprising because the preclinical evidence is from acute early-stage disease models, but the clinical trials included advanced PD patients. To conclude the value of NTF therapies, clinical studies should be performed in early-stage patients with prodromal symptoms, that is, before motor manifestations. In this review, we summarize currently available diagnostic and prognostic biomarkers that could help identify at-risk patients benefiting from NTF therapies. Focus is on biochemical and imaging biomarkers, but also other modalities are discussed. Neuroimaging is the most important diagnostic tool today, but α-syn imaging is not yet viable. Modern techniques allow measuring various forms of α-syn in cerebrospinal fluid, blood, saliva, and skin. Digital biomarkers and artificial intelligence offer new means for early diagnosis and longitudinal follow-up of degenerative brain diseases.

Individualized high-resolution analysis to categorize diverse learning and memory deficits in tau rTg4510 mice exposed to low-intensity blast.

Mild traumatic brain injury (mTBI) resulting from low-intensity blast (LIB) exposure in military and civilian individuals is linked to enduring behavioral and cognitive abnormalities. These injuries can serve as confounding risk factors for the development of neurodegenerative disorders, including Alzheimer's disease-related dementias (ADRD). Recent animal studies have demonstrated LIB-induced brain damage at the molecular and nanoscale levels. Nevertheless, the mechanisms linking these damages to cognitive abnormalities are unresolved. Challenges preventing the translation of preclinical studies into meaningful findings in "real-world clinics" encompass the heterogeneity observed between different species and strains, variable time durations of the tests, quantification of dosing effects and differing approaches to data analysis. Moreover, while behavioral tests in most pre-clinical studies are conducted at the group level, clinical tests are predominantly assessed on an individual basis. In this investigation, we advanced a high-resolution and sensitive method utilizing the CognitionWall test system and applying reversal learning data to the Boltzmann fitting curves. A flow chart was developed that enable categorizing individual mouse to different levels of learning deficits and patterns. In this study, rTg4510 mice, which represent a neuropathology model due to elevated levels of tau P301L, together with the non-carrier genotype were exposed to LIB. Results revealed distinct and intricate patterns of learning deficits and patterns within each group and in relation to blast exposure. With the current findings, it is possible to establish connections between mice with specific cognitive deficits to molecular changes. This approach can enhance the translational value of preclinical findings and also allow for future development of a precision clinical treatment plan for ameliorating neurologic damage of individuals with mTBI.

Therapeutics of the future: Navigating the pitfalls of extracellular vesicles research from an osteoarthritis perspective.

Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane-bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.

On animal pathophysiology-seeking models of takotsubo syndrome.

The aim of this viewpoint/commentary on a recent contribution by the Gothenburg takotsubo syndrome (TTS) laboratory, in which the authors provide a comprehensive review/state of the art report on the animal models, currently employed in the elucidation of the pathophysiology of TTS, is to intensify the debate as to what constitutes a suitable TTS animal model with as promising as possible translational potential to the human TTS.

Towards Stem Cell Therapy for Critical-Sized Segmental Bone Defects: Current Trends and Challenges on the Path to Clinical Translation.

The management and reconstruction of critical-sized segmental bone defects remain a major clinical challenge for orthopaedic clinicians and surgeons. In particular, regenerative medicine approaches that involve incorporating stem cells within tissue engineering scaffolds have great promise for fracture management. This narrative review focuses on the primary components of bone tissue engineering-stem cells, scaffolds, the microenvironment, and vascularisation-addressing current advances and translational and regulatory challenges in the current landscape of stem cell therapy for critical-sized bone defects. To comprehensively explore this research area and offer insights for future treatment options in orthopaedic surgery, we have examined the latest developments and advancements in bone tissue engineering, focusing on those of clinical relevance in recent years. Finally, we present a forward-looking perspective on using stem cells in bone tissue engineering for critical-sized segmental bone defects.

The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis.

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.

Antibody-drug conjugates for non-small cell lung cancer: Advantages and challenges in clinical translation.

Lung cancer is the leading cause of cancer death, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of all lung cancers and having a poor treatment and prognosis. Conventional clinical chemotherapy and immunotherapy are challenged by systemic toxicity and drug resistance, so researchers are increasingly focusing on antibody-drug conjugate (ADC), an innovative concept combining chemotherapy and targeted therapy, in which a drug selectively binds to antigens on the surface of a tumor cell via antibodies, which internalize the ADC, and then transfers the ADC to the lysosome via the endosomes to degrade the drug and kill the tumor cell. Despite the promising nature of ADCs, no ADC product for any indication including NSCLC has been approved for marketing by the FDA to date. In this review, we summarize the main advantages of ADCs and discuss in depth the design of the most desirable ADCs for NSCLC therapy. In addition to preclinical studies, we focus on the current state of clinical research on ADCs as interventions for the treatment of NSCLC by summarizing real-time clinical trial data from ClinicalTrials.gov, and reasonably speculate on the direction of the design of future generations of ADCs.

Spermbots and Their Applications in Assisted Reproduction: Current Progress and Future Perspectives.

Sperm quality is declining dramatically during the past decades. Male infertility has been a serious health and social problem. The sperm cell driven biohybrid nanorobot opens a new era for automated and precise assisted reproduction. Therefore, it is urgent and necessary to conduct an updated review and perspective from the viewpoints of the researchers and clinicians in the field of reproductive medicine. In the present review, we first update the current classification, design, control and applications of various spermbots. Then, by a comprehensive summary of the functional features of sperm cells, the journey of sperms to the oocyte, and sperm-related dysfunctions, we provide a systematic guidance to further improve the design of spermbots. Focusing on the translation of spermbots into clinical practice, we point out that the main challenges are biocompatibility, effectiveness, and ethical issues. Considering the special requirements of assisted reproduction, we also propose the three laws for the clinical usage of spermbots: good genetics, gentle operation and no contamination. Finally, a three-step roadmap is proposed to achieve the goal of clinical translation. We believe that spermbot-based treatments can be validated and approved for in vitro clinical usage in the near future. However, multi-center and multi-disciplinary collaborations are needed to further promote the translation of spermbots into in vivo clinical applications.

Clinical translation of nanomedicine with integrated digital medicine and machine learning interventions.

Nanomaterials based therapeutics transform the ways of disease prevention, diagnosis and treatment with increasing sophistications in nanotechnology at a breakneck pace, but very few could reach to the clinic due to inconsistencies in preclinical studies followed by regulatory hinderances. To tackle this, integrating the nanomedicine discovery with digital medicine provide technologies as tools of specific biological activity measurement. Hence, overcome the redundancies in nanomedicine discovery by the on-site data acquisition and analytics through integrating intelligent sensors and artificial intelligence (AI) or machine learning (ML). Integrated AI/ML wearable sensors directly gather clinically relevant biochemical information from the subject's body and process data for physicians to make right clinical decision(s) in a time and cost-effective way. This review summarizes insights and recommend the infusion of actionable big data computation enabled sensors in burgeoning field of nanomedicine at academia, research institutes, and pharmaceutical industries, with a potential of clinical translation. Furthermore, many blind spots are present in modern clinically relevant computation, one of which could prevent ML-guided low-cost new nanomedicine development from being successfully translated into the clinic was also discussed.

Exosome-based anticancer vaccines: From Bench to bedside.

Exosomes, a subset of extracellular vesicles, are released by all active cells and play a crucial role in intercellular communications. Exosomes could facilitate the transfer of various biologically active molecules, such as DNA, non-coding RNAs, and proteins, from donor to recipient cells, thereby participating in diverse biological and pathological processes. Besides, exosomes possess unique characteristics, including non-toxicity, low-immunogenicity, and stability within biological systems, rendering them highly advantageous for cancer drug development. Meanwhile, accumulating evidence suggests that exosomes originating from tumor cells and immune cells possess distinct composition profiles that play a direct role in anticancer immunotherapy. Of note, exosomes can transport their contents to specific cells, thereby exerting an impact on the phenotype and immune-regulatory functions of targeted cells. Therapeutic cancer vaccines, an emerging therapeutics of immunotherapy, could enhance antitumor immune responses by delivering a large number of tumor antigens, thereby augmenting the immune response against tumor cells. Therefore, the therapeutic rationale of cancer vaccines and exosome-based immunotherapy are almost similar to some extent, but some challenges have hindered their application in the clinical setting. Here, in this review, we first summarized the biogenesis, structure, compositions, and biological functions of exosomes. Then we described the roles of exosomes in cancer biology, particularly in tumor immunity. We also comprehensively reviewed current exosome-based anticancer vaccine development and we divided them into three types. Finally, we give some insights into clinical translation and clinical trial progress of exosome-based anticancer vaccines for future direction.

Toward the scale-up production of polymeric nanotherapeutics for cancer clinical trials.

Nanotherapeutics have gained significant attention for the treatment of numerous cancers, primarily because they can accumulate in and/or selectively target tumors leading to improved pharmacodynamics of encapsulated drugs. The flexibility to engineer the nanotherapeutic characteristics including size, morphology, drug release profiles, and surface properties make nanotherapeutics a unique platform for cancer drug formulation. Polymeric nanotherapeutics including micelles and dendrimers represent a large number of formulation strategies developed over the last decade. However, compared to liposomes and lipid-based nanotherapeutics, polymeric nanotherapeutics have had limited clinical translation from the laboratory. One of the key limitations of polymeric nanotherapeutics formulations for clinical translation has been the reproducibility in preparing consistent and homogeneous large-scale batches. In this review, we describe polymeric nanotherapeutics and discuss the most common laboratory and scale-up formulation methods, specifically those proposed for clinical cancer therapies. We also provide an overview of the major challenges and opportunities for scaling polymeric nanotherapeutics to clinical-grade formulations. Finally, we will review the regulatory requirements and challenges in advancing nanotherapeutics to the clinic.

A distributed, high-channel-count, implanted bidirectional system for restoration of somatosensation and myoelectric control.

Objective. We intend to chronically restore somatosensation and provide high-fidelity myoelectric control for those with limb loss via a novel, distributed, high-channel-count, implanted system.Approach.We have developed the implanted Somatosensory Electrical Neurostimulation and Sensing (iSens®) system to support peripheral nerve stimulation through up to 64, 96, or 128 electrode contacts with myoelectric recording from 16, 8, or 0 bipolar sites, respectively. The rechargeable central device has Bluetooth® wireless telemetry to communicate to external devices and wired connections for up to four implanted satellite stimulation or recording devices. We characterized the stimulation, recording, battery runtime, and wireless performance and completed safety testing to support its use in human trials.Results.The stimulator operates as expected across a range of parameters and can schedule multiple asynchronous, interleaved pulse trains subject to total charge delivery limits. Recorded signals in saline show negligible stimulus artifact when 10 cm from a 1 mA stimulating source. The wireless telemetry range exceeds 1 m (direction and orientation dependent) in a saline torso phantom. The bandwidth supports 100 Hz bidirectional update rates of stimulation commands and data features or streaming select full bandwidth myoelectric signals. Preliminary first-in-human data validates the bench testing result.Significance.We developed, tested, and clinically implemented an advanced, modular, fully implanted peripheral stimulation and sensing system for somatosensory restoration and myoelectric control. The modularity in electrode type and number, including distributed sensing and stimulation, supports a wide variety of applications; iSens® is a flexible platform to bring peripheral neuromodulation applications to clinical reality. ClinicalTrials.gov ID NCT04430218.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

Ferroptosis inhibitors: past, present and future.

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

Advances in ex vivo expansion of hematopoietic stem and progenitor cells for clinical applications.

As caretakers of the hematopoietic system, hematopoietic stem cells assure a lifelong supply of differentiated populations that are responsible for critical bodily functions, including oxygen transport, immunological protection and coagulation. Due to the far-reaching influence of the hematopoietic system, hematological disorders typically have a significant impact on the lives of individuals, even becoming fatal. Hematopoietic cell transplantation was the first effective therapeutic avenue to treat such hematological diseases. Since then, key use and manipulation of hematopoietic stem cells for treatments has been aspired to fully take advantage of such an important cell population. Limited knowledge on hematopoietic stem cell behavior has motivated in-depth research into their biology. Efforts were able to uncover their native environment and characteristics during development and adult stages. Several signaling pathways at a cellular level have been mapped, providing insight into their machinery. Important dynamics of hematopoietic stem cell maintenance were begun to be understood with improved comprehension of their metabolism and progressive aging. These advances have provided a solid platform for the development of innovative strategies for the manipulation of hematopoietic stem cells. Specifically, expansion of the hematopoietic stem cell pool has triggered immense interest, gaining momentum. A wide range of approaches have sprouted, leading to a variety of expansion systems, from simpler small molecule-based strategies to complex biomimetic scaffolds. The recent approval of Omisirge, the first expanded hematopoietic stem and progenitor cell product, whose expansion platform is one of the earliest, is predictive of further successes that might arise soon. In order to guarantee the quality of these ex vivo manipulated cells, robust assays that measure cell function or potency need to be developed. Whether targeting hematopoietic engraftment, immunological differentiation potential or malignancy clearance, hematopoietic stem cells and their derivatives need efficient scaling of their therapeutic potency. In this review, we comprehensively view hematopoietic stem cells as therapeutic assets, going from fundamental to translational.

Recent Updates of the CRISPR/Cas9 Genome Editing System: Novel Approaches to Regulate Its Spatiotemporal Control by Genetic and Physicochemical Strategies.

The genome editing approach by clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) is a revolutionary advancement in genetic engineering. Owing to its simple design and powerful genome-editing capability, it offers a promising strategy for the treatment of different infectious, metabolic, and genetic diseases. The crystal structure of Streptococcus pyogenes Cas9 (SpCas9) in complex with sgRNA and its target DNA at 2.5 Å resolution reveals a groove accommodating sgRNA:DNA heteroduplex within a bilobate architecture with target recognition (REC) and nuclease (NUC) domains. The presence of a PAM is significantly required for target recognition, R-loop formation, and strand scission. Recently, the spatiotemporal control of CRISPR/Cas9 genome editing has been considerably improved by genetic, chemical, and physical regulatory strategies. The use of genetic modifiers anti-CRISPR proteins, cell-specific promoters, and histone acetyl transferases has uplifted the application of CRISPR/Cas9 as a future-generation genome editing tool. In addition, interventions by chemical control, small-molecule activators, oligonucleotide conjugates and bioresponsive delivery carriers have improved its application in other areas of biological fields. Furthermore, the intermediation of physical control by using heat-, light-, magnetism-, and ultrasound-responsive elements attached to this molecular tool has revolutionized genome editing further. These strategies significantly reduce CRISPR/Cas9's undesirable off-target effects. However, other undesirable effects still offer some challenges for comprehensive clinical translation using this genome-editing approach. In this review, we summarize recent advances in CRISPR/Cas9 structure, mechanistic action, and the role of small-molecule activators, inhibitors, promoters, and physical approaches. Finally, off-target measurement approaches, challenges, future prospects, and clinical applications are discussed.