Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1ß (IL-1ß) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1ß and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling.

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-ß/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Bullous lichen sclerosus-generalized morphea overlap syndrome improved by tofacitinib.

We here report a case of a middle-aged man with an unusual case of bullous lichen sclerosus complicated with generalized morphea. He showed initial recurrent flaccid bullae, followed by ivory-white sclerotic plaques and extensive skin sclerosis, with additional walking disorder caused by knee-joint contracture, and ulcers on the lower extremities and back. The patient had no visceral involvement. After oral hydroxychloroquine and oral corticosteroids failed, the patient was given tofacitinib, which resolved his ulcers after 4 weeks and ameliorated his knee-joint contracture and skin sclerosis within 4 months. Owing to the occurrence of diffuse large B-cell lymphoma, he stopped using tofacitinib, and the ulcer and walking disorder reappeared. This is rare case of bullous lichen sclerosus-generalized morphea overlap syndrome. The patient recovered well after treatment with tofacitinib. His symptoms recurred after discontinuation of tofacitinib.

Nonsense Suppression Therapy: An Emerging Treatment for Hereditary Skin Diseases.

Nonsense mutations cause the premature termination of protein translation via premature termination codons (PTCs), leading to the synthesis of incomplete functional proteins and causing large numbers of genetic disorders. The emergence of nonsense suppression therapy is considered to be an effective method for the treatment of hereditary diseases, but its application in hereditary skin diseases is relatively limited. This review summarizes the current research status of nonsense suppression therapy for hereditary skin diseases, and discusses the potential opportunities and challenges of applying new technologies related to nonsense suppression therapy to dermatology. Further research is needed into the possible use of nonsense suppression therapy as a strategy for the safer and specific treatment of hereditary skin diseases.

The aryl hydrocarbon receptor: An environmental effector in the pathogenesis of fibrosis.

The aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that can be activated by small molecules provided by dietary, plant, or microbial metabolites, and environmental pollutants. AhR is expressed in many cell types and engages in crosstalk with other signaling pathways, and therefore provides a molecular pathway that integrates environmental cues and metabolic processes. Fibrosis, which is defined as an aberrant extracellular matrix formation, is a reparative process in the terminal stage of chronic diseases. Both environmental and internal factors have been shown to participate in the pathogenesis of fibrosis; however, the underlying mechanisms still remain elusive. In this review, the potential role of AhR in the process of fibrosis, as well as potential opportunities and challenges in the development of AhR targeting therapeutics, are summarized.

Swarm Autonomy: From Agent Functionalization to Machine Intelligence.

Swarm behaviors are common in nature, where individual organisms collaborate via perception, communication, and adaptation. Emulating these dynamics, large groups of active agents can self-organize through localized interactions, giving rise to complex swarm behaviors, which exhibit potential for applications across various domains. This review presents a comprehensive summary and perspective of synthetic swarms, to bridge the gap between the microscale individual agents and potential applications of synthetic swarms. It is begun by examining active agents, the fundamental units of synthetic swarms, to understand the origins of their motility and functionality in the presence of external stimuli. Then inter-agent communications and agent-environment communications that contribute to the swarm generation are summarized. Furthermore, the swarm behaviors reported to date and the emergence of machine intelligence within these behaviors are reviewed. Eventually, the applications enabled by distinct synthetic swarms are summarized. By discussing the emergent machine intelligence in swarm behaviors, insights are offered into the design and deployment of autonomous synthetic swarms for real-world applications.

Water-Induced Shape-Locking Magnetic Robots.

Untethered magnetic soft robots capable of performing adaptive locomotion and shape reconfiguration open up possibilities for various applications owing to their flexibility. However, magnetic soft robots are typically composed of soft materials with fixed modulus, making them unable to exert or withstand substantial forces, which limits the exploration of their new functionalities. Here, water-induced, shape-locking magnetic robots with magnetically controlled shape change and water-induced shape-locking are introduced. The water-induced phase separation enables these robots to undergo a modulus transition from 1.78 MPa in the dry state to 410 MPa after hydration. Moreover, the body material's inherent self-healing property enables the direct assembly of morphing structures and magnetic soft robots with complicated structures and magnetization profiles. These robots can be delivered through magnetic actuation and perform programmed tasks including supporting, blocking, and grasping by on-demand deformation and subsequent water-induced stiffening. Moreover, a water-stiffening magnetic stent is developed, and its precise delivery and water-induced shape-locking are demonstrated in a vascular phantom. The combination of untethered delivery, on-demand shape change, and water-induced stiffening properties makes the proposed magnetic robots promising for biomedical applications.

A magnetic multi-layer soft robot for on-demand targeted adhesion.

Magnetic soft robots have shown great potential for biomedical applications due to their high shape reconfigurability, motion agility, and multi-functionality in physiological environments. Magnetic soft robots with multi-layer structures can enhance the loading capacity and function complexity for targeted delivery. However, the interactions between soft entities have yet to be fully investigated, and thus the assembly of magnetic soft robots with on-demand motion modes from multiple film-like layers is still challenging. Herein, we model and tailor the magnetic interaction between soft film-like layers with distinct in-plane structures, and then realize multi-layer soft robots that are capable of performing agile motions and targeted adhesion. Each layer of the robot consists of a soft magnetic substrate and an adhesive film. The mechanical properties and adhesion performance of the adhesive films are systematically characterized. The robot is capable of performing two locomotion modes, i.e., translational motion and tumbling motion, and also the on-demand separation with one side layer adhered to tissues. Simulation results are presented, which have a good qualitative agreement with the experimental results. The feasibility of using the robot to perform multi-target adhesion in a stomach is validated in both ex-vivo and in-vivo experiments.

MiR-4769-3p suppresses adipogenesis in systemic sclerosis by negatively regulating the USP18/VDAC2 pathway.

Systemic sclerosis (SSc) is an autoimmune disease affecting multiple tissues. The underlying causes and mechanisms of subcutaneous adipose tissue (SAT) loss in SSc remain unclear. Recent studies have highlighted the role of microRNAs in adipogenesis. Our study found that miR-4769-3p was upregulated in SSc patients and its silencing promoted SAT recovery in bleomycin-induced SSc mice, suggesting that miR-4769-3p might affect adipogenesis in SSc. Manipulating miR-4769-3p expression in 3T3-L1 cells revealed that its inhibition enhanced adipogenesis, while its overexpression weakened it. Further investigations showed that miR-4769-3p bound to 3'UTR of ubiquitin-specific protease-18 (USP18), inhibiting its expression, while USP18 interacted with voltage-dependent anion channel-2 (VDAC2), both of which were reduced in SSc. Silencing either USP18 or VDAC2 attenuated adipogenesis. Notably, USP18 inhibited VDAC2 ubiquitination and degradation, whereas miR-4769-3p reversed the VDAC2-induced elevation of adipogenesis, suggesting that miR-4769-3p inhibited adipogenesis by negatively regulating the USP18/VDAC2 pathway, providing a potential therapeutic target for SSc.

Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway.

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

Biodegradable Microrobots and Their Biomedical Applications: A Review.

During recent years, microrobots have drawn extensive attention owing to their good controllability and great potential in biomedicine. Powered by external physical fields or chemical reactions, these untethered microdevices are promising candidates for in vivo complex tasks, such as targeted delivery, imaging and sensing, tissue engineering, hyperthermia, and assisted fertilization, among others. However, in clinical use, the biodegradability of microrobots is significant for avoiding toxic residue in the human body. The selection of biodegradable materials and the corresponding in vivo environment needed for degradation are increasingly receiving attention in this regard. This review aims at analyzing different types of biodegradable microrobots by critically discussing their advantages and limitations. The chemical degradation mechanisms behind biodegradable microrobots and their typical applications are also thoroughly investigated. Furthermore, we examine their feasibility and deal with the in vivo suitability of different biodegradable microrobots in terms of their degradation mechanisms; pathological environments; and corresponding biomedical applications, especially targeted delivery. Ultimately, we highlight the prevailing obstacles and perspective solutions, ranging from their manufacturing methods, control of movement, and degradation rate to insufficient and limited in vivo tests, that could be of benefit to forthcoming clinical applications.

Ultrafast Miniature Robotic Swimmers with Upstream Motility.

With the development of materials science and micro-nano fabrication techniques, miniature soft robots at millimeter or submillimeter size can be manufactured and actuated remotely. The small-scaled robots have the unique capability to access hard-to-reach regions in the human body in a noninvasive manner. To date, it is still challenging for miniature robots to accurately move in the diverse and dynamic environments in the human body (e.g., in blood flow). To effectively locomote in the vascular system, miniature swimmers with upstream swimming capability are required. Herein, we design and fabricate a miniature robotic swimmer capable of performing ultrafast swimming in a fluidic environment. The maximum velocity of the swimmer in water is 30 cm/s, which is 60 body lengths. Moreover, in a tubular environment, the swimmer can still obtain a swimming velocity of 17 cm/s. The swimmer can also perform upstream swimming in a tubular environment with a velocity of 5 cm/s when the flow speed is 10 cm/s. The ultrasound-guided navigation of the swimmer in a phantom mimicking a blood vessel is also realized. This work gives insight into the design of agile undulatory milliswimmers for future biomedical applications.

Micro/Nanorobotic Swarms: From Fundamentals to Functionalities.

Swarms, which stem from collective behaviors among individual elements, are commonly seen in nature. Since two decades ago, scientists have been attempting to understand the principles of natural swarms and leverage them for creating artificial swarms. To date, the underlying physics; techniques for actuation, navigation, and control; field-generation systems; and a research community are now in place. This Review reviews the fundamental principles and applications of micro/nanorobotic swarms. The generation mechanisms of the emergent collective behaviors among the micro/nanoagents identified over the past two decades are elucidated. The advantages and drawbacks of different techniques, existing control systems, major challenges, and potential prospects of micro/nanorobotic swarms are discussed.

Amphibious Miniature Soft Jumping Robot with On-Demand In-Flight Maneuver.

In nature, some semiaquatic arthropods evolve biomechanics for jumping on the water surface with the controlled burst of kinetic energy. Emulating these creatures, miniature jumping robots deployable on the water surface have been developed, but few of them achieve the controllability comparable to biological systems. The limited controllability and agility of miniature robots constrain their applications, especially in the biomedical field where dexterous and precise manipulation is required. Herein, an insect-scale magnetoelastic robot with improved controllability is designed. The robot can adaptively regulate its energy output to generate controllable jumping motion by tuning magnetic and elastic strain energy. Dynamic and kinematic models are developed to predict the jumping trajectories of the robot. On-demand actuation can thus be applied to precisely control the pose and motion of the robot during the flight phase. The robot is also capable of making adaptive amphibious locomotion and performing various tasks with integrated functional modules.

Untethered Small-Scale Machines for Microrobotic Manipulation: From Individual and Multiple to Collective Machines.

Untethered small-scale machines (USSMs) that can actively adjust their motion, deformation, and collective states in response to external stimuli have gained enormous interest in various manipulation, sensing, and biomedical applications. Because they can be efficiently operated in confined and tortuous environments, USSMs are capable of conducting wireless microrobotic manipulation tasks that tethered machines find hard to achieve. Over the past decade of development, significant research progress has been achieved in designing USSM-based manipulation strategies, which are enabled by investigating machine-object, machine-environment, and machine-machine interactions. This review summarizes the latest developments in USSMs for microrobotic manipulation by utilizing individual machines, coordinating multiple machines, and inducing collective behaviors. Providing recent studies and relevant applications in microrobotic and biomedical areas, we also discuss the challenges and future perspectives facing USSMs-based intelligent manipulation systems to achieve manipulation in complex environments with imaging-guided processes and increasing autonomy levels.

A review on microrobots driven by optical and magnetic fields.

Due to their small sizes, microrobots are advantageous for accessing hard-to-reach spaces for delivery and measurement. However, their small sizes also bring challenges in on-board powering, thus usually requiring actuation by external energy. Microrobots actuated by external energy have been applied to the fields of physics, biology, medical science, and engineering. Among these actuation sources, light and magnetic fields show advantages in high precision and high biocompatibility. This paper reviews the recent advances in the design, actuation, and applications of microrobots driven by light and magnetic fields. For light-driven microrobots, we summarized the uses of optical tweezers, optoelectronic tweezers, and heat-mediated optical manipulation techniques. For magnetically driven microrobots, we summarized the uses of torque-driven microrobots, force-driven microrobots, and shape-deformable microrobots. Then, we compared the two types of field-driven microrobots and reviewed their advantages and disadvantages. The paper concludes with an outlook for the joint use of optical and magnetic field actuation in microrobots.

UVA1 irradiation attenuates collagen production via Ficz/AhR/MAPK signaling activation in scleroderma.

Scleroderma is an autoimmune disease mainly characterized by progressive fibrosis of the skin. There are two types of scleroderma, namely localized scleroderma (LS) and systemic sclerosis (SSc); skin lesions in both types of scleroderma are histologically identical. Progressive skin sclerosis induces psychological and ecological burden for scleroderma patients. However, there is no effective treatment for scleroderma due to its unclear etiology. Aryl hydrocarbon receptor (AhR) is recognized as an environmental chemical effector that can respond to ultraviolet radiation, which has been demonstrated to participate in the pathogenesis of SSc in our previous study. In this study, we verify whether the anti-fibrosis effect of ultraviolet A1 (UVA1) phototherapy could be partially induced through Ficz/AhR/MAPK signaling activation for fibrotic lesions in both SSc and LS patients. This is the first study to show the association between the AhR pathway and the anti-fibrotic mechanism of UVA1 phototherapy, which provides additional evidence of the role of AhR in the fibrotic mechanism of systemic scleroderma from different perspectives. Ficz and other AhR agonists may replace UVA1 phototherapy as anti-fibrotic agents in scleroderma.

Identification of pyroptosis-related lncRNA signature and AC005253.1 as a pyroptosis-related oncogene in prostate cancer.

Background: Pyroptosis and prostate cancer (PCa) are closely related. The role of pyroptosis-related long non-coding RNAs (lncRNAs) (PRLs) in PCa remains elusive. This study aimed to explore the relationship between PRL and PCa prognosis. Methods: Gene expression and clinical signatures were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A PRL risk prediction model was established by survival random forest analysis and least absolute shrinkage and selection operator regression. Functional enrichment, immune status, immune checkpoints, genetic mutations, and drug susceptibility analyses related to risk scores were performed by the single-sample gene set enrichment analysis, gene set variation analysis, and copy number variation analysis. PRL expression was verified in PCa cells. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, wound healing, transwell, and Western blotting assay were used to detect the proliferation, migration, invasion, and pyroptosis of PCa cells, respectively. Results: Prognostic features based on six PRL (AC129507.1, AC005253.1, AC127502.2, AC068580.3, LIMD1-AS1, and LINC01852) were constructed, and patients in the high-score group had a worse prognosis than those in the low-score group. This feature was determined to be independent by Cox regression analysis, and the area under the curve of the 1-, 3-, and 5-year receiver operating characteristic curves in the testing cohort was 1, 0.93, and 0.92, respectively. Moreover, the external cohort validation confirmed the robustness of the PRL risk prediction model. There was a clear distinction between the immune status of the two groups. The expression of multiple immune checkpoints was also reduced in the high-score group. Gene mutation proportion in the high-score group increased, and the sensitivity to drugs increased significantly. Six PRLs were upregulated in PCa cells. Silencing of AC005253.1 inhibited cell proliferation, migration, and invasion in DU145 and PC-3 cells. Moreover, silencing of AC005253.1 promoted pyroptosis and inflammasome AIM2 expression. Conclusions: Overall, we constructed a prognostic model of PCa with six PRLs and identified their expression in PCa cells. The experimental verification showed that AC005253.1 could affect the proliferation, migration, and invasion abilities of PCa cells. Meanwhile, AC005253.1 may play an important role in PCa by affecting pyroptosis through the AIM2 inflammasome. This result requires further research for verification.