Advancing Open Science

Background/Objectives: Immune checkpoint inhibitor (ICI)-based combinations have significantly improved outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, a substantial number of patients fail to derive clinical benefit, highlighting the need for reliable predictive biomarkers. Circulating biomarkers represent an attractive, non-invasive alternative to tissue-based assays. This study aimed to evaluate the immunity-related genes ERVFRD-1 and MFSD2A as potential blood-based candidate biomarkers associated with response to ICI-based therapy in mccRCC. Methods: Peripheral blood samples were collected prior to treatment initiation from 34 patients with mccRCC receiving PD-1-based therapy. Gene expression levels of ERVFRD-1 and MFSD2A were quantified using real-time PCR. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral blood samples from healthy individuals were included as controls. Results: Both ERVFRD-1 and MFSD2A were significantly dysregulated in mccRCC patients compared with healthy controls. Their expression differed between patients with clinical benefit and those with progressive disease. Specifically, patients with progressive disease exhibited reduced ERVFRD-1 expression and increased MFSD2A expression compared with patients showing clinical benefit. Conclusions: ERVFRD-1 and MFSD2A were associated with treatment response in this pilot cohort and may represent promising blood-based biomarker candidates, requiring validation in larger prospective multicenter studies.

The survival and activation of both effector and regulatory CD4⁺T cells are promoted by cytokines in a complex series of interactions. Alloantigen-specific Regulatory T cells (Treg) constitutively express IL-2 receptor (CD25) and Foxp3. This discovery arose as the cells that transfer the alloantigen-specific transplant tolerance die in culture with specific alloantigens, unless the cultures are supplemented with cytokines from activated lymphocytes. One such cytokine was IL-2, but other cytokines are essential. We describe how the activation of Treg by antigens depends on cytokines produced by antigen-activated effector T cells. These cytokines also drive in parallel the activation of Treg. The Treg are induced to express similar transcription factors and chemokine receptors and have a similar cytokine responsiveness to the activated T effector cells. The activation of Treg by antigens is a two-step process: the first requires cytokines produced by effector T cells early in their activation, and the second step is driven by cytokines produced later by effector T cells during activation. Cytokines from Type 1 responses promote the induction of Th1-like Treg. Likewise, cytokines produced in Type 2, Type 3, and Tfh responses induce different pathways of Treg activation. Understanding the pathways for the activation and expansion of potent antigen-specific Treg will help produce Treg to control allograft rejection or autoimmunity. Currently, the complexity of the numerous potential pathways of activation of Treg remains incompletely understood. The dogma that IL-2 is the only driver of Treg activation may have hindered the development of highly potent antigen-specific Treg for therapy.

Pancreatic carcinoma (PC) is the most lethal malignancy due to its aggressive behavior and limited therapeutic response. Among the annexin family, Annexin A1 (ANXA1) is documented to promote PC aggressiveness, and conversely, the role of Annexin A6 (ANXA6) is less explored. Here, we report that ANXA6 is significantly upregulated in ANXA1 knockout (KO) MIA PaCa-2 cells. Using LAM20, our previously identified ANXA6 modulator, we show that inhibition of this protein impairs cell motility, and epithelial-to-mesenchymal transition markers, without affecting 2D/3D cell proliferation. ANXA6 siRNA-mediated knockdown reproduces LAM20 effects, suggesting a relationship with their impact on ANXA6. Interestingly, in ANXA1 KO cells, LAM20 reduced the migration/invasion rate differently from the ANXA1 inhibitor heparan sulfate, which retains effects on the wild-type (WT) MIA PaCa-2 counterpart. These findings suggest that in cells lacking ANXA1, ANXA6 plays a compensatory role in sustaining the aggressive phenotype, albeit to a lesser extent than in WT cells. Thus, LAM20 represents a promising therapeutic strategy to impair PC aggressiveness. Our study provides new insights into ANXA1/ANXA6 crosstalk and introduces a novel approach to disturb PC pro-invasive mechanisms. Targeting ANXA1 and ANXA6 is relevant because, where ANXA1 is downregulated/absent, ANXA6 expression can be restored in a compensatory manner, partially sustaining tumor progression.

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear. Methods: Through an integrated analysis of multiple public databases (including SangerBox 3.0, UALCAN, Kaplan–Meier Plotter, and TIMER), we identified PTH2R—a member of the family B1 GPCRs—as a candidate therapeutic target with significant prognostic value in LUAD. Subsequently, the antitumor effects of PTH2R knockdown and melatonin were evaluated through cell proliferation, colony formation, migration, and apoptosis assays. Transcriptome analysis revealed key biological processes and signaling pathways regulated by PTH2R, identified key genes modulated by PTH2R, and validated core gene expression via RT-qPCR. Results: PTH2R is a potential therapeutic target for lung adenocarcinoma. Both PTH2R knockdown and melatonin treatment significantly inhibited LUAD cell proliferation, colony formation, and migration capabilities while promoting apoptosis. Notably, the combination of PTH2R knockdown and melatonin treatment demonstrated synergistically enhanced antitumor effects. Transcriptome analysis revealed two key genes within the PTH2R signaling pathway, and RT-qPCR validated the expression of these two key genes. Conclusions: Our work provides the first evidence confirming the substantial value of PTH2R as a novel therapeutic target for LUAD. It preliminarily demonstrates the mechanism by which melatonin inhibits LUAD by targeting PTH2R, offering crucial experimental evidence and theoretical support for developing precision therapeutic strategies against this cancer.

Using plants to restore soils subjected to salinization and polychemic pollution can be an effective way to return agricultural land to circulation and obtain safe products. In this study, experiments were conducted with oats and lupine to evaluate their ability to purify soils contaminated with copper (II) and nickel (II) ions, carbonate and sulfate anions and oil and their combinations. The biological activity of the soil, phytotoxicity, and hydrocarbon content, as well as plant growth and biochemical parameters in polluted soil, were studied. The enzymes most sensitive to soil contamination were catalase, urease, and phosphatase. Copper ions inhibited oat root growth by 45.7% and lupine by 46.6%. Oil and its mixtures with other pollutants inhibited shoot growth by up to 50.3% in oats and up to 28.6% in lupine. The content of malonic dialdehyde increased in oats when exposed to copper, while in lupines, it increased 2.9-fold when exposed to oil. Flavonoids in oats increased with metal contamination (by 9–16.7%), while in lupines with oil (by 8.6%). Chlorophyll fluctuations were less pronounced in oats than in lupine. Despite the stress experienced by plants due to soil pollution, the degradation rate of petroleum hydrocarbons under oat and lupine crops was 33–46%. In general, oats and lupine are promising for the phytoremediation of complexly polluted and saline soils.

Background: Abrupt cessation of deep brain stimulation (DBS) in Parkinson’s disease (PD), most commonly due to implantable pulse generator (IPG) battery depletion, may lead to DBS withdrawal syndrome (DBS-WDS). However, withdrawal syndrome does not occur in all patients following stimulation cessation. Methods: We retrospectively analyzed 210 PD patients treated with DBS. Patients with documented stimulation cessation were evaluated for the presence of withdrawal syndrome based on established clinical criteria. Demographic, disease-related, and treatment characteristics were assessed, and descriptive analysis was conducted on severe cases requiring intensive care. Results: DBS battery shutdown occurred in 28 patients (13.3%). Most patients did not develop withdrawal syndrome and experienced only transient motor worsening. Severe DBS-WDS requiring intensive care was rare, occurring in only three patients (1.4%). Battery shutdown alone did not predict withdrawal, nor was preoperative levodopa equivalent daily dose associated with withdrawal risk. Conclusions: DBS battery shutdown is usually not accompanied by withdrawal syndrome, and severe DBS-WDS is uncommon. Proactive battery management may help to prevent this rare but serious complication.

This study investigates the machinability of Continuous Fiber-Reinforced Thermoplastic Composite (CFRTP) produced via Material Extrusion (MEX) additive manufacturing, focusing on drilling as a critical post-processing step in hybrid manufacturing. CFRTP components, fabricated from 3K carbon fibers and a PLA matrix, were subjected to systematic drilling tests under varying cutting speeds (50–110 m/min) and feed rates (0.06–0.24 mm/rev). Thrust force (Fz) and torque (Mz) were recorded using a high-precision dynamometer to evaluate the influence of cutting parameters on mechanical loads and damage mechanisms. Results indicate that increasing the feed rate significantly increases Fz and Mz, promoting fiber pull-out, delamination, and edge deformation, particularly at hole entry and exit regions. Conversely, higher cutting speeds reduce Fz and Mz due to thermal softening of the PLA matrix, enabling more controlled fiber–matrix interaction. Microscopic analyses revealed that damage severity correlates strongly with mechanical load levels. While high feed rates caused pronounced surface irregularities and matrix smearing, low feed rates combined with high cutting speeds yielded smoother hole morphology and preserved fiber–matrix integrity. The study concludes that optimal drilling conditions for CFRTP materials involve low feed rates and high cutting speeds, minimizing mechanical loads and suppressing damage formation. These findings provide a scientific basis for precision finishing strategies in hybrid manufacturing, enhancing dimensional accuracy and structural reliability of CFRTP components for advanced engineering applications.

The primary focus of enhancing the efficiency of operations in the Industry 4.0 setting is Predictive and Preventive Maintenance (PPM). The paper introduces a predictive-maintenance system based on the Unified Namespace (UNS), which involves real-time sensor measurements, photogrammetry, and modelling of a digital twin to improve fault prediction and responsiveness to maintenance. This experiment was conducted over six months in a medium-sized discrete electromechanical production plant equipped with motors, Variable Speed Drives (VSDs), robot/cobots, precision grip systems, pipework systems, Magnemotion/linear motor drives, and a CNC machine. The continuous data, such as high-frequency vibration, temperature, current, and pressure, were monitored and analysed with machine-learning models, including support-vector machines, Gradient Boosting, long-short-term memory, and Random Forest, through which temporal degradation can be predicted. UNS architecture integrated all sensor and imaging data into a vendor-neutral data model through OPC UA to help ensure that all experiments could be integrated consistently and be updated in real time to real digital twins. The suggested system correctly identified mechanical and electrical failures and predicted failures before they really took place. Consequently, machine downtime was reduced by 42.25%, and Mean Time to Repair (MTTR) by 36%, compared to the prior six-month baseline period. These improvements were associated with earlier anomaly detection and digital-twin-supported pre-inspection. Overall, the findings indicate that the integration of UNS with multi-modal sensing and digital-twin technologies may enhance predictive maintenance performance in comparable industrial settings. The framework provides a data-driven, scalable solution to organisations that aim to modernise their maintenance processes, attain greater reliability and better equipment utilisation, as well as enhanced Industry 4.0 preparedness.