Colon cancer remains one of the most prevalent and aggressive malignancies, underscoring the demand for targeted and biologically safe therapeutic strategies. Arginine deiminase (ADI) has gained increasing interest as a potential anticancer agent due to its ability to modulate cellular arginine availability and inhibit tumor progression.

Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the blood-brain barrier (BBB), marked intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). Immunotherapeutic strategies based on natural killer (NK) and T cells, leveraging antigen-independent cytotoxicity and antigen-specific precision, respectively, offer potential breakthroughs but are often limited by chronic neuroinflammation. A key driver of TME suppression is prostaglandin E2 (PGE2), produced via the cyclooxygenase-2 (COX-2) pathway. PGE2 exerts a dual role: Intracellularly, it can promote apoptosis, whereas extracellularly, it fosters tumor progression, immune evasion, and therapeutic resistance. Through activation of EP2 and EP4 receptors, PGE2 signals via Gαs proteins to elevate cyclic adenosine monophosphate (cAMP), leading to impaired cytotoxic immunity. This signaling downregulates NK cell activating receptors (e.g., NKG2D, NKp30), induces CD8⁺ T cell exhaustion, and promotes regulatory T cell expansion. The COX-2/PGE₂ axis further mediates resistance to checkpoint inhibitors, CAR-T therapy, and chemotherapy by enhancing neuronal excitation through EP1 receptor activation in GBM. Targeting this pathway has therefore emerged as a compelling therapeutic strategy, which can restore NK and T cell function and sensitize tumors to immunotherapy. Combining PGE₂ modulation with next-generation NK/T cell approaches-including CAR-NK and CAR-T platforms-holds promise to overcome immune resistance and redefine therapeutic paradigms for GBM and other central nervous system malignancies.

Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib remains a significant challenge. Previous studies have shown that sorafenib treatment induces the formation of truncated O-glycans in HCC cells, but the relationship between sorafenib-induced glycosylation changes and acquired therapy resistance remains unclear. Primary natural killer (NK) cells, freshly isolated from peripheral blood or following culture and expansion, expressed the glycoimmune checkpoints Siglec-7 and Siglec-9. HCC cells exhibited varying levels of Siglec-7/9 ligands on their surface. Sorafenib-resistant liver cancer cells displayed hypersialylation, leading to increased expression of surface Siglec-7/9 ligands, which conferred protection against NK cell-mediated cytotoxicity. Silencing ST3GAL1 significantly reduced Siglec-7 ligand expression on liver cancer cells, enhancing their susceptibility to NK-mediated cytotoxicity and cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) in epidermal growth factor receptor (EGFR)-expressing tumor cells. Furthermore, high ST3GAL1 expression correlated with poor clinical outcomes in patients with stage 1-2 HCC. This study highlights the critical role of ST3GAL1 in regulating Siglec-7 ligands to facilitate immune escape from NK cell cytotoxicity. Moreover, its elevated expression is associated with adverse clinical outcomes in HCC. Targeting ST3GAL1 may represent a promising strategy to enhance NK cell-mediated anti-tumor immunity in HCC.

Lung cancer is known as a top cause of cancer-related mortality worldwide, and urgent attention is needed to enhance treatment efficacy with innovative therapeutic strategies. In this study, plasmonic nanoantennas of gold-titania-curcumin (PGTCNA) were synthesized, characterized, and applied as a photo/radiosensitizer for phototherapy and radiodynamic therapy (RDT) of A549 non-small cell lung cancer (NSCLC) in monolayer and tumorsphere models. PGTCNA contained gold and titania nanoparticles with diameters of 40 ± 8 nm and 29 ± 4 nm, respectively, along with curcumin. PGTCNA characterization showed that PGTCNA had a band gap of 2.4 eV, a zeta potential of +58.3 ± 4.9 mV, and a photothermal conversion efficiency of 50.7%, with the desired stability, hemocompatibility, and intrinsic capacity for reactive oxygen species (ROS) generation, particularly singlet oxygen (1O2). In the monolayer model, MTT cytotoxicity assays revealed that PGTCNA had IC50 values of 93 and 229 µg mL-1 for cancerous (A549) and normal (MRC5) lung cells, respectively. In addition, laser light radiation following PGTCNA treatment resulted in disruption of mitochondrial membrane potential, photoporation, inhibition of cell migration, and alleviation of hypoxia-induced resistance in A549 cells. In both monolayer and tumorsphere models, treatment of A549 cells with PGTCNA in combination with 808-nm laser light and X-ray radiation (quadruple photodynamic/mild photothermal/radiodynamic/chemotherapy) synergistically reduced cell viability and enhanced ROS generation. In the tumorsphere model, the quadruple therapy triggered apoptosis in A549 tumorspheres. These findings suggested that PGTCNA acts as a promising photo/radiosensitizer to enhance the efficacy of photodynamic/mild photothermal/radiodynamic therapy of NSCLC, with the potential to overcome key challenges associated with radiotherapy.

Chimeric antigen receptor (CAR) is a receptor engineered to engraft defined specificity onto immune effector cells, usually T cells, and enhance cellular function. Currently, the anticancer effects of CAR-engineered T cells, macrophages, and NK cells are being intensively explored. Pre-eclampsia (PE) is a pregnancy-specific disease with complex pathogenesis, and no effective treatment exists other than delivery. Placental dysfunction is a major contributing factor; the abnormal placenta releases factors into the maternal bloodstream, leading to systemic inflammation and widespread endothelial dysfunction.

The extracellular matrix (ECM) is crucial in building the extracellular environment and translating extracellular information into biochemical signals that sustain tissue functions. Fibulin-5 (Fbln5) is a multifunctional ECM protein essential for forming elastic fibers and regulating cellular functions by binding to integrins. Although fibulin-5 expression decreases with age in human skin, its functional implications, particularly in epidermal stem cell regulation, remain largely unexplored. Here, we show that the loss of Fbln5 in mice leads to early impairments of epidermal stem cell properties that resemble changes observed during chronological skin aging. Fbln5 deficiency is associated with reduced expression of integrins and other cell junction proteins and decreased YAP activation in epidermal stem cells. Pharmacological inhibition of YAP reduces the fast-cycling stem cell region in mice and downregulates the fast-cycling epidermal stem cell marker SLC1A3 in human primary keratinocytes. At the cellular level, YAP activity and SLC1A3 expression are modulated by cell density, with low-density cultures exhibiting high nuclear YAP and elevated SLC1A3 expression, whereas high-density conditions suppress both. Under high-density conditions, fibulin-5 coating partially restores nuclear YAP localization and increases SLC1A3 expression. Together, these findings suggest that, beyond its structural role in elastic fiber formation, fibulin-5 contributes to the maintenance of epidermal stem cell balance during skin aging by linking extracellular alterations to YAP-dependent intracellular signaling.

ObjectiveEndothelial progenitor cells (EPCs) originate from hematopoietic stem cells and can be quantified in peripheral blood using flow cytometry. The anti-GM-CSFα antibody (CD116) may serve as a specific marker for EPC enumeration. This study aimed to quantify peripheral EPCs expressing CD116 and compare the results with other specific antibodies in newborns and adults.Materials and MethodsEPC enumeration was performed by flow cytometric analysis of peripheral blood leukocytes (PBLs) obtained from 50 individuals, including 25 newborns and 25 adults. A CD34-specific antibody was used to identify hematopoietic stem/progenitor cells, while an antibody panel consisting of CD116, CD146, CD31, and CD45 was employed for EPC identification.ResultsEnumeration of CD34+ hematopoietic progenitor cells (HPCs) demonstrated that the mean CD34+ HPC count per 106 PBLs was 1643 (935-1458) in newborns and 242.7 (163-190) in adults, with a statistically significant difference between the groups (p < 0.001). Using CD146 staining, the mean number of circulating EPCs per 106 PBLs was 94.2 (90.5-129.0) in newborns and 9.2 (7.4-12.4) in adults (p < 0.001). Similarly, enumeration based on CD31 staining revealed mean EPC counts of 19.0 (12.5-28.0) in newborns and 6.0 (5.0-7.0) in adults (p < 0.001). Enumeration using CD116 staining showed mean EPC numbers of 29.0 (23.0-34.0) in newborns and 3.0 (2.0-4.0) in adults, also indicating a significant difference between the two groups (p < 0.001).ConclusionEPC numbers are significantly higher in newborns than in adults, suggesting an important developmental role for these cells. The GM-CSFα-specific antibody (CD116) may serve as a novel auxiliary marker for the identification and quantification of circulating EPCsubpopulations. Furthermore, EPC numbers appear to vary across different life stages, with higher numbers in newborns potentially reflecting the presence of a highly regenerative microenvironment.

ABO-incompatible (ABOi) hematopoietic stem cell transplantation (HSCT) is often associated with ABO discrepancies post-HSCT. Re-emergence of the patient's original type post-HSCT may signal graft loss, disease relapse, recent transfusion, or soluble ABO antigen. We present a group A pediatric patient with leukemia who underwent a minor ABOi HSCT from a group O donor with persistent and increasing A reactivity 2 years post-HSCT.

The use of immune checkpoint inhibitors (ICIs) has deeply improved the outcome of relapsed or refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) patients. However, real-world data are still limited, and several aspects, including the need for consolidation strategies, remain to be fully elucidated. We report the results of the multicenter Italian retrospective observational PRIMICI study on R/R PMBCL patients treated with ICIs in a real-life (off-label) setting. Seventy-four patients, 42 treated with pembrolizumab and 32 with nivolumab-brentuximab vedotin (nivo-BV), were enrolled. The median follow-up was 34 months. The best overall response and complete response (CR) rates were 64% (n = 50) and 50% (n = 37), respectively. Of the 37 patients in CR, 11 received a consolidation treatment and 26 patients continued ICIs; CR were stable, independently from the use of consolidation, with a 4-year disease-free survival of 100%. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 60.4% (95% confidence interval [C.I.] 48.3%-70.6%) and 77.5% (95% C.I. 65.8%-85.6%), respectively. Nivo-BV was associated with faster and higher response rates and better OS compared to pembrolizumab. OS significantly improved after 2020 due to the use of salvage treatment with CAR T-cells. In conclusion, this study supported the safety and effectiveness of pembrolizumab or nivo-BV as a salvage therapy in R/R PMBCL patients. Importantly, the chance to obtain long-lasting responses, regardless of the use of a consolidation treatment, indicates that ICIs may be used with a curative intent in a significant subset of patients.

Skeletal stem cells (SSCs), a specialized subset of mesenchymal stem cells, drive bone regeneration. This study aimed to characterize the pathological effects of ionizing radiation (IR) on osteogenic precursor cells (MC3T3-E1) and to elucidate the therapeutic efficacy and underlying molecular mechanisms of SSC-mediated rescue.

Cancer stem cells (CSCs) are a key subpopulation within tumors, characterized by their self-renewal and differentiation potential, and they drive tumor initiation, progression, metastasis, and recurrence. Recent epitranscriptomic studies have revealed that RNA modifications, including m6A, m5C, ac4C, m7G, and m1A, play critical roles in maintaining CSC stemness, determining cell fate, reprogramming metabolism, and promoting therapy resistance. This review systematically summarizes the functions of different RNA modifications and their associated enzymes in CSCs. We also discuss how RNA modifications regulate core CSC signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, PI3K-AKT-mTOR, JAK/STAT, Hippo/YAP, and TGF-β/SMAD, and we highlight strategies targeting RNA modifications for CSC intervention along with their potential challenges. These findings suggest that RNA modifications and their regulators represent promising therapeutic targets in CSCs, providing a rationale for developing highly selective or combination treatment strategies.

Leukemias are heterogeneous hematologic malignancies that involve dysregulated proliferation and impaired differentiation of hematopoietic cells. The Wnt signaling pathway, which regulates hematopoietic stem cell self-renewal and lineage commitment, is dysregulated across leukemia subtypes. Non-coding RNAs (ncRNAs), which include microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs, have been identified as important post-transcriptional and epigenetic regulators of oncogenic signaling networks. There is growing evidence for a complex, bidirectional relationship between ncRNAs and the Wnt/β-catenin pathway, but this has not yet been summarized or integrated into the context of leukemia. This study examines how ncRNA manipulation of core Wnt components - β-catenin, Frizzled receptors, and Dvl (dishevelled) proteins - affect leukemic cell survival, proliferation, stemness, and treatment resistance. Furthermore, we discuss reciprocal regulation, in which Wnt stimulation affects ncRNA production, forming feed-forward loops that promote leukemogenesis. By synthesizing disparate findings from studies investigating ncRNA and Wnt signaling mechanisms across leukemia subtypes, we identify critical mechanistic gaps in the literature, as well as opportunities and controversies that could be that could be leveraged in evaluating ncRNA-Wnt interactions as diagnostic and therapeutic targets. This review presents a comprehensive study integrating ncRNA biology and Wnt-driven leukemic development in order to identify crucial insights into disease vulnerabilities and future research initiatives.

Infertility affects approximately 15% of couples worldwide, with male factors accounting for approximately half of the cases. Low-level laser therapy (LLLT) has been increasingly considered in modern medicine due to its high efficacy, ease of use, and lack of side effects. Evidence suggests that this method can prevent DNA damage in cells and activate key genes related to fertility. This study aimed to investigate the effects of LLLT on sperm production in azoospermic mice using in vitro and in vivo experimental models.

Neural injuries affecting both the central nervous system (CNS) and peripheral nervous system (PNS) pose a great clinical challenge due to the neural tissue's limited self-regenerative capacity. Human dental pulp stem cells (hDPSCs), derived from the neural crest and easily obtained from extracted teeth, exhibit considerable potential for neural regeneration. This potential is attributed to their ability to directly differentiate into various neuronal cell types, paracrine effects, and interactions with biomaterial scaffolds. In this review, we reviewed the molecular mechanisms by which hDPSCs support neural repair, highlighting their direct neuronal differentiation function, neuroprotection function via paracrine signaling, and recent innovations in biomaterial scaffolds that enhance the viability of hDPSCs for neuroregenerative applications. Preclinical studies have shown promising therapeutic effects of hDPSCs in spinal cord injuries (SCI), strokes, Parkinson's disease (PD), Alzheimer's disease (AD), and peripheral nerve injuries. However, challenges remain, including optimizing neuronal differentiation specificity, ensuring immunological safety, and achieving scalable clinical applications. Future research should focus on standardizing manufacturing protocols, implementing strict quality control, and developing functional assays linked to neural recovery to maximize the potential of hDPSCs for nervous system regeneration.

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options, necessitating novel treatment strategies. This study investigates the potential of emodin, a natural anthraquinone, to suppress HCC by inducing cuproptosis, a newly identified form of regulated cell death.

Relapsed/refractory RUNX1::RUNX1T1-positive acute myeloid leukemia remains a therapeutic challenge due to high relapse rates post-allogeneic hematopoietic stem cell transplantation. Preclinical evidence suggests that RUNX1::RUNX1T1 fusion proteins sensitize cells to poly ADP-ribose polymerase inhibitors by suppressing homologous recombination repair. This study explores the safety and efficacy of a novel conditioning regimen incorporating olaparib (a PARPi) for relapsed/refractory RUNX1::RUNX1T1+ AML patients undergoing allo-HSCT.

Forkhead Box A2 (FOXA2) is a transcription factor essential for endodermal development and the formation and function of several metabolic organs, including the liver and pancreas. Within the pancreatic lineage, FOXA2 plays a crucial role in orchestrating islet development, maintaining β-cell identity, and regulating genes central to glucose sensing and insulin secretion. This review provides a comprehensive overview of FOXA2's dual role in both developmental and mature stages of pancreatic islets, highlighting its function as a gatekeeper of lineage specification and metabolic homeostasis. We describe FOXA2's dynamic expression patterns during embryogenesis, its regulatory interactions with other key transcription factors, such as PDX1 and NKX6.1, and its influence on chromatin accessibility during islet cell differentiation. Furthermore, we discuss the consequences of FOXA2 dysregulation, including impaired α- and β-cell maturation, loss of functional identity, and contributions to the pathogenesis of diabetes. Insights from mouse models, human stem cell-derived islets, and patient genetics underscore the clinical relevance of FOXA2 in monogenic and complex forms of diabetes. By integrating developmental biology, genomics, and disease modeling approaches, this review highlights FOXA2 as a central regulator connecting pancreatic organogenesis with long-term metabolic control. Understanding FOXA2's regulatory networks may open new avenues for therapeutic strategies aimed at restoring or preserving β-cell function in diabetes.

Antibacterial prophylaxis has long been a cornerstone of supportive care in patients with haematological malignancies undergoing intensive chemotherapy and haematopoietic stem cell transplantation (HSCT), particularly in the setting of prolonged and profound neutropenia. However, the widespread use of fluoroquinolone (FQ) prophylaxis has increasingly raised concerns related to antimicrobial resistance, microbiota disruption, drug-related toxicity, and Clostridioides difficile infection, challenging its universal application. At the same time, the therapeutic landscape of haematology is rapidly evolving, with the introduction of novel agents and cellular therapies such as chimeric antigen receptor (CAR) T cells, bispecific antibodies (BsAbs), antibody-drug conjugates, and immune-based treatments, each associated with distinct patterns of immunosuppression and infectious risk. In this narrative review, we critically examine the role of antibacterial prophylaxis through the lens of antimicrobial stewardship, integrating evidence from traditional chemotherapy and transplantation with emerging data from innovative therapies. We summarize current guideline recommendations, real-world evidence, and recent studies questioning the net benefit of routine FQ prophylaxis, particularly in settings with high resistance prevalence. Alternative strategies, including non-FQ agents and selective omission of prophylaxis, are also discussed. Overall, available evidence supports a shift from universal prophylaxis toward a risk-adapted, individualized approach that accounts for treatment modality, expected duration and depth of neutropenia, patient-specific factors, and local epidemiology. Embedding antibacterial prophylaxis decisions within structured antimicrobial stewardship programs is essential to balance infection prevention with long-term patient safety and resistance containment in modern haematological practice.

Severe acute pancreatitis (SAP) is a complex inflammatory disorder with severe immune imbalance. This study investigates the therapeutic potential of extracellular vesicles derived from human adipose mesenchymal stem cells (hADSC-EVs) in modulating Treg differentiation and alleviating SAP. We conducted a phosphoproteomics analysis to evaluate phosphorylation levels, and administered hADSC-EVs in a mouse model of SAP and assessed their impact on Treg differentiation. Phosphoproteomics revealed a significant increase in p-STK3 following hADSC-EVs treatment, restoring Foxp3 level diminished by STK3 knockdown. HADSC-EVs promoted Treg differentiation in a concentration-dependent manner by targeting Foxp3 transcription. In the SAP mouse model, hADSC-EVs improved survival rates and mitigated histopathological alterations. In conclusion, our study revealed that STK3 effectively promotes Treg differentiation and enhances their immunosuppressive capabilities, thereby ameliorating inflammation and attenuating the pathological phenotypes associated with SAP. These findings provide valuable insights into the potential role of hADSC-EVs in regulating immune responses and promoting tissue repair.

Sponges are capable of rebuilding functional individuals from cell aggregates (primmorphs), a process termed whole-body regeneration that morphologically parallels larval development. To systematically compare these processes, we established an in vitro primmorph regeneration model in Haliclona simulans and performed multi-level analyses across planktonic, settled, and metamorphic stages. Although both processes formed similar structures (e.g., the aquiferous system), planktonic primmorphs exhibited a reduced stem cell proportion (archeocyte/choanocyte), along with the increase of seemingly dedifferentiating cells and vacuolar cells. Microbiome diverged: while sharing core symbionts (e.g., AqS1), primmorphs enriched Tenacibaculum and Vibrio species during remodeling process. Transcriptomics revealed distinct signatures: regeneration upregulated genes potentially related to DNA repair and dedifferentiation but downregulated stem cell markers. Our integrative study indicates that regeneration and development constitute distinct processes, achieving similar functional outcomes via divergent cellular, microbial, and molecular profiles that provides a foundational framework for future mechanistic studies of regeneration.