Triple-negative breast cancer (TNBC) represents a significant therapeutic challenge owing to the scarcity of targeted medicines and elevated recurrence rates. We previously reported the development of the nuclease-resistant RNA sTN58 aptamer, which selectively targets TNBC cells. Here, sTN58 aptamer was employed to capture and purify its binding target from the membrane protein fraction of cisplatin-resistant mesenchymal stem-like TNBC cells. Mass spectrometry in conjunction with aptamer binding assays across various cancer cell lines identified CD44 as the cellular target of sTN58. By binding to CD44, sTN58 inhibits the invasive growth and hyaluronic acid-dependent tube formation in chemoresistant TNBC cells, where CD44 serves as a key driver of tumor cell aggressiveness and stem-like plasticity. Moreover, in vivo studies demonstrated the aptamer's high tumor targeting efficacy and its capacity to significantly inhibit tumor growth and lung metastases following intravenous administration in mice with orthotopic TNBC. Overall, our findings reveal the striking potential of sTN58 as a targeting reagent for the recognition and therapy of cancers overexpressing CD44.

Early detection and diagnosis are key to improving the survival rate and reducing the fatality rate linked to gastric cancer. The precancerous lesion of gastric cancer is referred to as gastric high-grade intraepithelial neoplasia (HGIN). Both the sensitivity and specificity of current biomarkers that aid in the diagnosis of gastric HGIN are still relatively low. Furthermore, proteomic data on gastric HGIN are still scarce. The present study aimed to explore candidate protein biomarkers for gastric HGIN screening with proteomics and bioinformatics technology. A total of 10 serum samples were collected and categorized into two groups, i.e., the gastric HGIN and the healthy control groups. Label-free quantification in conjunction with liquid chromatography with tandem mass spectrometry was employed to identify the probable biomarkers for gastric HGIN. Furthermore, differentially expressed proteins (DEPs) were quantified by proteomics analysis. In total, 1,192 distinct serum proteins were discovered between the gastric HGIN group and the healthy control group. DEPs were identified in the further analyses, utilizing a threshold of a 1.5-fold difference in expression level (P<0.05) in comparison with the control group. There were 18 upregulated and 12 downregulated proteins in the gastric HGIN group in comparison with the control group. Bioinformatics analyses were performed using Gene Ontology and KEGG pathway enrichment analyses. The GO analysis revealed that the DEPs were enriched in biological processes such as 'cellular', 'biological regulation', 'multicellular organismal', 'developmental' and 'reaction to stimulus processes', localized to 'cell', 'intracellular' and 'protein-containing complex', and involved in molecular functions such as 'molecular function modulator', 'binding' and 'catalytic activity'. The KEGG pathway enrichment analysis manifested that the DEPs were predominantly enriched in 'antigen processing and presentation', 'diabetic cardiomyopathy', 'Epstein-Barr virus infection', 'herpes simplex virus 1 infection', 'human immunodeficiency virus 1 infection' and 'human cytomegalovirus infection'. In conclusion, the present data provide more biological information for the formation of gastric HGIN and clues for further research on the pathogenesis of early gastric cancer.

Receptor-mediated targeted drug delivery has emerged as a pivotal strategy in cancer therapy, offering precision and specificity in combating malignant diseases while minimizing systemic toxicity. This review explores the multifaceted role of receptors in cancer biology, emphasizing their contributions to cancer progression, metastasis, and their potential as therapeutic targets. Ligand-based targeting approaches highlight the utility of small molecules, peptides, and antibodies, as well as the development of novel targeting ligands. A critical focus is placed on engineering receptor-targeted nanoparticles and advanced drug delivery systems. Innovations in dual-targeting strategies and the targeted delivery to the tumour microenvironment (TME) and metastatic niches are discussed, underscoring their potential to enhance therapeutic efficacy. Additionally, receptor-targeted imaging is reviewed for its dual role in diagnosis and real-time treatment monitoring. To address the challenges of side effects and off-target toxicity, strategies that minimize these risks while targeting overexpressed receptors in solid tumours are explored. Finally, the review outlines future directions in receptor-targeted cancer therapy, emphasizing the need for interdisciplinary research to refine these strategies further. This comprehensive analysis aims to provide a roadmap for advancing receptor-based therapeutic approaches, ultimately improving outcomes for cancer patients.

CAR T cells are genetically modified T cells that target specific epitopes. CAR T cell therapy has proven effective in difficult-to-treat B cell cancers and is now expanding into hematology and solid tumors. To date, approved CAR therapies target only two specific epitopes on cancer cells. Identifying more suitable targets is challenged by the lack of truly cancer-specific structures and the potential for on-target off-tumor toxicity. We analyzed gene expression of potential targets in single-cell data from cancer and healthy tissues. Because safety and efficacy can ultimately only be defined clinically, we selected approved and investigational targets for which clinical trail data are available. We generated atlases using >300,000 cells from 48 patients with follicular lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia, and integrated over 3 million cells from 35 healthy tissues, harmonizing datasets from over 300 donors. To contextualize findings, we compared target expression patterns with outcome data from clinical trials, linking target profiles to efficacy and toxicity, and ranked 15 investigational targets based on their similarity to approved ones. Target expression did not significantly correlate with reported clinical toxicities in patients undergoing therapy. This may be attributed to the intricate interplay of patient-specific variables, the limited amount of metadata, and the complexity underlying toxicity. Nevertheless, our study serves as a resource for retrospective and prospective target evaluation to improve the safety and efficacy of CAR therapies.

Solid tumors present significant therapeutic challenges due to their complex pathophysiology, including poor vascularization, dense extracellular matrix, multidrug resistance, and immune evasion. Conventional treatment strategies, such as chemotherapy, radiotherapy, and surgical interventions, are often associated with systemic toxicity, suboptimal drug accumulation at the tumor site, and chemoresistance. Nanostructured lipid carriers (NLCs) have emerged as a promising approach to enhance anticancer therapy. NLCs offer several advantages, including high drug loading capacity, improved bioavailability, controlled release, and enhanced stability. Recent advancements in active targeting strategies have led to the development of ligand-decorated NLCs, which exhibit selective tumor targeting, improved cellular uptake, and reduced systemic toxicity. By functionalizing NLCs with different targeting ligands, site-specific drug delivery can be achieved for better therapeutic efficacy. This review comprehensively explores the potential of ligand-decorated NLCs in solid tumor therapy, highlights their design principles, and mechanisms of tumor targeting. Furthermore, it discusses various receptor-targeted NLCs for the effective treatment of solid tumors. The potential of ligand-decorated NLCs in combination therapy, gene therapy, photothermal therapy, and photodynamic therapy is also explored. Overall, ligand-decorated NLCs represent a versatile and effective strategy to achieve better therapeutic outcomes in solid tumor therapy.

Pancreatic cancer (PC) is a highly lethal and aggressive malignancy, currently one of the leading causes of cancer-related deaths worldwide, in both women and men. PC is highly resistant to standard chemotherapy (CT) because its immunosuppressive and hypoxic tumor microenvironment and a dense desmoplastic stroma compartment extensively limit drug accessibility and perfusion. Although CT is one of the main therapeutic strategies for PC management contributing to tumor eradication through a cytotoxic effect, CT is associated with a poor pharmacokinetic profile and provokes deleterious systemic toxicity. This low efficacy-poor safety scenario urgently calls for innovative and highly specific therapeutic strategies to counteract this urgent clinical challenge. Nanotechnology-based precision materials for cancer may help improve drug stability and minimize the systemic cytotoxic effects by increasing drug tumor accumulation and also enabling controlled release, but several drawbacks still persist, such as the poor targeting efficiency. In the last few years increased attention has been paid to bioinspired nanosystems that can mimic either partially or totally biological systems, including lipid layers as suitable stealth coatings resembling the composition of cell membranes, lipoprotein- and blood protein-based nanosystems, and cell membrane-derived systems, such as extracellular vesicles, cell membrane nanovesicles and cell membrane-coated nanosystems, which display intrinsic cancer-targeting abilities, enhanced biocompatibility, decreased immunogenicity, and prolonged blood circulation profile. This review covers the recent breakthroughs on advanced biomimetic PC-targeted nanosystems, focusing on their design, properties and applications as innovative, multifunctional and versatile tools paving the way to improved PC diagnosis and treatment.

Cancer, being one of the most outrageous diseases, contributed to 48 % of the mortality in 2022, with lung cancer leading the race with a 12.4 % incidence rate. Conventional treatment modalities like radio-, chemo-, photo-, and immunotherapy employing nanocarriers often face several setbacks, such as non-specific delivery, off-site toxicity, rapid opsonization via the host immune system, and greater tumor recurrence rates. Moreover, the heterogeneous variability in the tumor microenvironment is responsible for existing therapy failure. With the advent of biomimetic nanoparticles as a novel and intriguing platform, researchers have exploited the inherent functionalities of the Cluster of Differentiation proteins (CD) as cell surface biomarkers and imparted the nanocarriers with enhanced homologous tumor targetability, immune evasion capability, and stealth properties, paving the way for improved therapy and diagnosis. This article explores pathogenesis and the multifaceted role of immune cells in non-small cell lung cancer. Moreover, the agenda of this article is to shed light on biomimetic nanoarchitectonics with respect to their fabrication, evaluation, and applications unraveling their synergistic effect with conventional therapies. Further discussion mentions the hurdles in clinical translation with viable solutions. The regulatory bottlenecks underscore the need for a regulatory roadmap with respect to commercialization. We believe that biomimetic nanoarchitectonics will be a beacon of hope in warfare against lung cancer.

SPP1+ macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of SPP1 + macrophages in CRC. Our findings revealed a pronounced elevation of SPP1 + macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial-mesenchymal transition, glycolysis, hypoxia, and immunosuppression. SPP1 protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the SPP1-CD44, SPP1-PTGER4, and SPP1-a4b1 complex axes. Patients with a high proportion of SPP1 + macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, CSF1R expression was significantly enriched in C1QC + macrophages versus SPP1 + macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an SPP1 + macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.

Regulatory T cells can suppress activated T-cell proliferation by direct cell contact, although the exact mechanism is poorly understood. Identification of a Treg-specific cell surface molecule that mediates suppression would offer a unique target for cancer immunotherapy to inhibit Treg immunosuppressive function or deplete Tregs in the tumor microenvironment. In this study, we explored a method of whole-cell immunization using a Treg-like cell line (MoT cells) to generate and screen monoclonal antibodies that bound cell surface proteins in their native conformations and functionally reversed Treg-mediated suppression. From the 105 hybridomas that bound to the MoT cell surface, a functional screen utilizing conventional Treg suppression assays revealed 32 candidate antibodies that exhibited functional activity (reversed or enhanced suppressive activity). As an example, we characterized 1 anti-MoT mAb, 12E7, that exhibited strong binding to MoT cells and conventional Treg cell surfaces. This candidate antibody was subsequently found to bind to a potential suppressive target, CD44, and demonstrated the ability to partially reverse MoT and conventional human Treg-mediated suppression.

Pancreatic cancer is a malignancy with a poor prognosis and high mortality. Survival outcomes remain very poor despite significant advances in molecular diagnostics and therapeutics in clinical practice. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage, and most cancers recur after surgery. Treatments other than surgery, including chemotherapy and immunotherapy, still offer disappointing results. Multidisciplinary treatment approaches through appropriate carriers have provided new solutions for improving the prognosis of pancreatic cancer. Herein, we reported an in situ formed thermo-responsive hybrid hydrogel loaded with gemcitabine and manganese dioxide nanoparticles, which exhibited good injectability, high photothermal hyperthermia, and biocompatibility, leading to efficient multidisciplinary treatment of pancreatic cancer in combination with chemotherapy and photothermal therapy (PTT). The hybrid hydrogel could be heated to 51 °C under 808 nm laser irradiation in five minutes. In situ intratumoral injection results suggested that the hybrid hydrogel exhibited high photothermal efficiency in killing rabbit pancreatic tumors. In vivo results indicated that the multidisciplinary treatment almost completely eliminated subcutaneous tumors in mice within 14 days. This development offers an efficient multidisciplinary treatment for pancreatic cancer.

Cancer stem cells (CSCs) play a critical role in the initiation and heterogeneity of a variety of cancers due to their pluripotent nature and capacity for asymmetric cell division. Therefore, uncovering the carcinogens that increase the CSC population in target tissues is crucial for understanding the genesis of cancer. The therapeutic potential of Operculina turpethum (OT) derived silver nanoparticles (AgNPs) was assessed in diethylnitrosamine (DEN)-induced CSC populations; CD73+, CD44+, and CD90 + of hepatic tissues in male rats.

Histopathology, fluorescence-activated cell sorting (FACS), and RT-qPCR were performed on the control, DEN, DEN + AgNPs, and AgNPs-treated groups. AgNPs were characterized by FTIR, EDX, XRD, and SEM.

AgNPs were confirmed by intense surface plasmon resonance at 425 nm. Antioxidants, the reducing sugars responsible for Ag+ 1 reduction and subsequent conjugate formation with nanoparticles, were confirmed by vibrational spectra. The spherical morphology, composition, and conjugation of silver nanoparticles to phytoconstituents with partially crystalline, face-centered cubic structure were established through SEM, EDX spectrum, and XRD, respectively. Disrupted tissue architecture, cell enlargement, mild pleomorphism, and expanded central veins were observed in hepatic tissues of DEN-treated animals. However, a moderate inflammatory response was observed in the DEN + AgNPs-treated group. CSC populations were significantly increased in the DEN-treated group, but decreased with AgNPs-treatment. The mRNA expression levels of CD90, CD44, and CD73 genes were significantly up-regulated in the DEN-treated group compared to control group however, in DEN + AgNPs and AgNPs groups it were similar to control group.

All together, DEN-induced the hepatic CSC cell populations and the OT mediated AgNPs have therapeutic potential to attenuate the harmful effects of DEN. This study provides evidenced that OT-synthesised AgNPs may be considered as a therapeutic agent for liver related malignancies.

RNA therapeutics offer a promising approach to cancer treatment by precisely regulating cancer-related genes. While lipid nanoparticles (LNPs) are currently the most advanced nonviral clinically approved vectors for RNA therapeutics, their antitumor efficacy is limited by their unspecific hepatic accumulation after systemic administration. Thus, there is an urgent need to enhance the delivery efficiency of LNPs to target tumor-residing tissues. Here, we conjugated the cluster of differentiation 44 (CD44)-specific targeting peptide A6 (KPSSPPEE) to the cholesterol of LNPs via PEG, named AKPC-LNP, enabling specific tumor delivery. This modification significantly improved delivery to breast cancer cells both in vitro and in vivo, as shown by flow cytometry and confocal microscopy. We further used AKPC-siYT to codeliver siRNAs targeting the transcriptional coactivators YAP and TAZ, achieving potent gene silencing and increased cell death in both 2D cultures and 3D tumor spheroids, outperforming unmodified LNPs. In a breast tumor cell xenografted zebrafish model, systemically administered AKPC-siYT induced robust silencing of YAP/TAZ and downstream genes and significantly enhanced tumor suppression compared to unmodified LNPs. Additionally, AKPC-siYT effectively reduced proliferation in prostate cancer organoids and tumor growth in a patient-derived xenograft (PDX) model. Overall, we developed highly efficient AKPC-LNPs carrying RNA therapeutics for targeted cancer therapy.

The metastatic cascade is a complicated process where cancer cells travel across multiple organs distant from their primary site of onset. Despite the wide acceptance of the 'seed and soil' theory, mechanisms driving metastasis organotropism remain mystery. Using breast cancer of different subtypes as the disease model, we characterized the 'metastatic profile of cancer cells' and the 'redox status of the organ microenvironment' as the primary determinants of cancer metastasis organotropism. Mechanically, we identified a positive correlation between cancer metabolic plasticity and stemness, and proposed oxidative stress as the selection power of cancer cells succeeding the metastasis cascade. Therapeutically, we proposed the use of pro-oxidative therapeutics in ablating cancer cells taking advantages of this fragile moment during metastasis. We comprehensively reviewed current pro-oxidative strategies for treating cancers that cover the first line chemo- and radio-therapies, approaches relying on naturally existing power including magnetic field, electric field, light and sound, nanoparticle-based anti-cancer composites obtained through artificial design, as well as cold atmospheric plasma as an innovative pro-oxidative multi-modal modality. We discussed possible combinations of pro-oxidative approaches with existing therapeutics in oncology prior to the forecast of future research directions. This paper identified the fundamental mechanics driving metastasis organotropism and proposed intervention strategies accordingly. Insights provided here may offer clues for the design of innovative solutions that may open a new paradigm for cancer treatment.

Meningiomas (MGs), which arise from meningothelial cells of the dura mater, represent a significant proportion of primary tumours of the central nervous system (CNS). Despite advances in treatment, the management of malignant meningioma (MMG) remains challenging due to diagnostic, surgical, and resection limitations. Cancer stem cells (CSCs), a subpopulation within tumours capable of self-renewal and differentiation, are highlighted as key markers of tumour growth, metastasis, and treatment resistance. Identifying additional CSC-related markers enhances the precision of malignancy evaluations, enabling advancements in personalised medicine. The review discusses key CSC biomarkers that are associated with high levels of expression, aggressive tumour behaviour, and poor outcomes. Recent molecular research has identified CSC-related biomarkers, including Oct-4, Sox2, NANOG, and CD133, which help maintain cellular renewal, proliferation, and drug resistance in MGs. This study highlights new therapeutic strategies that could improve patient prognosis with more durable tumour regression. The use of combination therapies, such as hydroxyurea alongside diltiazem, suggests more efficient and effective MG management compared to monotherapy. Signalling pathways such as NOTCH and hedgehog also offer additional avenues for therapeutic development. CRISPR/Cas9 technology has also been employed to create meningioma models, uncovering pathways related to cell growth and proliferation. Since the efficacy of traditional therapies is limited in most cases due to resistance mechanisms in CSCs, further studies on the biology of CSCs are warranted to develop therapeutic interventions that are likely to be effective in MG. Consequently, improved diagnostic approaches may lead to personalised treatment plans tailored to the specific needs of each patient.

Cancer treatment is among today's most active and challenging research fields. In recent years, significant progress has been made in developing new cancer therapies, including nutraceuticals and natural compounds with anticancer properties. Lactoferrin, a glycoprotein present in mammals, is of significant interest due to its pleiotropic behavior, demonstrating a broad spectrum of biological activities such as antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. In this review, we examine the current knowledge of Lf's role in cancer. In addition, it exhibits a synergistic effect along with conventional drugs, potentially enhancing their efficacy and, at the same time, reducing the side effects associated with most traditional therapies. However, it is essential to consider the precise molecular mechanism by which Lf exerts its antitumor activity. Searching interactions with several molecules can provide insight into this mechanism. Additionally, finding lactoferrin receptors can improve the strategies for the specific release of the conjugates. For all these reasons, Lactoferrin becomes a potential therapeutic agent that should be examined in depth.

Cell Adhesion Molecules (CAMs) play a crucial role in regulating immune responses and repairing damage caused by hypoxia. However, the relationship between the expression characteristics of CAMs in yak lung tissues and their adaptation to the plateau environment remains unclear. To address this question, we compared lung tissues from yaks and cattle at the same altitude. After digesting the lung tissues with trypsin or Type I collagenase for varying durations, we observed that fewer cells were isolated from yak tissues compared to cattle. RNA sequencing (RNA-seq) analysis revealed that the Differentially Expressed Genes (DEGs) in lung tissues of yaks and cattle were significantly enriched in cell adhesion-related pathways. Quantitative real-time PCR (qRT-PCR) further identified changes in the expression levels of five distinct types of CAMs. Among these, the cadherin family (CDH1, CDH2, CDH11, PCDH12, CD34) exhibited significantly higher expression in yaks than in cattle. These cadherins play a critical role in regulating lung inflammation and maintaining the alveolar-capillary barrier, thereby ensuring the structural stability of the lungs. Immunohistochemical staining demonstrated that the expression patterns of cell adhesion-related proteins (CDH1, CDH11, ITGB6, SELP, CD44) were largely consistent with the qRT-PCR results. In conclusion, compared to cattle, the enhanced cell adhesion capacity of yak lung tissues contributes to their superior adaptation to the harsh plateau environment.

Sessile serrated lesions (SSLs) are recognized as precursor lesions in the pathogenesis of colorectal cancer, particularly in the context of microsatellite instability (MSI). This study evaluates the role of immunohistochemical (IHC) markers in understanding the molecular and immunologic characteristics of SSLs.

A retrospective analysis was performed on 45 colonic neoplastic lesions diagnosed as SSLs. An IHC staining panel was conducted, including MLH1, p53, CD44, CD3, CD8, MUC2, MUC5AC, MUC6, chromogranin and Ki67 antibodies.

MLH1 and p53 expressions showed correlations with dysplastic changes. Immunological markers CD3 and CD8 indicated a variable immune response, potentially reflecting the tumor's ability to evade immune surveillance in certain situations. CD44 was overexpressed in all SSLs. The number of neuroendocrine cells was overall reduced.

SSLs are heterogeneous lesions, exhibiting a wide range of histological and molecular features. Using IHC might enhance diagnostic accuracy, particularly in lesions with ambiguous histological features, when dysplasia develops. Accurate identification of SSLs and understanding their molecular characteristics are crucial for assessing their malignant potential.

Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.

Cluster of differentiation 44 (CD44) is a transmembrane protein expressed in normal cells but overexpressed in several types of cancer. CD44 plays a major role in tumor progression, both locally and systemically, by direct interaction with the extracellular matrix, inducing tissue remodeling, activation of different cellular pathways, such as Akt or mechanistic target of rapamycin (mTOR), and stimulation of angiogenesis. As a prognostic marker, CD44 has been identified as a major player in cancer stem cells (CSCs). CSCs with a CD44 phenotype are associated with chemoresistance, alone or in combination with other CSC markers, such as CD24 or aldehyde dehydrogenase 1 (ALDH1), and may be used for patient stratification. In the therapy setting, CD44 has been explored as a viable target, directly or indirectly. It has revealed promising potential, paving the way for its future use in the clinical setting. Immunohistochemistry effectively detects CD44 overexpression, enabling patients to be accurately selected for surgery and targeted anti-CD44 therapies. In this review, we highlight the properties of CD44, its expression in normal and tumoral tissues through immunohistochemistry and potential treatment options. We also discuss the clinical significance of this marker and its added value in therapeutic decision-making.

This study evaluated the differential expression of four placental markers-vitamin D receptor (VDR), Cluster of Differentiation 44 (CD44), osteopontin (OPN), and cyclooxygenase-2 (COX-2)-in response to pathogens, which may contribute to our understanding of pathogen-specific impacts on pregnancy outcomes. We immunohistochemically (IHC) analyzed placental tissues obtained from 70 healthy-term pregnant women in the control group and compared them to tissues obtained from 78 women with pregnancy above 24 weeks of gestation, single-pathogen vaginal infection, and premature rupture of membranes/preterm premature rupture of membranes (PROM/PPROM). We detected high expression of these four molecules in cases of Group B Streptococcus (GBS) and Ureaplasma urealyticum vaginal infections, and moderate expression in cases of Enterobacteriaceae infections, except for Klebsiella; the cases with Klebsiella and Candida species (spp.) vaginitis exhibited a lower expression compared to the healthy control group. VDR, CD44, and OPN had increased placental expression in GBS and Ureaplasma urealyticum vaginal infections; the opportunistic pathogenicity of both Escherichia coli and Candida spp. explains their low IHC positivity, and the tremendous ability of Gram-negative bacteria to elude the host immunity is revealed by the negative IHC staining in cases of Klebsiella vaginitis. These findings suggest that pathogen-specific alterations in the expression of these markers may contribute to the differential risk stratification of pregnancy complications and may mitigate the risks of adverse maternal and fetal outcomes. Interventions aiming to modulate these pathways might improve pregnancy outcomes.

Human serum albumin (HSA) has emerged as a promising carrier for nanodrug delivery, offering unique structural properties that can be engineered to overcome key challenges in cancer treatment, especially resistance to chemotherapy. This review focuses on the cellular uptake of albumin-based nanoparticles and the modifications that enhance their ability to bypass resistance mechanisms, particularly multidrug resistance type 1 (MDR1), by improving targeting to cancer cells. In our unique approach, we integrate the chemical properties of albumin, its interactions with cancer cells, and surface modifications of albumin-based delivery systems that enable to bypass resistance mechanisms, particularly those related to MDR1, and precisely target receptors on cancer cells to improve treatment efficacy. We discuss that while well-established albumin receptors such as gp60 and gp18/30 are crucial for cellular uptake and transcytosis, their biology remains underexplored, limiting their translational potential. Additionally, we explore the potential of emerging targets, such as cluster of differentiation 44 (CD44), cluster of differentiation (CD36) and transferrin receptor TfR1, as well as the advantages of using dimeric forms of albumin (dHSA) to further enhance delivery to resistant cancer cells. Drawing from clinical examples, including the success of albumin-bound paclitaxel (Abraxane) and new formulations like Pazenir and Fyarro (for Sirolimus), we identify gaps in current knowledge and propose strategies to optimize albumin-based systems. In conclusion, albumin-based nanoparticles, when tailored with appropriate modifications, have the potential to bypass multidrug resistance and improve the targeting of cancer cells. By enhancing albumin's ability to efficiently deliver therapeutic agents, these carriers represent a promising approach to addressing one of oncology's most persistent challenges, with substantial potential to improve cancer treatment outcomes.

Cancer chemoresistance presents a challenge in oncology, often leading to treatment failure and disease progression. CD44, a multifunctional cell surface glycoprotein, has garnered attention for its involvement in various aspects of cancer biology. Through alternative splicing, CD44 can form isoforms with the inclusion of only standard exons, typical for normal tissue, or with the addition of variant exons, frequently expressed in cancer tissue and associated with chemoresistance. The functions of CD44 involved in regulation of cancer signaling pathways are being actively studied, and the significance of specific variant exons in modulating cell death pathways, central to the response of cancer cells to chemotherapy, begins to become apparent. This review provides a comprehensive analysis of the association of CD44 variant exons/total CD44 with clinical outcomes of patients undergoing chemotherapy. The role of CD44 variant exons v6, v9 and others with a significant effect on patient chemotherapy outcomes by means of key cellular death pathways such as apoptosis, ferroptosis and autophagy modulation is further identified, and their impact on drug resistance is highlighted. An overview of clinical trials aimed at targeting variant exon-containing isoforms is provided, and possible directions for further development of CD44-targeted therapeutic strategies are discussed.

Camptothecin (CPT) exhibits potent anticancer activity, but its clinical application is limited by poor solubility and severe side effects. Hyaluronic acid (HA) is gaining attention in drug delivery systems due to its excellent biocompatibility and tumor-targeting properties. In this study, we conjugated CPT to the reducing end of ultra-low molecular weight HA to create a series of HA-decorated CPT conjugates. These novel conjugates offer significant advantages over traditional HA-drug formulations, including well-defined structures and consistent drug-loading rates. In vitro studies demonstrated that these HA-decorated conjugates exhibited enhanced anti-proliferative and targeting effects towards various tumor cells. Furthermore, in vivo studies showed that HA-CPT nanoparticles significantly inhibited tumor growth with minimal side effects, as evidenced by stable body weight and histological analyses in treated mice. The approach of using structurally well-defined HA as a carrier for site-specific drug modification expands the potential applications of HA and enhances the therapeutic efficacy of conventional drugs.

This review discusses the literature data on the synthesis, physicochemical properties, and cytotoxicity of composite nanoparticles bearing the mitochondrial protein cytochrome c (cytC), which can act as a proapoptotic mediator in addition to its main function as an electron carrier in the electron transport chain. The introduction of exogenous cytC via absorption of carrier particles, the phagocytosis of colloid particles of submicrometric size, or the receptor-mediated endocytosis of nanoparticles in cancer cells, initiates the process of apoptosis-a multistage cascade of biochemical reactions leading to complete destruction of the cells. CytC-carrier composite particles have the potential for use in the treatment of neoplasms with superficial localization: skin, mouth, stomach, colon, etc. This approach can solve the two main problems of anticancer therapy: selectivity and non-toxicity. Selectivity is based on the incapability of the normal cell to absorb (nano)particles, except for the cells of the immune system. The use of cytC as a protein that normally functions in mitochondria is harmless for the macroorganism. In this review, the factors limiting cytotoxicity and the ways to increase it are discussed from the point of view of the physicochemical properties of the cytC-carrier particles. The different techniques used for the preparation of cytC-bearing colloids and nanoparticles are discussed. Articles reporting the achievement of high cytotoxicity with each of the techniques are critically analyzed.

Hyaluronic acid has been shown to possess notable properties in wound healing, skin regeneration, and anti-inflammatory effects. The formation of scar tissue is a common and unintended phenomenon during the wound-healing process, potentially leading to diverse consequences for individuals.

In the dynamic realm of translational nanorobotics, the endeavor to develop nanorobots carrying therapeutics in rational in vivo applications necessitates a profound understanding of the biological landscape of the human body and its complexity. Within this landscape, biological membranes stand as critical barriers to the successful delivery of therapeutic cargo to the target site. Their crossing is not only a challenge for nanorobotics but also a pivotal criterion for the clinical success of therapeutic-carrying nanorobots. Nevertheless, despite their urgency, strategies for membrane crossing in translational nanorobotics remain relatively underrepresented in the scientific literature, signaling an opportunity for further research and innovation. This review focuses on nanorobots with various propulsion mechanisms from chemical and physical to hybrid mechanisms, and it identifies and describes four essential biological membranes that represent the barriers needed to be crossed in the therapeutic journey of nanorobots in in vivo applications. First is the entry point into the blood stream, which is the skin or mucosa or intravenous injection; next is the exit from the bloodstream across the endothelium to the target site; further is the entry to the cell through the plasma membrane and, finally, the escape from the lysosome, which otherwise destroys the cargo. The review also discusses design challenges inherent in translating nanorobot technologies to real-world applications and provides a critical overview of documented membrane crossings. The aim is to underscore the need for further interdisciplinary collaborations between chemists, materials scientists and chemical biologists in this vital domain of translational nanorobotics that has the potential to revolutionize the field of precision medicine.

Alzheimer's disease (AD) is a slow brain degeneration disorder in which the accumulation of beta-amyloid precursor plaque and an intracellular neurofibrillary tangle of hyper-phosphorylated tau proteins in the brain have been implicated in neurodegeneration. In this study, we identified the most important genes that are unique and sensitive in the entorhinal region of the brain to target AD effectively. At first, microarrays data are selected and constructed protein-protein interaction network (PPIN) and gene regulatory network (GRN) from differentially expressed genes (DEGs) using Cytoscape software. Then, networks analysis was performed to determine hubs, bottlenecks, clusters, and signaling pathways in AD. Finally, critical genes were selected as targets for repurposing drugs. Analyzing the constructed PPIN and GRN identified CD44, ELF1, HSP90AB1, NOC4L, BYSL, RRP7A, SLC17A6, and RUVBL2 as critical genes that are dysregulated in the entorhinal region of AD suffering patients. The functional enrichment analysis revealed that DEG nodes are involved in the synaptic vesicle cycle, glutamatergic synapse, PI3K-Akt signaling pathway, retrograde endocannabinoid signaling, endocrine and other factor-regulated calcium reabsorption, ribosome biogenesis in eukaryotes, and nicotine addiction. Gentamicin, isoproterenol, and tumor necrosis factor are repurposing new drugs that target CD44, which plays an important role in the development of AD. Following our model validation using the existing experimental data, our model based on previous experimental reports suggested critical molecules and candidate drugs involved in AD for further investigations in vitro and in vivo.

CD44, a pivotal cell surface molecule, plays a crucial role in many cellular functions, including cell-cell interactions, adhesion, and migration. It serves as a receptor for hyaluronic acid and is involved in lymphocyte activation, recirculation, homing, and hematopoiesis. Moreover, CD44 is a commonly used cancer stem cell marker associated with tumor progression and metastasis. The development of CD44 aptamers that specifically target CD44 can be utilized to target CD44-positive cells, including cancer stem cells, and for drug delivery. Building on the primary sequences of our previously selected thioaptamers (TAs) and observed variations, we developed a bead-based X-aptamer (XA) library by conjugating drug-like ligands (X) to the 5-positions of certain uridines on a complete monothioate backbone. From this, we selected an XA with high affinity to the CD44 hyaluronic acid binding domain (HABD) from a large combinatorial X-aptamer library modified with N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (ADDA). This XA demonstrated an enhanced binding affinity for the CD44 protein up to 23-fold. The selected CD44 X-aptamers (both amine form and ADDA form) also showed enhanced binding affinity to CD44-overexpressing human ovarian cancer IGROV cells. Secondary structure predictions of CD44 using MFold identified several binding motifs and smaller constructs of various stem-loop regions. Among our identified binding motifs, X-aptamer motif 3 and motif 5 showed enhanced binding affinity to CD44-overexpressing human ovarian cancer IGROV cells with ADDA form, compared to the binding affinities with amine form and scrambled sequence. The effect of ADDA as a binding affinity enhancer was not uniform within the aptamer, highlighting the importance of optimal ligand positioning. The incorporation of ADDA not only broadened the XA's chemical diversity but also increased the binding surface area, offering enhanced specificity. Therefore, the strategic use of site-directed modifications allows for fine-tuning aptamer properties and offers a flexible, generalizable framework for developing high-performance aptamers that target a wide range of molecules.

Hyaluronic acid (HA) represents a pivotal component of the extracellular matrix, particularly within the context of the skin. The absorption and metabolism of orally ingested HA have been extensively investigated due to the prevalence of HA-based supplements. The objective of this study was to evaluate the impact of a combination of non-animal HA and Bifidobacterium longum novaBLG1 on dermal health following intestinal transit. The bioavailability of the compound was evaluated using a model that reproduced the human intestinal barrier in vitro, and its biological effects were investigated on skin cells via the gut-skin axis. The results demonstrated that probiotics augmented the absorption of non-animal HA by approximately 30% in comparison to non-animal HA alone and by 82% in comparison to sodium hyaluronate. Furthermore, the combination demonstrated a notable enhancement in skin cell proliferation, with increases of 16%, 8%, and 29.7% over 144 h in comparison to non-animal hyaluronan, Bifidobacterium longum novaBLG1, and sodium hyaluronate, respectively. The combination was observed to positively affect all markers of skin health and well-being, achieving its goals without any adverse effects on the gut. This approach offers a novel method for enhancing skin health.

Hyaluronic acid (HA) has received considerable attention in the reconstruction of lost periodontal tissues. HA has been proposed to play a role in cell proliferation, differentiation, migration, and cell-matrix as well as cell-cell interactions. Although various studies have been conducted, further research is needed to expand our knowledge based on HA such as its effects on cell proliferation and osteogenic differentiation. The aim of this study is to assess, in single- and multi-culture plate models, the effect of HA on the proliferation, viability, and function of periodontal ligament fibroblasts, osteoblasts, and gingival epithelial cells. A novel multi-culture cell plate was chosen to simulate a cell-cell communication as close as possible to a real clinical condition in an in vitro setting. We found that HA exclusively enhanced epithelial cell proliferation, while intercellular communication stimulated the proliferation and osteogenic potential of the osteoblasts, independently from HA use. The proliferation and function of the periodontal ligament fibroblasts were not changed by HA or the cellular interplay. The use of multi-culture plates could represent a promising method to investigate and compare dental biomaterials in experiments mimicking an in vivo environment.

The investigation of changes in the membrane of cancer cells holds great potential for biomedical applications. Malignant cells exhibit overexpression of receptors, which can be used for targeted drug delivery, therapy, and bioimaging. Targeted bioimaging is one the most accurate imaging methods with a non-invasive nature, allowing for localization of the malignant cell without disrupting cellular integrity. Also, bioimaging has the potential to enhance the quality of established imaging techniques like magnetic resonance imaging (MRI). The utilization of nanoparticles in targeted bioimaging enhances the imaging quality and efficiency. Biocompatible nanoparticles can easily penetrate cell membranes, while they can be readily functionalized on their surfaces toward cell receptors. This study reviews reports on the application of new advanced photoluminescent materials for targeted bioimaging using the cell membrane receptors. Also, the limitations and advantages of the application of nanoparticles have been reviewed along with the clinical consideration of their uses in bioimaging.

In recent years, hyaluronic acid (HA) has attracted increasing attention as a promising biomaterial for the development of drug delivery systems. Due to its unique properties, such as high biocompatibility, low toxicity, and modifiability, HA is becoming a basis for the creation of targeted drug delivery systems, especially in the field of oncology. Receptors for HA overexpressed in subpopulations of cancer cells, and one of them, CD44, is recognized as a molecular marker for cancer stem cells. This review examines the role of HA and its receptors in health and tumors and analyzes existing HA-based delivery systems and their use in various types of cancer. The development of new HA-based drug delivery systems will bring new opportunities and challenges to anti-cancer therapy.

Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential.

Using both primary donor AML cells and cell lines, we developed an in vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistance.

We identified that anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signaling as a contributing factor; the adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing the adhesion of the most primitive CD34high AML cells in primary autologous co-cultures.

Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanized monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

This comprehensive review explores the biological functions of Perilla frutescens seed proteins and peptides, highlighting their significant potential for health and therapeutic applications. This review delves into the mechanisms through which perilla peptides combat oxidative stress and protect cells from oxidative damage, encompassing free radical scavenging, metal chelating, in vivo antioxidant, and cytoprotective activities. Perilla peptides exhibit robust anti-aging properties by activating the Nrf2 pathway, enhancing cellular antioxidant capacity, and supporting skin health through the promotion of keratinocyte growth, maintenance of collagen integrity, and reduction in senescent cells. Additionally, they demonstrate antidiabetic activity by inhibiting α-amylase and α-glucosidase. The cardioprotective effects of perilla peptides are underscored by ACE-inhibitory activities and combat oxidative stress through enhanced antioxidant defenses. Further, perilla peptides contribute to improved gut health by enhancing beneficial gut flora and reinforcing intestinal barriers. In liver, kidney, and testicular health, they reduce oxidative stress and apoptotic damage while normalizing electrolyte levels and protecting against cyclophosphamide-induced reproductive and endocrine disruptions by restoring hormone synthesis. Promising anticancer potential is also demonstrated by perilla peptides through the inhibition of key cancer cell lines, alongside their anti-inflammatory and immunomodulating activities. Their anti-fatigue effects enhance exercise performance and muscle function, while perilla seed peptide nanoparticles show potential for targeted drug delivery. The diverse applications of perilla peptides support their potential as functional food additives and therapeutic agents.

The high incidence and mortality rates of colorectal cancer (CRC) in Alabama African Americans (AAs) and Oklahoma American Indians (AIs) are recognized as cancer disparities, yet the underlying causes have been poorly demonstrated. By evaluating CRC whole-exome sequencing and mutational profiles, here we report sets of mutated genes whose frequencies differed significantly (p < 0.05) in a race-specific manner. Secondary screening with cancer database identified "survival-critical genes (SCGs)" (i.e., genes whose mutations/alterations are associated with significant differences in the patients' survival rates) among the differentially mutated genes. Notable SCGs with race-pronounced variants were different from DEGs and their involved pathways included nucleotide catabolism and cell cycle checkpoints for AAs, and extracellular matrix organization for AIs. The inclusion of these SCGs with race-pronounced variants in the clinical CRC next-generation sequencing panels and the development of targeting drugs will serve as refinements for precision medicine to overcome racial disparities in health outcomes of CRC.

Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated tamoxifen-inducible TGF-β type II receptor (TβRII) knockout mice, specifically targeting ECs (TβRIIiΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRIIiΔEC mice exhibited increased tumor angiogenesis with fragile new blood vessels, increased bleeding, and hypoxia compared to control mice. Consequently, the compromised tumor microenvironment precipitated a notable surge in circulating tumor cells. Paradoxically, lung metastasis showed a significant decline. This intriguing discrepancy was explained by a reduction in the engraftment between cancer cells and ECs. Disruption of TGF-β signaling downregulated CD44 on ECs, hindering cancer cell adhesion. These findings highlight TGF-β's role in promoting metastasis by modulating EC function.

Dynamic hydrogels are emerging as advanced materials for engineering tissue-like environments that mimic cellular microenvironments. We introduce a diselenide-cross-linked hydrogel system with light-responsive properties, designed for precise control of tumor organoid growth and light-initiated radical inactivation, particularly for dendritic cell (DC) vaccines. Diselenide exchange enables stress relaxation and hydrogel remodeling, while recombination and quenching of seleno radicals (Se•) reduce cross-linking density, leading to controlled degradation. We demonstrate a 2D to 3D growth strategy, where tumor cells inoculate on the hydrogel surface, expand, and gradually form spherical organoids within the 3D hydrogel. These tumor organoids show significantly higher drug resistance compared to 2D-cultured cells. High-density light irradiation enhances diselenide exchange, inducing hydrogel degradation, tumor cell death, and release of functional antigens. This system serves as a dynamic platform for tumor organoid culture and antigen release, offering significantly advanced approaches for in vitro tumor modeling and immunological research. Our findings position diselenide-cross-linked hydrogels as versatile materials for precision cellular engineering, with broad applications in cancer research and beyond.