Search Results (279)

Venetoclax-based therapy is effective in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but tumor lysis syndrome (TLS) risk necessitates a resource-intensive five-week dose ramp-up with intravenous hydration, frequent laboratory monitoring, and clinic-based observation, creating logistical barriers particularly in community settings. We conducted a single-center, IRB-approved retrospective pilot study of 30 patients with CLL/SLL who underwent a cytoreduction-adapted, IV-free outpatient venetoclax ramp-up with reduced laboratory monitoring between 2023 and 2026. All patients received cytoreductive therapy—predominantly single-agent BTKi—and met protocol-defined low-tumor-burden criteria (ALC < 20 × 10⁹/L, lymph nodes < 5 cm, no splenomegaly, CrCl > 45 mL/min) before venetoclax initiation. Venetoclax was self-administered at home with laboratory monitoring reduced to a single approximately 12-h post-dose assessment per dose-escalation week. Median age was 71 years; 80% had received ≥2 prior therapy lines, and 37% had high-risk cytogenetics. Monitoring compliance was 100%. No laboratory or clinical TLS, IV hydration, hospitalizations, dose interruptions, treatment discontinuations, or deaths occurred during ramp-up. These pilot data support the feasibility and early safety of simplified outpatient venetoclax initiation in adequately cytoreduced patients and warrant prospective multicenter validation. Full article

Background: Glioblastoma (GBM) has emerged as a model of resistance to immunotherapy because of the immunosuppressive tumor microenvironment (TME), which is closely associated with tryptophan metabolism. Inhibiting the expression of indoleamine 2,3-dioxygenase-1 (IDO1, a key enzyme in tryptophan metabolism) is a promising strategy for improving the immunosuppressive TME. Meanwhile, Gasdermin B (GSDMB)-mediated pyroptosis is a newly identified mechanism for activating the immune response. Methods: We prepared a GBM cell membrane (CM)-modified lipid nanoparticle (CMLNP) to deliver CRISPR/Cas9 components and mRNA encoding the N-terminal domain of GSDMB (GSDMB^NT mRNA). Results: The CM modification endowed the LNP with a tumor homing/homotypic targeting effect. Then, CRISPR/Cas9 components realized the knockdown of the IDO1 gene, thus remodeling the TME. GSDMB^NT mRNA triggers pyroptosis, thus eliciting an immune response. Conclusions: This system generated potent antitumor immunity and offered a novel strategy for GBM immunotherapy. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Background: Critical upper airway obstruction caused by advanced laryngeal malignancy poses an extreme risk of airway loss during induction of anesthesia and instrumental airway management. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has emerged as a strategy to enable safe performance of high-risk airway interventions. However, reports on heparin-free protocols in this setting remain scarce. Methods: A 46-year-old male with progressive dyspnea caused by a large laryngeal tumor reducing the residual glottic lumen to ~1 mm was admitted urgently. Safe endotracheal intubation was deemed impossible. Elective heparin-free VV-ECMO was established under local anesthesia via percutaneous femoro-femoral cannulation before induction of general anesthesia. Results: Under ECMO support, a technically demanding tracheostomy and tumor biopsy were performed without hypoxemic episodes. VV-ECMO was maintained postoperatively for 48 h without systemic anticoagulation and was weaned without hemorrhagic or thrombotic complications. Histopathology confirmed squamous cell carcinoma grade 2; the patient was discharged home after initiation of systemic immunotherapy. Conclusions: Elective heparin-free VV-ECMO can provide effective and safe respiratory support for patients with critical airway obstruction undergoing high-risk airway procedures. Pre-emptive cannulation under local anesthesia, femoro-femoral access in anatomically compromised necks, and short heparin-free circuit runs mitigate both airway and hemorrhagic risk. Prospective studies are needed to establish standardized patient selection criteria and anticoagulation protocols. Full article

Colorectal cancer (CRC) presents high incidence and mortality, largely due to late diagnosis and the persistence of cancer stem cells (CSCs), which contribute to chemoresistance and poor patient outcomes. TRAIL (TNF-related apoptosis-inducing ligand) is considered a promising therapeutic agent because of its ability to selectively induce apoptosis through DR4/DR5 receptors. Mesenchymal stem cells (MSCs) have been explored as TRAIL delivery vehicles, taking advantage of their tumor-homing capacity and sustained protein expression. However, TRAIL monotherapy has shown limited efficacy, prompting research into strategies to enhance its pro-apoptotic effect, including its combination with chemotherapeutics that upregulate TRAIL receptors. Methods: We evaluated the effect of irinotecan (IRINO) in Caco-2 cells and primary CRC cultures. In addition, we analyzed the cytotoxic activity of sTRAIL-MSCs and its impact on CSC markers, both alone and in combination with IRINO in Caco-2 cells. Results: Caco-2 cells and 87.5% of primary cultures were resistant to IRINO. sTRAIL-MSCs induced higher cell death (50–80%) at ratios of 1:3 and 1:6, while its combination with IRINO achieved 50–60%. Additionally, sTRAIL-MSCs reduced CSC marker expression at 24 and 48 h. Conclusions: IRINO did not enhance the cytotoxicity of sTRAIL-MSC, but it did enhance downregulated markers such as KRT-18, CD44v6, and EpCAM, and it represents a promising therapeutic strategy against CRC. Full article

Macrophage-derived extracellular vesicles (EVs) have emerged as promising biomimetic platforms for targeted cancer drug delivery due to their biocompatibility, immune-modulatory properties, and tumor-homing capabilities. Among macrophage subtypes, M1-polarized macrophages exhibit potent anti-tumor functions characterized by pro-inflammatory cytokine secretion, improved antigen presentation, and the ability to remodel the tumor microenvironment (TME). Utilizing these properties, M1-polarized macrophage-derived EVs serve as cell-free therapeutic systems capable of delivering bioactive cargo while simultaneously promoting anti-tumor immune responses. However, the clinical application of natural EVs is limited by low yield, heterogeneity, and challenges in large-scale production. Artificial nanovesicles (ANVs) have been developed to address these limitations, offering improved scalability, compositional control, and reproducibility. This review provides an overview of macrophage differentiation and polarization, with a focus on the immunological profile and anti-tumor mechanisms of M1-polarized macrophages. It further discusses current methodologies for EV isolation and ANV generation, along with cargo loading strategies that balance encapsulation efficiency and vesicle stability. In addition, this review also emphasizes their targeting approaches, cellular uptake pathways, and the intracellular trafficking mechanisms that influence delivery efficiency and therapeutic outcomes. Key challenges, including standardization, biological barriers, and functional consistency, are critically evaluated. Emerging strategies that integrate vesicle engineering with personalized medicine underscore the potential of these systems to advance precision oncology. Full article

Antibody–drug conjugates (ADCs) are a promising therapeutic modality for treating cancer. TM4SF1 is an integral membrane protein that internalizes from the cell surface along microtubules to the nucleus and is highly expressed on the surface of both tumor endothelium and tumor cells. We previously reported that in human tumor xenografts in mice, an ADC directed to mouse TM4SF1 (2A7A-LP2) effectively regressed tumors through an anti-vascular mechanism, and an ADC directed to human TM4SF1 (v1.10-LP2) effectively regressed tumors through an anti-tumor cell mechanism. In this study, we investigated the actions of the mouse TM4SF1-directed ADC on VEGF-A-provoked angiogenic vessels. We employed an adenovirus expressing mouse VEGF-A¹⁶⁴ (Ad-VEGF-A) to induce surrogate tumor blood vessels in the ears of nude mice. We showed that an immune effector function-ablated ADC, 3m2A7A-LP2, was better tolerated than its parent 2A7A-LP2. Homing of 3m2A7A to Ad-VEGF-A-induced new blood vessels became evident within six hours after intraperitoneal injection. A single dose of 3m2A7A-LP2 at 3 mg/kg disrupted evolving Ad-VEGF-A-provoked blood vessels within forty-eight hours, and three doses of 3m2A7A-LP2 at 48 h intervals caused striking local ear necrosis; in each case, there was no apparent harm to vessels in the corresponding control virus-injected ears and the surrounding tissues of the same mice. Our studies demonstrate that an ADC-directed against mouse TM4SF1 specifically targeted the newly formed blood vessels induced by Ad-VEGF-A at multiple stages of their development. Thus, TM4SF1-directed ADCs, through their ability to target angiogenic vessels, represent an alternative anti-angiogenic approach for treating solid tumors. Full article

Integrins and other cell adhesion molecules play a critical role in the migration and homing of leukocytes. This study investigates whether metastatic tumor cells can exploit leukocyte-like rolling and arrest mechanisms during early vascular steps of metastatic dissemination. B16 melanoma cell adhesion to activated bEnd.3 endothelial monolayers or immobilized VCAM-1 were analyzed under defined shear flow using a parallel-plate chamber. Function-blocking antibodies, divalent cation modulation, pertussis toxin, and low-temperature conditions were used as classical controls. B16-BL6 melanoma cells exhibited robust VLA-4-dependent rolling and arrest on activated endothelial monolayers and on immobilized VCAM-1 under physiological shear stresses (0.7–2 dyn/cm²), independent of chemokine-related Gαi signaling. These findings identify a chemokine-independent mechanism of VLA-4-mediated vascular capture by melanoma cells under shear flow, providing a potential mechanistic basis for early steps in metastatic dissemination. Full article

Background: Exosomes (Exos) derived from immune cells are emerging as potent drug delivery vectors. However, their biodistribution in clinically relevant lung cancer models remains underexplored. This study aimed to evaluate the lung-homing ability of NK cell Exos (NK-Exos) compared to mesenchymal stem cell Exos (MSC-Exos) in an orthotopic lung cancer model. Methods: Male SCID mice were orthotopically injected with luciferase-tagged A549 cells into the left lung to establish the tumor model. Mice were randomized into four groups: G1 (Healthy Control), G2 (Tumor Control + PBS), G3 (Tumor + DiR-labeled NK-Exos; 5 µM DiR + 5–7 × 10⁹ Exo particles/100 μL/mouse), and G4 (Tumor + DiR-labeled MSC-Exos; 5 µM DiR + 5–7 × 10⁹ Exo particles/100 μL/mouse). Six hours (15 min, 1 h, 2 h, 4 h, 6 h) post-intravenous injection, ex vivo biodistribution was assessed using the MILabs Spectrum imaging system. Results: Umbilical cord blood-NK-Exos (UCB-NK-Exos; G3) exhibited superior accumulation in lung tissues compared to UCB-MSC-Exos (G4), suggesting enhanced pulmonary retention. Intra-pulmonary analysis revealed an asymmetric distribution, with significantly higher radiant efficiency in the right lung (non-tumor bearing) compared to the left lung (tumor injection site) across Exo-treated groups. Conclusions: UCB-NK-Exos demonstrate distinct lung-targeting properties superior to MSC-Exos, supporting their potential as therapeutic carriers. Full article

Background/Objectives: The F3 peptide, a tumor-homing peptide known to bind cell-surface nucleolin, is frequently employed as a targeting vector in cancer research. However, the impact of the modification site on its cellular binding properties has not been investigated yet. In this work, we aimed to design an improved F3-based radioconjugate by identifying the optimal conjugation site and establishing a protocol for its biological evaluation in vitro. To achieve this, we compared F3 peptide derivatives modified at their N- or C-termini with DOTA for complexation of indium-111 (¹¹¹In) for SPECT or Auger electron therapy or a fluorophore (FITC) for optical imaging. Methods: N-and C-terminal DOTA-modified F3 peptides were radiolabeled with indium-111 and compared for their in vitro stability in different physiologically relevant media. Suitable nucleolin-positive cell lines for further in vitro studies were identified by confocal microscopy of a FITC-labeled F3 peptide derivative. The radioconjugates were then investigated on MDA-MB-231 (breast cancer) and PC-3 (prostate cancer) cells for nucleolin-specific cell binding and uptake, and several parameters of the in vitro assays were varied to establish a suitable protocol. Results: In general, in vitro assays with F3 peptide conjugates are challenging, as the outcome depends on a number of experimental parameters, leading, in some cases, to varying results. In particular, the presence of Ca²⁺ and Mg²⁺ had a decisive impact on the results, likely because the metal ions compete with the binding of F3 conjugates to nucleolin. The C-terminal modified, ¹¹¹In-labeled F3 radioconjugate performed better than the N-terminal modified analog. While several parameters of the in vitro experiments were optimized, the overall cell uptake in vitro of radioactivity was still low (<2% of applied radioactivity). Conclusions: A standardized in vitro protocol for evaluating F3 peptide conjugates on cancer cells was established, revealing that the C-terminus is the preferred site for modification. Because the cellular uptake of the radiotracer was shown to likely not be sufficient for radiotracer development, further studies on the optimization of the F3 peptide conjugates, including structural modifications, are required. Full article

Background/Objectives: Treatment disruptions and discontinuations during systemic cancer therapy are common and can compromise treatment delivery and outcomes. Structured exercise and mind–body interventions improve cancer-related symptoms, but their impact on treatment disruptions and discontinuations remains unclear. This secondary analysis of the IMPROVE trial evaluated whether participation in Integrative Medicine at Home (IM@Home), a digital multimodal mind–body and structured exercise program, was associated with differences in treatment discontinuation and related treatment disruption outcomes among patients undergoing systemic therapy. Methods: A total of 127 adults with solid tumors were randomized to IM@Home (n = 64) or enhanced usual care (EUC; n = 63) for 12 weeks. Treatment discontinuation, dose delays, dose reductions, and overall treatment disruptions were compared between arms using chi-square tests and regression models adjusted for cancer type and disease stage. Results: In unadjusted analyses, treatment discontinuation occurred less frequently in the IM@Home group compared with EUC (9.4% vs. 22.6%; p = 0.043), but this association was attenuated after adjustment for cancer type and disease stage (aOR 0.41, 95% CI 0.13–1.17; p = 0.105). The proportion of patients experiencing any treatment disruption, as well as rates of dose delays and dose reductions, did not differ significantly between groups (p = 0.16, p = 0.18, and p = 0.85, respectively). In contrast, IM@Home participants experienced fewer treatment disruption events per patient (adjusted RR 0.58, 95% CI 0.35–0.96; p = 0.036). Conclusions: These exploratory findings suggest that digital structured exercise and mind–body programs may help mitigate treatment interruptions during systemic cancer therapy and should be explored further in an adequately powered prospective trial to confirm these promising findings. Full article

Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to conventional chemotherapy. We evaluated a cell-based enzyme–prodrug therapy using adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) or carboxylesterase 2 (CE2), paired with their respective prodrugs 5-fluorocytosine (5-FC) or irinotecan (CPT-11), to compare their antitumor efficacy. Materials and Methods: Human telomerase reverse transcriptase (hTERT)-immortalized ADSCs were transduced with CD or CE2, and transgene expression and stem cell phenotype were confirmed. CD expression was verified at the transcript level and by functional 5-FC-to-5-fluorouracil (5-FU) conversion, whereas CE2 expression was verified by transcript analysis and immunoblotting. Tumor tropism toward PC3 prostate cancer cells was tested using migration assays and analysis of chemoattractant ligand/receptor expression. Prodrug-induced self-killing and bystander tumor cell killing were assessed through viability assays and co-culture with PC3 cells. For the CE2/CPT-11 system, SN-38 was not directly quantified; functional activity was inferred from prodrug-dependent cytotoxicity and in vivo efficacy. In vivo efficacy was evaluated in nude mice with PC3 tumors treated systemically with engineered ADSCs plus prodrug. Results: CD- and CE2-expressing ADSCs were successfully established and retained mesenchymal stem cell (MSC) characteristics. Both cell types exhibited significant migration toward PC3 cells. The CE2/CPT-11 system produced stronger prodrug-mediated cytotoxicity than CD/5-FC, with CE2-modified ADSCs showing higher sensitivity to CPT-11 and inducing greater apoptosis in co-cultured PC3 cells. In vivo, both treatments suppressed tumor growth, but CE2/CPT-11 achieved greater inhibition (tumor volume ~26% of control vs. ~32% for CD/5-FC at day 14). No overt clinical toxicity was observed based on body weight and daily clinical monitoring; however, hematology/serum chemistry were not assessed. Conclusions: Engineered ADSCs home to CRPC tumors and enable local prodrug activation, producing significant antitumor effects. Within the constraints of our in vitro assays and subcutaneous xenograft model, CE2/CPT-11 demonstrated stronger efficacy outcomes than CD/5-FC. Mechanistic attribution to intratumoral SN-38 exposure should be confirmed by direct metabolite measurements in future studies. Full article

Conventional drug delivery systems often suffer from problems such as limited targeting specificity, short half-lives, poor biocompatibility, and systemic toxicity, which significantly limit their therapeutic efficacy against major diseases like cancer. Blood cells, as native components of the human circulatory system, offer distinct advantages including low immunogenicity, long circulation times, remarkable mechanical flexibility, and innate ability to home to disease sites. These attributes make blood cells a promising platform for next-generation targeted drug carriers. In this review, we examine the biological and mechanical properties of red blood cells, white blood cells, platelets, and cell-derived membrane vesicles. We highlight recent advances in how these cells are engineered and loaded with drugs, and their application in tumor-targeted therapy, while also considering their potential in other diseases. We also discuss current technical challenges and outline future directions for clinical translation, offering a practical perspective on advancing blood cell-based delivery technologies. Full article

Ustilago maydis is an economically significant biotrophic smut fungus, capable of infecting maize. This is a localized infection where tumors are formed, potentially in any of the aboveground parts of the plant. In extreme cases, maize plants may die. It is also dimorphic, i.e., it is capable of switching from yeast-like to filamentous forms. The switch can be induced by nitrogen sources, pH, and some lipids/oils. The active infectious form is the filamentous form which is capable of penetrating plant cells using the appressorium. This study focuses on understanding the mitochondrial genome diversity in U. maydis, the selection pressure on the genes encoded in the mitochondrial genome, and the phylogeny of the strains investigated. The results suggest that the strains maintained high consistency in genome architecture and synteny. The cox1 and cob genes in the genomes possessed different intron numbers, with the presence or absence of homing endonuclease genes (HEGs), which overall contributed to the differences in the genome sizes. Among the genes in the mitogenome, nad6 was the only gene that has a non-synonymous nucleotide change, but the overall changes within the mitogenomes suggest purifying selection. The study helped identify the different mitotypes using PCR, although further markers or whole-genome sequencing may be required to fully distinguish mitotypes. Full article

Background: Exercise has been suggested as a supplementary modality for Inflammatory Bowel Disease (IBD), but supporting evidence remains scarce. We aimed to assess whether a 12-week physical exercise intervention improves quality of life (QOL) in adults with active IBD. Methods: An open-labeled randomized controlled trial examining the efficacy of a 12-week physical exercise intervention on QOL in adults (18–65 years) with active IBD. Participants were randomized 1:1 into either an intervention group, with two weekly supervised exercise sessions and one home session, or a control group with standard care. QOL by the Inflammatory Bowel Disease Questionnaire (IBDQ) was the primary outcome. Secondary outcomes were the European Quality of Life 5 Dimensions (EQ5D), waist circumference, blood pressure, disease activity, and lipid status. Explorative outcomes were C-reactive protein, fecal calprotectin, and cytokines (interleukin-6, -8, and -10 and tumor necrosis factor). Results: We screened 183 patients and included 44 participants, with 22 in each group. Eleven participants completed more than 50% of the exercise sessions. Among the participants, 17 were male, 27 were female, and the mean age was 37 years. The mean IBDQ scores at week 12 showed no statistically significant difference: 172 for the intervention group (95%CI: 158–185) and 164 for the control group (95%CI: 151–178). No clinically significant differences for secondary or exploratory outcomes were found. Conclusions: We did not find any difference in the QOL after a 12-week exercise intervention in patients with active IBD compared to standard care. Recruiting proved difficult, as did adherence to exercise sessions, mostly due to scheduling issues. Full article