Search Results (4,880)

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The search for effective, new antineoplastic drugs with fewer side effects for the treatment of CRC continues, with marine-derived compounds emerging as promising candidates. Objectives: This study investigates the anticancer potential of Frondanol, a nutraceutical derived from the Atlantic Sea cucumber Cucumaria frondosa, known for its potent anti-inflammatory properties. Methods: Two human CRC cell lines, Caco-2 and HT-29, were used to test the effects of Frondanol using various in vitro approaches. Results: Frondanol significantly inhibited cell viability in a dose- and time-dependent manner. At a 1:10,000 dilution, viability decreased to around 30% in Caco-2 and 20% in HT-29 after 24 h, dropping to nearly 5% at 48 h. Furthermore, a clonogenic assay showed around 50% reduction in colony formation in both cell lines. Flow cytometry-based Annexin V staining revealed that Frondanol increased early apoptosis to ~5.2% in Caco-2 and ~9.4% in HT-29 cells, while cell cycle analysis showed accumulation of the sub G0 (apoptotic) phase increasing from 1.5% to 14.7% (Caco-2) and from 1.9% to 23.8% (HT-29). At the molecular level, Frondanol treatment significantly decreased anti-apoptotic protein B-cell lymphoma (Bcl)-2 expression while increasing the expression of the proapoptotic protein Bcl-2-associated X-protein. Additionally, Frondanol markedly induced cytochrome c release from the mitochondria and activated caspase-9, caspase-7, and caspase-3 after treatment, alongside cleavage of the caspase-3 substrate poly (ADP-ribose) polymerase. Frondanol inhibited 5-lipoxygenase activity, further contributing to its anticancer effects. Conclusions: In conclusion, Frondanol inhibits CRC cell proliferation and induces apoptosis through the mitochondrial pathway in vitro, suggesting that it is a potential nutraceutical for the prevention of human colorectal cancer or a valuable source of anticancer compounds. Full article

Background/Objectives: Adult survivors of childhood and young adult Hodgkin’s lymphoma (HL) are at a higher risk than the general population for moderate to life-threatening chronic health conditions (CHCs) including cardiac, vascular, endocrine and pulmonary impairments. Regular physical activity (PA) can improve physical fitness, reducing the risk of severity for CHCs. However, it is unclear whether adult survivors of HL experience the same benefits from PA as their peers. This scoping review aims to describe the associations between PA, physical fitness, perceived health, chronic disease and mortality in adult survivors of HL. In addition, body composition, autonomic dysfunction and associated treatment-related risk factors were included. Methods: MEDLINE (via PubMed), Web of Science, CINAHL and Cochrane databases were searched for potential studies that involved PA or physical fitness and outcomes such as body composition, autonomic dysfunction, associated treatment-related risk factors, associated chronic disease/mortality or perceived health. Results: A total of 2886 records were retrieved. After screening, 20 studies were included for review. In comparison to the general population, adult survivors of HL reported lower PA levels and had lower physical fitness. In addition, survivors were more likely to have abnormalities in body composition (i.e., reduced bone mineral density) and perceived health, autonomic dysfunctions and a higher risk of chronic disease and mortality than controls. An exposure to thoracic and neck radiotherapy seemed to be consistently associated with poor fitness (i.e., reduced muscle strength, lower cardiopulmonary fitness) and body composition, physical inactivity and autonomic dysfunctions. Conclusions: Interventional studies are needed to determine the maximum effective doses of PA regarding frequency, intensity, time, type, volume and progression (exercise prescription principles) that best optimize cardiovascular adaptations and health benefits in adult survivors of HL. Full article

Human Immunodeficiency Virus (HIV) infection is associated with a wide spectrum of urological manifestations, reflecting both the direct effects of viral infection and the indirect consequences of immunosuppression, opportunistic infections, malignancies and long-term combined antiretroviral therapy (cART). This narrative review provides a contemporary, multifaceted overview of the clinical and pathological presentations of urological conditions in people living with HIV (PLWHIV), based on articles published between 1989 and 2025. Conditions discussed include HIV-associated nephropathy (HIVAN), opportunistic genitourinary infections, malignancies such as Kaposi sarcoma and lymphoma, as well as non-infectious complications such as HIV-associated nephropathy and erectile dysfunction (ED). The review highlights the evolving epidemiology of these conditions in the cART era, with a noted decline in opportunistic infections but a rising burden of chronic kidney disease and malignancies, largely due to improved survival and ageing of the HIV-positive population. Pathological insights are explored and discussed, including mechanisms of HIV-associated renal injury, such as direct viral infection of renal epithelial cells and genetic predispositions linked to Apolipoprotein L1 (APOL1) variants. In addition, psychosocial factors, including anxiety, stress, stigma, and alcohol use, are discussed, as they may contribute to late presentation to clinical urology services. The review also considers the challenges faced in low and middle-income countries, the impact of HIV on urological services, and the important role of palliative care in advanced disease. Ultimately, this review underscores the need for early recognition, comprehensive diagnostic and surgical evaluation, and integrated social, psychological, and palliative management strategies tailored to the unique needs of PLWHIV. A deeper understanding of the interplay between HIV, cART, psychosocial determinants, and urological health is essential for improving patient outcomes and guiding future research in this evolving field. Full article

Background and Objectives: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous neoplasms. CD79B and MYD88 mutations are associated with the activated B-cell-like (ABC) subtype of DLBCL and often co-occur and lead to constitutive activation of the NF-κB pathway. Several different genetic classifications to date have recognized CD79B- and MYD88-mutated DLBCLs as a unique subtype with poor response to therapy and unfavorable survival. However, little is known about gene expression in DLBCLs with mutated CD79B (and MYD88) in comparison to their wild type counterparts. The objective of this study was to compare the gene expression in DLBCLs according to their CD79B mutational status. Methods: A total of 48 primary, treatment-naïve DLBCLs (CD79B-mutated: 35%/n = 17, CD79B-wild type: 65%/n = 31) were investigated using RNA expression profiling (770 genes), followed by immunohistochemical analysis of the up-regulated genes and survival analysis. Results: The gene expression analysis revealed that downstream of CD79B CARD11 and the NF-κB targets NFKBIZ, IL10, IL12A, PIM1 and BCL2A1 were up-regulated in CD79B-mutated DLBCLs. The strongest up-regulation was detected for ARNT2 and WNT11. Other up-regulated genes included the apoptosis-related BID and granzyme B, as well as genes of cell cycle regulation such as RUNX1, RUNX1T1 and RASGRF1. Up-regulation was also found for IL7, STAT3, MLLT4, CD14 and the HSP90B1 subunit. TP53 mutation showed an association with poorer overall survival in a secondary analysis, consistent with prior reports, while survival by CD79B/MYD88 mutation status and the differentially expressed genes showed no significant differences in this cohort. Conclusions: In conclusion, the current study identified novel up-regulated genes in CD79B-mutated DLBCLs beyond NF-κB pathway signaling, which may contribute to a better definition of potential therapeutic targets and further improves the characterization of this distinct and aggressive DLBCL subgroup. Full article

Colon cancer (CC) is a common malignancy characterized by poor prognostic outcomes and considerable mortality. Oxaliplatin (OXP) is commonly used in the treatment of CC; however, its efficacy may be limited by side effects and the development of resistance. β-sitosterol (β-Sit), a phytosterol derived from plants, has been documented to be effective in the treatment of tumors. This study aimed to investigate the potential of β-Sit to enhance the antitumor efficacy of OXP in COLO-205 cells, focusing on apoptosis induction and suppression of the vascular endothelial growth factor A (VEGF-A)/survival pathway. Molecular docking studies were performed to assess the binding affinity of β-Sit with the target proteins B-cell lymphoma 2 (Bcl-2), phosphoinositide 3-kinase (PI3K), and VEGF receptor-2 (VEGFR-2). COLO-205 cells were treated with OXP, β-Sit, or a combination of OXP + β-Sit for 48 h. The combination treatment substantially lowered the IC₅₀ achieved with 3.24 µM of OXP and 36.01 µM of β-Sit, compared to 25.64 µM for OXP alone and 275.9 µM for β-Sit alone, demonstrating a pronounced synergistic impact. The combined therapy altered the cell cycle distribution by decreasing the number of cells in the G0/G, S, and G2/M phases, coupled with an increase in the Sub-G1 population. Furthermore, apoptosis was augmented by a shift in cell death from necrosis to late apoptosis, as indicated by an increased BAX/BCL2 ratio relative to each treatment alone. Moreover, the inhibitory effect on angiogenesis was enhanced via the reduction of VEGF-A, and β-catenin and nuclear factor κB (NF-κB-p65) were suppressed, thereby preventing the growth and survival of resistant cancer cells. Additionally, molecular docking supported high binding affinities of β-Sit to Bcl-2, PI3K, and VEGFR-2. This study highlights the potential of β-Sit to enhance the anti-cancer efficacy of OXP in CC. Full article

Background/Objectives: Three-dimensional (3D) in vitro cell culture models have recently stimulated great interest since they may have more pre-clinical value than conventional in vitro 2D models. In fact, 3D culture models may mimic the in vivo biophysical 3D structure of tumors and cell-to-cell interaction, thereby representing a more useful approach to testing drug responses. In this study we have developed a 3D culture model of an EBV+/CD30+cell line, D430B, previously characterized as an Anaplastic Large Cell Lymphoma of B phenotype (B-ALCL), to determine the cytotoxic activity of the antibody–drug conjugate Brentuximab Vedotin. Methods: By using of ultra-low attachment plates, we developed D430B spheroids that appeared particularly homogenous in terms of growth and size. Results: Brentuximab Vedotin treatment (1 to 20 μg/mL) turned out to be significantly cytotoxic to these cells, while the addition of the anti-CD20 chimeric antibody Rituximab (10 μg/mL) appeared almost ineffective, even though these cells express CD20. Moreover, when we co-cultured D430B cells with stromal cells (HS5), to re-create a microenvironment representative of neoplastic cell/mesenchymal cell interactions within the lymph node, we observed a significant, although faint, protective effect. Conclusions: This simple and reproducible method of generating D430B-ALCL spheroids to evaluate their response to Brentuximab Vedotin treatment, as here described, may provide a valuable preliminary tool for the future pre-clinical screening of patients’ primary lymphoma cells or the development of novel therapies for this type of pathology and related diseases. Full article

Background: Cancer-related cachexia remains a significant cause of death, particularly for undiagnosed or untreated malignancies. Lymphomas, especially in uncommon locations, may go unrecognized until their advanced stages. Methods: We report the case of a 34-year-old woman who died from cancer-related cachexia due to undiagnosed, untreated cervical non-Hodgkin lymphoma. Four months postpartum, she reported having excluded malignancy through medical investigations, which were later confirmed to have never been performed. The Judicial Authority ordered an autopsy to determine the cause of death. A narrative literature review was conducted via PubMed using the terms “Non-Hodgkin Lymphoma” and “Autopsy,” limited to English-language human studies published between January 2000 and February 2025. Results: At autopsy, marked fat depletion and a 1350 g cervical mass were found, with significant anatomical distortion and airway narrowing due to epiglottic edema. Microscopic examination identified a diffuse large B-cell lymphoma of germinal center origin. A literature review on lymphoma-related autopsy findings identified common diagnostic challenges, including nonspecific symptoms, rapid clinical deterioration, the rarity of certain subtypes, and a lack of medical compliance. Conclusions: Early recognition and proper investigation of lymphoproliferative disorders are crucial to prevent fatal outcomes. Postmortem findings can offer valuable insights into missed diagnoses and inform strategies to reduce diagnostic delay. Full article

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with a spectrum of clinical outcomes, ranging from lifelong asymptomatic carriage to severe conditions such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although antibody responses are known to shape immune regulation, the functional relevance of IgG idiotype repertoires in HTLV-1 pathogenesis remains poorly understood. This study investigated the immunomodulatory effects of IgG from individuals with distinct HTLV-1 clinical outcomes. IgG was purified from pooled serum samples of asymptomatic carriers (ACs), HAM/TSP, and ATLL patients and used to stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors. Cytokine production in CD4⁺, CD8⁺, and γδ T cells was assessed by flow cytometry. Additionally, proteome-wide IgG reactivity was evaluated using a human protein microarray encompassing over 21,000 proteins, and bioinformatic analyses were conducted to identify protein–protein interaction networks and tissue-specific autoreactivity. HAM/TSP-derived IgG selectively enhanced IFN-γ production in all T-cell subsets and suppressed IL-4 in CD4⁺ T cells. ATLL-derived IgG induced IL-9 and IL-13 production in CD4⁺ T cells, and both HAM/TSP and ATLL IgG elevated IL-13 levels in CD8⁺ T cells. Microarray data revealed distinct autoreactive IgG profiles across clinical groups, targeting immune-related proteins, apoptotic regulators, and proteins expressed in T cells, monocytes, and non-immune tissues such as brain and testis. Notably, no functional or structural clustering was observed in protein–protein interaction networks, suggesting these reactivities reflect complex, idiotype-specific immune alterations rather than compensatory responses. The present findings suggest that HTLV-1 infection may be associated with the development of distinct IgG repertoires that potentially modulate cytokine responses and exhibit broad reactivity toward human proteins. Such patterns could contribute to immune dysregulation and may partially explain the divergent clinical trajectories observed in HAM/TSP and ATLL. Further investigations are warranted to validate these observations at the individual level and to clarify their mechanistic relevance in disease progression. Full article

Waldenström Macroglobulinaemia is an indolent disease which is recognised as contributing to a diverse range of disabling symptoms which can impact quality of life. Little data are available in evaluating patient and healthcare professional views on quality-of-life questionnaires (QLQ) used to evaluate quality of life in Waldenström Macroglobulinaemia. We aimed to assess patient perception of their disease and the relevance of the currently employed QLQs in practice by patients and healthcare professionals. One-hundred-and-twenty patients (22% treatment-naïve) and thirty-four healthcare professionals completed an international survey to understand their perception of the relevance of the currently employed QLQ. Out of 415 questions, 257 questions were classified by patients as relevant. Five themes were discerned as relevant: fatigue, mobility, dyspnoea, paraesthesia, pain in the hands and feet, sleep (physical health limitations); contentment (psychological impact); social and family support. The following were considered irrelevant: lumps or swelling, dry mouth, trouble hearing, sexual dysfunction (physical symptoms); post-traumatic stress (psychological impact); education and training and financial support. Healthcare professionals identified EORTC QLQ-C30 as the most commonly used instruments for Waldenström Macroglobulinaemia trials. Full article

Perioperative anesthesia might directly alter cancer cell biology. We investigated the effects of levobupivacaine treatment on lung adenocarcinoma cells. A549 cells were treated with levobupivacaine at concentrations of 0.1 mM and 0.5 mM for 2 h. Transfection with angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) was performed 6 h before the levobupivacaine treatment. Cell proliferation was assessed using a cell counting kit 8 (CCK-8), and ATP synthesis was evaluated with the CellTiter-Glo^® 2.0 assay at 0 and 24 h after anesthesia exposure. RT-PCR was performed to examine various biomarkers. The levobupivacaine treatment suppressed ATP synthesis without affecting cell proliferation. This was associated with the upregulation of ACE2 and the downregulation of pro-cancer biomarkers, including HIF-1α, MMP-9, and β-catenin. The anticancer effect of levobupivacaine was negated when ACE2 siRNA was introduced, and it was further suppressed when combined with levobupivacaine. The RT-PCR results indicated that the expressions of B-cell/CLL lymphoma 2 (BCL2) and wingless/integrated 1 (WNT1) were reduced after levobupivacaine treatment, but these effects were reversed with ACE2 siRNA induction. The administration of levobupivacaine suppressed A549 cell metabolism and downregulated HIF-1α, MMP-9, WNT1, EGFR, and BCL2 in an ACE2-dependent manner. Full article

L-asparaginase (L-ASNase) is a vital enzymatic drug widely used for treating acute lymphoblastic leukemia (ALL) and certain lymphomas. However, its clinical application is often limited by a short plasma half-life, pronounced immunogenicity, and systemic toxicities. To address these challenges, we recently developed conjugates of L-ASNase with cationic polymers, enhancing its cytostatic activity by increasing enzyme binding with cancer cells. The present study focuses on the development of liposomal formulations of E. coli L-asparaginase (EcA) and its conjugates with cationic polymers: the natural oligoamine spermine (spm) and a synthetic polyethylenimine–polyethyleneglycol (PEI-PEG) copolymer. This approach aims to improve enzyme encapsulation efficiency and stability within liposomes. Various formulations—including EcA conjugates with polycations incorporated into 100 nm and 400 nm phosphatidylcholine/cardiolipin (PC/CL, 80/20) anionic liposomes—were synthesized as a delivery system of high enzyme load. Fourier Transform Infrared (FTIR) spectroscopy confirmed successful enzyme association with liposomal carriers by identifying characteristic changes in the vibrational bands corresponding to both protein and lipid components. In vitro release studies demonstrated that encapsulating EcA formulations in liposomes more than doubled their half-release time (T_1/2), depending on the formulation. Cytotoxicity assays against Raji lymphoma cells revealed that liposomal formulations, particularly 100 nm EcA-spm liposomes, exhibited markedly superior anti-proliferative activity, reducing cell viability to 4.5%, compared to 35% for free EcA. Confocal Laser Scanning Microscopy (CLSM) provided clear visual and quantitative evidence that enhanced cellular internalization of the enzyme correlates directly with its cytostatic efficacy. Notably, formulations showing higher intracellular uptake produced greater cytotoxic effects, emphasizing that hydrolysis of asparagine inside cancer cells, rather than extracellularly, is critical for therapeutic success. Among all tested formulations, the EcA-spermine liposomal conjugate demonstrated the highest fluorescence intensity within cells providing enhanced cytotoxicity. These results strongly indicate that encapsulating cationically modified L-ASNase in liposomes is a highly promising strategy to improve targeted cellular delivery and prolonged enzymatic activity. This strategy holds significant potential for developing more effective and safer antileukemic therapies. Full article

Cell-mediated drug delivery systems represent a promising frontier in dermatologic therapy by offering enhanced targeting precision, prolonged drug release, and reduced systemic toxicity. These systems leverage the intrinsic properties of immune cells, stem cells, and skin-resident cells to migrate toward inflamed or diseased skin and deliver therapeutic agents in a controlled and biocompatible manner. This review explores the mechanistic foundations of cell-mediated delivery, including chemotaxis, phagocytosis, and immune modulation, and examines current applications in inflammatory skin diseases such as atopic dermatitis and psoriasis, cutaneous malignancies such as melanoma and cutaneous T-cell lymphoma, and chronic wound healing. Engineering approaches such as cell surface modification, exosome loading, and integration with gene editing technologies are also discussed. Finally, we highlight translational challenges related to immunogenicity, manufacturing scalability, and regulatory considerations, and propose future directions for clinical adoption in dermatology. This review provides a comprehensive overview of the current landscape and outlines the potential for cell-based delivery systems to transform the treatment of chronic and refractory skin diseases. Full article

Background: The aim was to evaluate whether an artificial intelligence (AI)-based tool for the automated quantification of the total metabolic tumour volume (tMTV) in patients with Hodgkin lymphoma (HL) could support nuclear medicine specialists in lesion segmentation and thereby enhance inter-observer agreement. Methods: Forty-eight consecutive patients who underwent staging with [18F]FDG PET/CT were included. Eight invited specialists from different hospitals were asked to manually segment lesions for tMTV calculations in 12 cases without AI advice, and to use automated AI segmentation in a further 12 cases, with editing as required, i.e., segmenting/adjusting 24 cases each. Each case was segmented by two specialists manually and by two different specialists using the AI tool, allowing for the pairwise comparison of inter-observer variability. Results: The median difference between two specialists performing manual tMTV segmentations was 26 cm³ (IQR 10–86 cm³) corresponding to 23% (IQR 7–50%) of the median tMTV in the dataset, while the median difference between two specialists tMTV adjustments using AI segmentations was 12 cm³ (IQR 4–39 cm³) corresponding to 9% (IQR 2–21%) (p = 0.023). The median difference in tMTV between measurements with and without AI was 3.3 cm³, corresponding to 2.3% of the median tMTV. Conclusions: An automated AI-based tool can significantly increase agreement among specialists quantifying tMTV in HL patients staged with [18F]FDG PET/CT, without markedly changing the measurements. Full article

Background and Objective: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), has demonstrated promising efficacy in chronic lymphocytic leukemia (CLL), including treatment-naïve (TN) and relapsed/refractory (R/R) patients. However, evidence synthesis across clinical trials remains limited. We conducted a systematic review and single-arm meta-analysis to evaluate the efficacy of zanubrutinib in CLL. Methods: This study was performed in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Medline, Scopus, and Web of Science were searched up to August 2025 using terms related to zanubrutinib and CLL/SLL. Eligible studies included clinical trials of zanubrutinib in TN or R/R CLL/SLL patients. Risk of bias was assessed using the JBI tool for non-randomized studies and for RCTs. Pooled estimates of efficacy outcomes were calculated using a random-effects model. Pooled estimates were calculated using the DerSimonian–Laird random-effects model, which accounts for both within- and between-study variability. Results: Seven studies (n > 1000) were included, enrolling both TN and R/R patients across diverse global populations. The pooled overall response rate (ORR) was 93.3% (95% CI, 86.7–99.8%) in mixed TN and R/R populations, 94.4% (95% CI, 91.6–97.3%) in TN patients, and 83.9% (95% CI, 75.0–92.8%) in R/R patients. Complete response (CR) rates were 12.2% (95% CI, 0.3–24.2%) overall, 13.8% (95% CI, 1.5–26.2%) in TN patients, and 5.0% (95% CI, 0.3–9.8%) in R/R patients. Partial response (PR) rates reached 86.0% (95% CI, 82.6–89.5%) in TN and 63.2% (95% CI, 53.5–73.0%) in R/R patients. Progressive disease was rare (≤1% in R/R cohorts). Heterogeneity was moderate to high across several outcomes. Conclusions: Zanubrutinib demonstrates favorable efficacy in CLL, achieving high ORR in both TN and R/R patients, with particularly durable responses in TN populations. Although complete response rates remain modest, especially among R/R patients, overall disease control appears consistent. These findings support zanubrutinib as an effective treatment option across CLL settings; however, variability among studies and the modest CR rates highlight the need for longer follow-up and direct comparative trials to further define its clinical role. Full article

Background: Recent landmark clinical trials have introduced the role of targeted therapy with surgery for resectable non-small cell lung cancers (NSCLCs). Methods: This narrative review summarizes data from recent clinical trials and retrospective studies to highlight the evolving interplay between targeted therapy and resectable NSCLC. Results: For patients with epidermal growth factor receptor (EGFR) mutations, the ADAURA trial demonstrated significant improvements in disease-free and overall survival with adjuvant osimertinib after complete resection. The NeoADAURA trial expanded the role of osimertinib to neoadjuvant treatment as it showed benefit in major pathologic response rates when compared to chemotherapy alone. Neoadjuvant osimertinib may facilitate surgical resection, especially for patients with lymph node involvement. Furthermore, the ALINA trial established the role of adjuvant alectinib, another targeted therapy, for patients with anaplastic lymphoma kinase (ALK) positive resectable NSCLC. Given the evidence for use of these novel targeted therapies in patients with resectable lung cancer, early molecular profiling is critical for patients with NSCLC to help guide pre- and postoperative treatment. The use of targeted therapies may even expand to stage IV NSCLC as clinical trials are ongoing and could possibly redefine the role of surgery in advanced disease. Conclusions: While there are ongoing trials to clarify the optimal timing of targeted therapies and surgical resection, current data supports the use of targeted therapies as part of multimodality care in surgically resectable NSCLC. Full article