Search Results (1,777)

Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the underlying mechanisms remain incompletely understood. This study highlights a notable increase in the expressions of ALCAT1 and PLSCR3 during the advanced stage of lipopolysaccharide (LPS)-induced SCM. This up-regulation potential contribution to mitochondrial dysfunction and cellular apoptosis—as indicated by the augmented oxidative stress and cytochrome c (Cytc) release—coupled with reduced mitophagy, decreased levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) and lowered cell viability. Additionally, the timing of LPS-induced apoptosis coincides with the decline in both autophagy and mitophagy at the late stages, implying that these processes may serve as protective factors against LPS-induced SCM in HL-1 cells. Together, these findings reveal the mechanism of LPS-induced CL changes in the center of SCM, with a particular emphasis on the importance of pathological remodeling and translocation of CL to mitochondrial function and apoptosis. Additionally, it highlights the protective effect of mitophagy in the early stage of SCM. This study complements previous research on the mechanism of CL changes in mediating SCM. These findings enhance our understanding of the role of CL in cardiac pathology and provide a new direction for future research. Full article

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates. Full article

Diffuse large B-cell lymphoma is considered the most found non-Hodgkin lymphoma in adults. Diffuse large B-cell lymphoma, which also occurs in sporadic forms, is associated with some pathological conditions, including human immunodeficiency virus infection, especially if it progresses to AIDS. The authors report the case of a 45-year-old man with AIDS in whom a postmortem diagnosis of diffuse large B-cell lymphoma was performed. The proposed images document extensive pluri-visceral involvement, already visible macroscopically, and subsequently confirmed through histological examination. Full article

Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, with ~40% of patients experiencing refractory or relapsed disease. Given the low response rates to current therapy, alternative treatment strategies are necessary to improve patient outcomes. Here, we sought to develop an easily accessible new xenograft mouse model that better recapitulates the human disease for preclinical studies. We generated two Luciferase (Luc)-EGFP-expressing human DLBCL cell lines representing the different DLBCL cell-of-origin subtypes. After intravenous injection of these cells into humanized NSG mice, we monitored the tumor growth and evaluated the organ-specific engraftment/progression period. Our results showed that human IL6-expressing NSG (NSG-IL6) mice were highly permissive for DLBCL cell growth. In NSG-IL6 mice, systemic engraftments of both U2932 activated B cell-like- and VAL germinal B cell-like-DLBCL (engraftment rate; 75% and 82%, respectively) were detected within 2nd-week post-injection. In the organ-specific ex vivo evaluation, both U2932-Luc and VAL-Luc cells were initially engrafted and expanded in the spleen, liver, and lung and subsequently in the skeleton, ovary, and brain. Consistent with the dual BCL2/MYC translocation association with poor patient outcomes, VAL cells showed heightened proliferation in human IL6-conditioned media and caused rapid tumor expansion and early death in the engrafted mice. We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts. Full article

Background: Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells. Methods: Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 mM for 2 h. Angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) transfection was performed 6 h prior to ropivacaine administration. Cell proliferation and migration were assessed with cell counting kit 8 (CCK-8) and a wound healing assay at 0 and 24 h after anesthesia exposure. PCR arrays were performed, followed by PCR validation. Results: Ropivacaine administration inhibited A549 cell proliferation and migration in a concentration-dependent manner, with ACE2 upregulation and HIF1α (hypoxia-inducible factor 1α) downregulation. The anticancer effect of ropivacaine was canceled out via ACE2 siRNA transfection. PCR arrays showed specific gene change patterns in the ropivacaine and respective ACE2-knockdown groups. EGFR (epidermal growth factor receptor), BAX (Bcl-2-associated X protein) and BCL2 (B-cell/CLL lymphoma 2) were suppressed with ropivacaine administration; these effects were reversed via ACE2 siRNA induction. Conclusion: Ropivacaine administration inhibited A549 cell biology in conjunction with ACE2 upregulation via the inhibition of the Wnt1 (wingless/Integrated 1) pathway. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy worldwide. Molecular classifications have tried to improve cure rates. We prospectively examined and correlated the mutational landscape with the clinical features and outcomes of 185 Mexican patients (median age 59.3 years, 50% women) with newly diagnosed DLBCL. A customized panel of 79 genes was designed, based on previous international series. Most patients had ECOG performance status (PS) < 2 (69.2%), advanced-stage disease (72.4%), germinal-center phenotype (68.1%), and double-hit lymphomas (14.1%). One hundred and ten (59.5%) patients had at least one gene with driver mutations. The most common mutated genes were as follows: TP53, EZH2, CREBBP, NOTCH1, and KMT2D. The median follow-up was 42 months, and the 5-year relapse-free survival (RFS) and overall survival (OS) rates were 70% and 72%, respectively. In the multivariate analysis, both age > 50 years and ECOG PS > 2 were significantly associated with a worse OS. Our investigation did not reveal any discernible correlation between the presence of a specific mutation and survival. In conclusion, using a customized panel, we characterized the mutational landscape of a large cohort of Mexican DLBCL patients. These results need to be confirmed in further studies. Full article

Oxidative stress (OS) and apoptosis are critical factors in placental development and function. Their interplay influences trophoblast proliferation, differentiation, and invasion, as well as vascular development. An imbalance between these processes can lead to pregnancy-related disorders such as preeclampsia, intrauterine growth restriction, and even spontaneous abortion. Our study seeks to elucidate the associations between preventive antioxidant/protective OS response factors—glutathione (GSH), MutT Homolog 1 (MTH1), and apoptotic regulation modulators—tumor protein p53 and B-cell lymphoma (Bcl-2) transcripts, in the context of spontaneous abortion (30 samples) versus elective termination of pregnancy (20 samples), using immunohistochemistry (IHC) to determine their proteomic expression in chorionic villi within abortive fetal placenta tissue samples. Herein, comparative statistical analyses revealed that both OS response factors, GSH and MTH1, were significantly under-expressed in spontaneous abortion cases as compared to elective. Conversely, for apoptotic regulators, p53 expression was significantly higher in spontaneous abortion cases, whereas Bcl-2 expression was significantly lower in spontaneous abortion cases. These findings suggest that a strong pro-apoptotic signal is prevalent within spontaneous abortion samples, alongside reduced anti-apoptotic protection, depleted antioxidant defenses and compromised oxidative DNA damage prevention/repair, as compared to elective abortion controls. Herein, our hypothesis that OS and apoptosis are closely linked processes contributing to placental dysfunction and spontaneous abortion was thus seemingly corroborated. Our results further highlight the importance of maintaining redox homeostasis and apoptotic regulation for a successful pregnancy. Understanding the mechanisms underlying this interplay is essential for developing potential therapies to manage OS, promote placentation, and avoid unwanted apoptosis, ultimately improving pregnancy outcomes. Antioxidant supplementation, modulation of p53 activity, and the enhancement of DNA repair mechanisms may represent potential approaches to mitigate OS and apoptosis in the placenta. Further research is needed to explore these strategies and their efficacy in preventing spontaneous abortion. Full article

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas. Full article

Cervical cancer is a leading cause of gynecological malignancies and cancer-related deaths among women worldwide. This study investigates the anti-cancer activity of Thua Nao, a Thai fermented soybean, against HeLa cervical carcinoma cells, and explores its underlying mechanisms. Our findings reveal that the ethyl acetate fraction of Thua Nao (TN-EA) exhibits strong anti-cancer potential against HeLa cells. High-performance liquid chromatography (HPLC) analysis identified genistein and daidzein as the major isoflavones in TN-EA responsible for its anti-cancer activity. TN-EA and genistein reduced cell proliferation and induced G2/M phase arrest, while daidzein induced G1 arrest. These responses were associated with the downregulation of cell cycle regulators, including Cyclin B1, cycle 25C (Cdc25C), and phosphorylated cyclin-dependent kinase 1 (CDK-1), and the upregulation of the cell cycle inhibitor p21. Moreover, TN-EA and its active isoflavones promoted apoptosis in HeLa cells through the intrinsic pathway, evidenced by increased levels of cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3, loss of mitochondrial membrane potential, and the downregulation of anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), cellular inhibitor of apoptosis proteins 1 (cIAP), and survivin. Additionally, TN-EA and its active isoflavones effectively reduced cell invasion and migration by downregulating extracellular matrix degradation enzymes, including Membrane type 1-matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), and reduced the levels of the mesenchymal marker N-cadherin. At the molecular level, TN-EA suppressed STAT3 activation via the regulation of JNK and Erk1/2 signaling pathways, leading to reduced proliferation and invasion of HeLa cells. Full article

Microsatellite instability (MSI) is a crucial feature in cancer biology, yet its prevalence and significance in canine cancers remain largely unexplored. This study conducted a comprehensive analysis of MSI across 10 distinct canine cancer histotypes using whole-exome sequencing data from 692 tumor-normal sample pairs. MSI was detected in 64% of tumors, with prevalence varying significantly among cancer types. B-cell lymphomas exhibited the highest MSI burden, contrasting with human studies. A novel “MSI-burden” score was developed, correlating significantly with tumor mutational burden. MSI-high (MSI-H) tumors showed elevated somatic mutation counts compared to MSI-low and microsatellite stable tumors. The study identified 3632 recurrent MSI-affected genomic regions across cancer types. Notably, seven of the ten cancer types exhibited MSI-H tumors, with prevalence ranging from 1.5% in melanomas to 37% in B-cell lymphomas. These findings highlight the potential importance of MSI in canine cancer biology and suggest opportunities for targeted therapies, particularly immunotherapies. The high prevalence of MSI in canine cancers, especially in B-cell lymphomas, warrants further investigation into its mechanistic role and potential as a biomarker for prognosis and treatment response. Full article

Background: Patients with B-lymphocyte malignancies (BCMs) receiving B-lymphocyte-targeted therapies have increased risk of severe COVID-19 outcomes and impaired antibody response to SARS-CoV-2 mRNA vaccination in comparison to non-hematologic oncologic patients or general population. Consequently, it is vital to explore vaccine-induced T-lymphocyte responses in patients referred for the understanding of immune protection against SARS-CoV2 infections. The objective of the present study was to analyze the recall immune responses carried out by T lymphocytes after two COVID-19 mRNA vaccine doses. Methods: We enrolled 40 patients with BCMs and 10 healthy controls (HCs) after 4 weeks from the second mRNA vaccine dose. Spike (S)-specific T-lymphocyte responses were assessed in peripheral blood mononuclear lymphocytes (PBMCs) by intracellular IFN-γ staining combined with flow cytometry. Furthermore, the humoral response was assessed with the measurement of anti-spike antibodies. Results: From March to July 2021, 40 patients (median age 68) received mRNA vaccines. The overall antibody response for BCMs was 52.5% versus 100% for the healthy controls (p = 0.008). The antibody response was different across BCMs: 18.75% for non-Hodgkin lymphoma, 54.5% for chronic lymphocytic leukemia, and 92.3% for multiple myeloma. Responses varied by malignancy type and treatment, with anti-CD20 therapies showing the lowest response (6.7%). T-lymphocyte analysis revealed reduced numbers and altered differentiation stages in patients compared to the controls. However, the vaccine-induced T response was generally robust, with variations in specific T subpopulations. Conclusions: mRNA vaccines induced significant humoral and cellular immune responses in B-cell lymphoid malignancy patients, although responses varied by treatment type and malignancy. Further research is needed to optimize vaccination strategies in this population. Full article

Drug resistance remains a critical barrier in cancer therapy, diminishing the effectiveness of chemotherapeutic, targeted, and immunotherapeutic agents. Overexpression of proteins such as B-cell lymphoma 2 (Bcl-2), inhibitor of apoptosis proteins (IAPs), protein kinase B (Akt), and P-glycoprotein (P-gp) in various cancers leads to resistance by inhibiting apoptosis, enhancing cell survival, and expelling drugs. Although several inhibitors targeting these proteins have been developed, their clinical use is often hampered by systemic toxicity, poor bioavailability, and resistance development. Nanoparticle-based drug delivery systems present a promising solution by improving drug solubility, stability, and targeted delivery. These systems leverage the Enhanced Permeation and Retention (EPR) effect to accumulate in tumor tissues, reducing off-target toxicity and increasing therapeutic efficacy. Co-encapsulation strategies involving anticancer drugs and resistance inhibitors within nanoparticles have shown potential in achieving coordinated pharmacokinetic and pharmacodynamic profiles. This review discusses the mechanisms of drug resistance, the limitations of current inhibitors, and the advantages of nanoparticle delivery systems in overcoming these challenges. By advancing these technologies, we can enhance treatment outcomes and move towards more effective cancer therapies. Full article

Background: Spinal cord lymphomas represent a minority of extranodal lymphomas and often pose diagnostic challenges by imitating primary spinal tumors or inflammatory/infective lesions. This paper presents a unique case of primary cauda equina lymphoma (PCEL) and conducts a comprehensive review to delineate the clinical and radiological characteristics of this rare entity. Case Report: A 74-year-old male presented with progressive paresthesia, motor weakness, and symptoms indicative of cauda equina syndrome. Neurological examination revealed paraparesis and sphincter dysfunction. Imaging studies initially suggested an intradural meningioma. However, surgical intervention revealed a diffuse large B-cell lymphoma infiltrating the cauda equina. Findings: A systematic review of the pertinent literature identified 18 primary cauda equina lymphoma cases. These cases exhibited diverse clinical presentations, treatments, and outcomes. The mean age at diagnosis was 61.25 years for women and 50 years for men, with an average follow-up of 16.2 months. Notably, 35% of patients were alive at 18 months, highlighting the challenging prognosis associated with PCEL. Discussion: Primary spinal cord lymphomas, especially within the cauda equina, remain rare and diagnostically complex due to their nonspecific clinical manifestations. The review highlights the need to consider spinal cord lymphoma in patients with neurological symptoms, even without a history of systemic lymphoma. Diagnostic Approaches: Magnetic resonance imaging (MRI) serves as the primary diagnostic tool but lacks specificity. Histopathological examination remains the gold standard for definitive diagnosis. The review underscores the importance of timely biopsy in suspected cases to facilitate accurate diagnosis and appropriate management. Management and Prognosis: Current management involves biopsy and chemotherapy; however, optimal treatment strategies remain ambiguous due to the rarity of PCEL. Despite aggressive therapeutic interventions, prognosis remains poor, emphasizing the urgency for enhanced diagnostic and treatment modalities. Conclusions: Primary cauda equina lymphoma poses diagnostic and therapeutic challenges, necessitating a high index of suspicion in patients with atypical spinal cord symptoms. Collaborative efforts between neurosurgical, oncological, and infectious diseases teams are imperative for timely diagnosis and management. Advancements in diagnostic precision and therapeutic options are crucial for improving patient outcomes. Full article

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T–cell lymphomas (PTCLs) represent aggressive mature T–cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T–cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments. Full article

10-hydroxy-2-decenoic acid (10-HDA), which is a unique bioactive fatty acid of royal jelly synthesized by nurse bees for larvae and adult queen bees, is recognized for its dual utility in medicinal and nutritional applications. Previous research has indicated that 10-HDA exerts antitumor effects on numerous tumor cell lines, including colon cancer cells, A549 human lung cancer cells, and human hepatoma cells. The present study extends this inquiry to lymphoma, specifically evaluating the impact of 10-HDA on the SU-DHL-2 cell line. Our findings revealed dose-dependent suppression of SU-DHL-2 cell survival, with an IC₅₀ of 496.8 μg/mL at a density of 3 × 10⁶ cells/well after 24 h. For normal liver LO2 cells and human fibroblasts (HSFs), the IC₅₀ values were approximately 1000 μg/mL and over 1000 μg/mL, respectively. The results of label-free proteomics revealed 147 upregulated and 347 downregulated differentially expressed proteins that were significantly enriched in the complement and coagulation cascades pathway (adjusted p-value = 0.012), including the differentially expressed proteins prothrombin, plasminogen, plasminogen, carboxypeptidase B2, fibrinogen beta chain, fibrinogen gamma chain, and coagulation factor V. The top three hub proteins, ribosomal protein L5, tumor protein p53, and ribosomal protein L24, were identified via protein–protein interaction (PPI) analysis. This result showed that the complement and coagulation cascade pathways might play a key role in the antitumor process of 10-HDA, suggesting a potential therapeutic avenue for lymphoma treatment. However, the specificity of the effect of 10-HDA on SU-DHL-2 cells warrants further investigation. Full article