Search Results (12,908)

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of abnormal plasma cells within the bone marrow, followed by potential dissemination to extramedullary sites. The bone marrow barrier (BMB) plays a pivotal role in plasma cell homing and disease progression. Bone marrow endothelial cells (BMECs) and bone marrow stromal cells (BMSCs), through their interactions with MM cells, secrete adhesion molecules, angiogenic cytokines, anti-apoptotic factors, and growth-promoting signals that support MM cell survival and proliferation. This review examines the components of the BMB and the major pathways involved in MM pathogenesis. Targeting the interactions between MM cells and the BMB may offer novel therapeutic opportunities. Full article

Breast cancer (BC) is the most common malignancy and the second-leading cause of cancer-related mortalities in women. Epidemiological studies suggested the reduced BC incidence in Mediterranean populations due to the daily consumption of diets rich in extra-virgin olive oil (EVOO). EVOO secoiridoid phenolics are widely known for their positive outcomes on multiple cancers, including BC. The current study investigates the suppressive effects of individual and combined EVOO phenolics for BC progression and motility. Screening of a small library of EVOO phenolics at a single dose of 10 µM against the viability of the BC cell lines ZR-75-1 (luminal A) and MDA-MB-231 (triple negative BC, TNBC) identified oleocanthal (OC) and ligstroside aglycone (LA) as the most active hits. Screening of EVOO phenolics for BC cells migration inhibition identified OC, LA, and the EVOO lignans acetoxypinoresinol and pinoresinol as the most active hits. Combination studies of different olive phenolics showed that OC combined with LA had the best synergistic inhibitory effects against the TNBC MDA-MB-231 cells migration. A combination of 5 µM of each of OC and LA potently suppressed the migration and invasion of the MDA-MB-231 cells versus LA and OC individual therapies and vehicle control (VC). Animal studies using the ZR-75-1 BC cells orthotopic xenografting model in female nude mice showed significant tumor progression suppression by the combined OC-LA, 5 mg/kg each, ip, 3X/week treatments compared to individual LA and OC treatments and VC. The BC suppressive effects of the OC-LA combination were associated with the modulation of SMYD2–EZH2–STAT3 signaling pathway. A metastasis–clonogenicity animal study model using female nude mice subjected to tail vein injection of MDA-MB-231-Luc TNBC cells also revealed the effective synergy of the combined OC-LA, 5 mg/kg each, compared to their individual therapies and VC. Thus, EVOO cultivars rich in OC with optimal LA content can be useful nutraceuticals for invasive hormone-dependent BC and TNBC progression and metastasis. Full article

Malignant mediastinal tumors are a group representing some of the most demanding oncological challenges for early, multi-level, and successful management. The timely identification of any suspicious clinical symptomatology is urgent in achieving an accurate, staged histological diagnosis, in order to follow up with an equally detailed medical therapeutic plan (interventional or not) and determine the principal goals regarding efficient overall treatment in these patients. We report a case of a 24-year-old male patient with an incident-free prior medical history. An initial chest X-ray was performed after the patient reported short-term, consistent moderate chest pain symptomatology, early work fatigue, and shortness of breath. The following imaging procedures (chest CT, PET-CT) indicated the presence of an anterior mediastinal mass (meas. ~11 cm × 10 cm × 13 cm, SUV: 8.7), applying additional pressure upon both right heart chambers. The Alpha-Fetoprotein (aFP) blood levels had exceeded at least 50 times their normal range. Two consecutive diagnostic attempts with non-specific histological results, a negative-for-malignancy fine-needle aspiration biopsy (FNA-biopsy), and an additional tumor biopsy, performed via mini anterior (R) thoracotomy with “suspicious” cellular gatherings, were performed elsewhere. After admission to our department, an (R) Video-Assisted Thoracic Surgery (VATS) was performed, along with multiple tumor biopsies and moderate pleural effusion drainage. The tumor’s measurements had increased to DMax: 16 cm × 9 cm × 13 cm, with a severe degree of atelectasis of the Right Lower Lobe parenchyma (RLL) and a pressure-displacement effect upon the Superior Vena Cava (SVC) and the (R) heart sinus, based on data from the preoperative chest MRA. The histological report indicated elements of a combined, non-seminomatous germ-cell mediastinal tumor, posthuberal-type teratoma, and embryonal carcinoma. The imminent chemotherapeutic plan included a “BEP” (Bleomycin^®/Cisplatin^®/Etoposide^®) scheme, which needed to be modified to a “VIP” (Cisplatin^®/Etoposide^®/Ifosfamide^®) scheme, due to an acute pulmonary embolism incident. While the aFP blood levels declined, even reaching normal measurements, the tumor’s size continued to increase significantly (DMax: 28 cm × 25 cm × 13 cm), with severe localized pressure effects, rapid weight loss, and a progressively worsening clinical status. Thus, an emergency surgical intervention took place via median sternotomy, extended with a complementary “T-Shaped” mini anterior (R) thoracotomy. A large, approx. 4 Kg mediastinal tumor was extracted, with additional RML and RUL “en-bloc” segmentectomy and partial mediastinal pleura decortication. The following histological results, apart from verifying the already-known posthuberal-type teratoma, indicated additional scattered small lesions of combined high-grade rabdomyosarcoma, chondrosarcoma, and osteosarcoma, as well as numerous high-grade glioblastoma cellular gatherings. No visible findings of the previously discovered non-seminomatous germ-cell and embryonal carcinoma elements were found. The patient’s postoperative status progressively improved, allowing therapeutic management to continue with six “TIP” (Cisplatin^®/Paclitaxel^®/Ifosfamide^®) sessions, currently under his regular “follow-up” from the oncological team. This report underlines the importance of early, accurate histological identification, combined with any necessary surgical intervention, diagnostic or therapeutic, as well as the appliance of any subsequent multimodality management plan. The diversity of mediastinal tumors, especially for young patients, leaves no place for complacency. Such rare examples may manifest, with equivalent, unpredictable evolution, obliging clinical physicians to stay constantly alert and not take anything for granted. Full article

Background/Objectives: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by the replacement of healthy bone marrow (BM) with malignant and fibrotic tissue. In a healthy state, bone marrow is composed of approximately 60–70% fat cells, which are replaced as disease progresses. Proton density fat fraction (PDFF), a non-invasive and quantitative MRI metric, enables analysis of BM architecture by measuring the percentage of fat versus cells in the environment. Our objective is to investigate variance in quantitative PDFF-MRI values over time as a marker of disease progression and response to treatment. Methods: We analyzed existing data from three cohorts of mice: two groups with MF that failed to respond to therapy with approved drugs for MF (ruxolitinib, fedratinib), investigational compounds (navitoclax, balixafortide), or vehicle and monitored over time by MRI; the third group consisted of healthy controls imaged at a single time point. Using in-house MATLAB programs, we performed a voxel-wise analysis of PDFF values in lower extremity bone marrow, specifically comparing the variance of each voxel within and among mice. Results: Our findings revealed a significant difference in PDFF values between healthy and diseased BM. With progressive disease non-responsive to therapy, the expansion of hematopoietic cells in BM nearly completely replaced normal fat, as determined by a markedly reduced PDFF and notable reduction in the variance in PDFF values in bone marrow over time. Conclusions: This study validated our hypothesis that the variance in PDFF in BM decreases with disease progression, indicating pathologic expansion of hematopoietic cells. We can conclude that disease progression can be tracked by a decrease in PDFF values. Analyzing variance in PDFF may improve the assessment of disease progression in pre-clinical models and ultimately patients with MF. Full article

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

Background: Peritoneal dissemination in colorectal cancer (CRC) is associated with poor prognosis due to limited efficacy of current therapeutic strategies. The cholinergic receptor nicotinic beta 2 subunit (CHRNB2), a component of the acetylcholine receptor, has been implicated in other malignancies, but its role in CRC remains unknown. Methods: This study evaluated the expression and function of CHRNB2 in CRC. CHRNB2 mRNA levels were quantified by qRT-PCR in cell lines and clinical specimens. Functional assays were conducted using CRC cell lines with high CHRNB2 expression, in which CHRNB2 was knocked down by shRNA. Cell proliferation, migration, and invasion were assessed in vitro. In vivo effects were evaluated using subcutaneous and peritoneal xenograft models. The impact of CHRNB2 monoclonal antibody (mAb) treatment on CRC cell proliferation was also examined. Clinical correlations were assessed between CHRNB2 expression and clinicopathological features, including recurrence patterns. Results: CHRNB2 expression varied among CRC cell lines, with the highest levels observed in LOVO cells. CHRNB2 knockdown significantly inhibited proliferation, migration, and invasion in vitro and suppressed tumor growth in vivo. CHRNB2 mAb treatment reduced cell proliferation. Clinically, high CHRNB2 expression correlated with a significantly higher cumulative rate of peritoneal recurrence, but not with recurrence in the liver, lungs, or lymph nodes. Multivariate analysis identified high CHRNB2 expression and T4 tumor depth as independent predictors of peritoneal recurrence. Conclusions: CHRNB2 promotes the malignant phenotype of CRC, particularly in peritoneal dissemination. These findings suggest that CHRNB2 may serve as a novel diagnostic biomarker and therapeutic target for CRC with peritoneal metastasis. Full article

Background and Clinical Significance: Myxoid liposarcoma (MLS) is a malignant soft tissue tumor that often presents as a painless, slow-growing mass and is known for its atypical extrapulmonary metastatic pattern. Although sciatic nerve involvement is rare, when present, it usually causes neurologic symptoms. In this case, a large MLS silently expanded and completely encased the sciatic nerve without causing deficits, highlighting the importance of early imaging, multidisciplinary planning, and individualized surgical strategy in managing complex soft tissue sarcomas. Case Presentation: This case report describes a 67-year-old male with a 30 cm encapsulated myxoid liposarcoma of the posterior left thigh. The tumor had grown insidiously over one year and completely encased the sciatic nerve without causing pain, paresthesia, or motor impairment. Selective embolization was performed preoperatively to minimize blood loss. A posteromedial surgical approach allowed for en bloc resection with negative margins and preservation of sciatic nerve integrity. Histopathology confirmed a myxoid liposarcoma composed primarily of spindle-shaped tumor cells. The patient experienced no postoperative complications or neurologic deficits. At the two-year follow-up, he remains disease-free with full functional recovery. Conclusions: This case illustrates the potential for large, asymptomatic myxoid liposarcomas to encase critical neurovascular structures without infiltration. Preoperative embolization as part of a multidisciplinary plan was key to achieving safe resection and excellent functional outcomes. Full article

Nonspecific toxicity to normal and malignant cells restricts the clinical utility of many anticancer drugs. In particular, anemia in cancer patients develops due to drug-induced toxicity to red blood cells (RBCs). The anticancer alkaloid, cepharanthine (CEP), elicits distinct forms of cell death including apoptosis and autophagy, but its cytotoxicity to RBCs has not been investigated. Colorimetric and fluorometric techniques were used to assess eryptosis and hemolysis in control and CEP-treated RBCs. Cells were labeled with Fluo4/AM and annexin-V-FITC to measure Ca²⁺ and phosphatidylserine (PS) exposure, respectively. Forward scatter (FSC) was detected to estimate cell size, and extracellular hemoglobin along with lactate dehydrogenase and aspartate transaminase activities were assayed to quantify hemolysis. Physiological manipulation of the extracellular milieu and various signaling inhibitors were tested to dissect the underlying mechanisms of CEP-induced RBC death. CEP increased PS exposure and hemolysis indices and decreased FSC in a concentration-dependent manner with prominent membrane blebbing. Although no Ca²⁺ elevation was detected, chelation of intracellular Ca²⁺ by BAPTA-AM reduced hemolysis. Whereas SB203580, D4476, acetylsalicylic acid, necrosulfonamide, and melatonin inhibited both PS exposure and hemolysis, staurosporin, L-NAME, ascorbate, caffeine, adenine, and guanosine only prevented hemolysis. Interestingly, sucrose had a unique dual effect by exacerbating PS exposure and reversing hemolysis. Of note, blocking KCl efflux augmented PS exposure while aggravating hemolysis only under Ca²⁺-depleted conditions. CEP activates Ca²⁺-independent pathways to promote eryptosis and hemolysis. The complex cytotoxic profile of CEP can be mitigated by targeting the identified modulatory pathways to potentiate its anticancer efficacy. Full article

Relapsed/refractory diffuse large B-cell lymphoma and other non-Hodgkin lymphomas represent significant clinical challenges, particularly in patients who have exhausted standard immunochemotherapy and cellular therapies. Bispecific antibodies and antibody–drug conjugates have emerged as promising treatments, offering targeted and more effective treatment options compared to current standards. Bispecific antibodies, including epcoritamab and glofitamab, third-line therapies for diffuse large B-cell lymphoma, are recombinant immunoglobulins engineered to recognize two distinct antigens or epitopes simultaneously. This capability enhances therapeutic precision by bridging immune effector cells and tumor cells and modulating multiple signaling pathways involved in the pathogenesis of non-Hodgkin lymphoma. In the context of new therapies, antibody–drug conjugates, such as loncastuximab tesirine, are therapies composed of monoclonal antibodies linked to cytotoxic agents, in which the antibody selectively binds to tumor-associated antigens, delivering the cytotoxic payload directly to cancer cells while minimizing off-target effects. They combine the specificity of antibodies with the potency of chemotherapy, offering enhanced efficacy and safety in hematological malignancies. Ongoing clinical trials are investigating other molecules like odronextamab and the use of bispecific antibodies in combination regimens and earlier lines of therapy. The aim of this review is to explore actual therapies in relapsed/refractory diffuse large B-cell lymphoma, focusing on bispecific antibodies and antibody–drug conjugates. Full article

Cancer presents significant challenges owing to its complex molecular pathways and resistance to therapy. Natural metabolites have significant medicinal potential by regulating the sensing and signaling pathways associated with cancer development. Recognizing their interactions within the tumor microenvironment may unveil innovative techniques for inhibiting malignant activities and improve therapy success. This article highlights studies regarding ovarian cancer metabolism, signaling mechanisms, and therapeutic natural substances. This study summarizes clinical and experimental results to emphasise the synergistic effects of alkaloids, flavonoids, and terpenoids in improving therapeutic effectiveness and alleviating drug resistance. Bioactive compounds are essential in regulating ovarian cancer metabolism and signaling pathways, affecting glycolysis, lipid metabolism, and the survival of tumor cells. This review examines metabolic programming and essential pathways, including glycolysis, TCA cycle, lipid metabolism, PI3K/AKT/mTOR, AMPK, and MAPK, emphasizing their therapeutic significance. The integration of metabolic treatments with medicines based on natural compounds has significant potential for enhancing treatment effectiveness and mitigating therapeutic resistance. Ovarian cancer needs an integrated strategy that includes metabolic reprogramming, signaling modulation, and drugs derived from natural products. Natural chemicals provide intriguing approaches to address chemotherapy resistance and improve treatment efficacy. Further research is required to enhance these methodologies and evaluate their practical applicability for improved patient outcomes. Full article

The biggest challenge in cancer therapy is tumor resistance to the classical approach. Thus, research interest has shifted toward the cancer stem cell population (CSC). CSCs are a small subpopulation of cancer cells within tumors with self-renewal, differentiation, and metastasis/malignant potential. They are involved in tumor initiation and development, metastasis, and recurrence. Method. A narrative review of significant scientific publications related to the topic and its applicability in endometrial cancer (EC) was performed with the aim of identifying current knowledge about the identification of CSC populations in endometrial cancer, their biological significance, prognostic impact, and therapeutic targeting. Results: Therapy against the tumor population alone has no or negligible effect on CSCs. CSCs, due to their stemness and therapeutic resistance, cause tumor relapse. They target CSCs that may lead to noticeable persistent tumoral regression. Also, they can be used as a predictive marker for poor prognosis. Reverse transcription–polymerase chain reaction (RT-PCR) demonstrated that the cultured cells strongly expressed stemness-related genes, such as SOX-2 (sex-determining region Y-box 2), NANOG (Nanog homeobox), and Oct 4 (octamer-binding protein 4). The expression of surface markers CD133+ and CD44+ was found on CSC as stemness markers. Along with surface markers, transcription factors such as NF-kB, HIF-1a, and b-catenin were also considered therapeutic targets. Hypoxia is another vital feature of the tumor environment and aids in the maintenance of the stemness of CSCs. This involves the hypoxic activation of the WNT/b-catenin pathway, which promotes tumor survival and metastasis. Specific antibodies have been investigated against CSC markers; for example, anti-CD44 antibodies have been demonstrated to have potential against different CSCs in preclinical investigations. Anti-CD-133 antibodies have also been developed. Targeting the CSC microenvironment is a possible drug target for CSCs. Focusing on stemness-related genes, such as the transcription pluripotency factors SOX2, NANOG, and OCT4, is another therapeutic option. Conclusions: Stemness surface and gene markers can be potential prognostic biomarkers and management approaches for cases with drug-resistant endometrial cancers. Full article

The c-ErbB receptor family is a fundamental cell signaling system that regulates cell proliferation, motility, apoptosis, differentiation, and other key cellular functions. Overexpressed and mutated in some tumors, c-ErbB receptors play a pivotal role in their progression but are also present in many non-malignant cells, including those that are promising from the point of view of regenerative medicine, such as mesenchymal stromal cells (MSCs). The role of c-ErbB receptors in these cells is not clearly understood, and the data on their expression are sporadic. Therefore, the systemic characterization of c-ErbB receptor family expression in MSCs from a wide range of tissues is of high priority. Here, using RT-qPCR and Western blotting analysis, we evaluated the c-ErbB receptors expression pattern at the mRNA and protein levels in human MSCs isolated from six different tissues. We found that MSCs possess considerable EGFR and HER2 mRNA levels comparable to those in some malignant cells while showing trace HER3 and HER4 expression. However, EGFR but not HER2 was detected in MSCs at the protein level. We also show that the absence of HER2 protein is not associated with its rapid lysosomal degradation. We conclude that c-ErbB signaling in human MSCs is exclusively mediated by EGFR. Full article

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC. Full article

The serrated pathway represents a significant route to colorectal cancer (CRC), accounting for approximately 15–30% of cases, yet the specific epithelial cell subpopulations driving this pathway remain poorly understood. This study explores the causal relationship between serrated epithelial cells and CRC risk using single-cell transcriptomics and Mendelian randomization (MR). Publicly available single-cell RNA sequencing data were utilized to analyze epithelial cell subpopulations in CRC, focusing on specific serrated cells (SSCs). By integrating genome-wide association study data, MR was employed to assess the causal relationship between gene expression patterns and CRC risk. The study found that an increase in SSCs is closely associated with CRC progression. MR analysis revealed a significant correlation between expression changes in specific genes, such as IER3 in SSCs, and CRC risk (p < 0.05). Functional analyses indicated that IER3 may promote malignancy by regulating cell proliferation, adhesion, and immune evasion. Several genetic loci related to SSC gene expression were identified and validated for CRC risk association. This study demonstrates the significant role of serrated epithelial cell subpopulations in CRC development, particularly through key genes such as IER3, providing new perspectives for understanding CRC pathogenesis and future therapeutic strategies. Full article

Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds 6, 9, 14, and 18) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure–activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds 9 and 14 toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target. Full article