Malignant Research Articles

Dihydroartemisinin-driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer.

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.

Neutrophils in Cancer immunotherapy: friends or foes?

Neutrophils play a Janus-faced role in the complex landscape of cancer pathogenesis and immunotherapy. As immune defense cells, neutrophils release toxic substances, including reactive oxygen species and matrix metalloproteinase 9, within the tumor microenvironment. They also modulate the expression of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand, augmenting their capacity to induce tumor cell apoptosis. Their involvement in antitumor immune regulation synergistically activates a network of immune cells, bolstering anticancer effects. Paradoxically, neutrophils can succumb to the influence of tumors, triggering signaling cascades such as JAK/STAT, which deactivate the immune system network, thereby promoting immune evasion by malignant cells. Additionally, neutrophil granular constituents, such as neutrophil elastase and vascular endothelial growth factor, intricately fuel tumor cell proliferation, metastasis, and angiogenesis. Understanding the mechanisms that guide neutrophils to collaborate with other immune cells for comprehensive tumor eradication is crucial to enhancing the efficacy of cancer therapeutics. In this review, we illuminate the underlying mechanisms governing neutrophil-mediated support or inhibition of tumor progression, with a particular focus on elucidating the internal and external factors that influence neutrophil polarization. We provide an overview of recent advances in clinical research regarding the involvement of neutrophils in cancer therapy. Moreover, the future prospects and limitations of neutrophil research are discussed, aiming to provide fresh insights for the development of innovative cancer treatment strategies targeting neutrophils.

Feasibility of Optical Biopsy During Endoscopic Sinus Surgery With Confocal Laser Endomicroscopy: A Pilot Study.

Confocal laser endomicroscopy (CLE) is an optical imaging technique that allows in vivo, real-time, microscope-like assessment of superficial lesions. Although there is substantial data on CLE use in the upper GI tract, there is limited information regarding its application in the nasal cavity and paranasal sinuses. This study aims to assess the feasibility and diagnostic metrics of CLE in the nasal cavity and paranasal sinuses regarding differentiation between healthy/benign and malignant tissue. These structures show, however, a wider variety of frequent and concomitant benign and malignant pathologies, which could pose an increased challenge for optical biopsy by CLE. We performed CLE on a case series of six patients with various findings in the nose (three chronic rhinosinusitis, adenocarcinoma, meningoenzephalozele, esthesionneuroblastoma). Forty-two sequences (3792 images) from various structures in the nasal cavity and/or paranasal sinuses were acquired. Biopsies were taken at corresponding locations and analyzed in hematoxylin and eosin staining as a standard of reference. Three independent examiners blinded to the histopathology assessed the sequences. Healthy and inflamed mucosa could be distinguished from malignant lesions with an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 84.1%, 85.4%, 83.1%, 72.5%, and 92.1%, respectively, with a substantial agreement between raters (Fleiss κ = 0.62). This technique shows, despite its limitations, potential as an adjunctive imaging technique during sinus surgery; however, the creation of a scoring system based on reproducible and defined characteristics in a larger more diverse population should be the focus of further research to improve its diagnostic value and clinical utility. NA Laryngoscope, 2024.

Человек - мессия

This lecture is dedicated to the messianic activity of Louis Pasteur, one of the most outstanding figures in humane and veterinary medicine, the founder of microbiology and immunology, who made the most significant fundamental contribution to the scientific solution of microbiological problems of global significance. Together with his colleagues and followers, he was the first to establish the role of microbes in life on Earth, including in pathology, the bacterial etiology of infectious diseases and the universal nature of anti-infective immunity, discovered the phenomenon of artificially attenuation the pathogenic properties of infectious agents and created means and methods of protection against the most malignant diseases of animals and humans - vaccines against anthrax and rabies, immediately, even during his lifetime, which found wide application in veterinary and medical practice around the world with outstanding socio-economic efficiency.

Sclerosing mesenteritis as a surgical problem: a review of the literature and own clinical observation

The problem of studying the pathology of mesenteric fat of the small intestine in surgical practice has not yet received enough attention. A number of questions remain unresolved regarding the etiology and pathogenesis of mesenteric diseases, their possible connection with benign and malignant diseases, methods of their laboratory and instrumental diagnosis, possible options for conservative and surgical treatment, as well as systematization and structuring of the classification. One of the poorly studied representatives of diseases of the mesentery of the small intestine continues to be Sclerosing mesenteritis, characterized by various histological variants of damage to mesenteric fat and a varied nonspecific clinical picture. Taken together, this leads to certain difficulties in diagnosis, patients seeking access to doctors of various profiles, which ultimately negatively affects the results of treatment and can lead to social maladjustment and possible disability. Reports on the occurrence of this pathology in the medical literature are few and, as a rule, describe extremely rare clinical cases. However, in recent years, the frequency of detection of this pathology continues to grow steadily, which is associated with the progressive aging of the population, a high degree of surgical activity in relation to urgent diseases of the abdominal organs, and the improvement of instrumental diagnostic methods. Issues of etiology, pathogenesis, differential diagnosis of this disease and its possible connection with the paraneoplastic process currently continue to cause debate. Further accumulation of clinical experience, a better understanding of the pathogenesis of the disease, and improvement of imaging techniques will allow us to develop clearer diagnostic and clinical criteria, narrow the diagnostic search and, ultimately, improve and standardize treatment. The article provides a review of the literature on this rare surgical pathology, presents our own clinical observation, and discusses diagnostic issues and treatment options for this disease.

Cross-Talks between Raf Kinase Inhibitor Protein and Programmed Cell Death Ligand 1 Expressions in Cancer: Role in Immune Evasion and Therapeutic Implications.

Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond-there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3β, cytokines IFN-γ and IL-1β, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response-addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone.

Mechanical shear flow regulates the malignancy of colorectal cancer cells.

Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm2 for 1 and 2 h separately. Resulting elevated caspase-9 and -3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G1 phase. An elevated phosphor-eNOSS1177 increased the production of nitric oxide and led to reactive oxygen species-mediated oxidative stress. Shear flow also regulated epithelial-mesenchymal transition (EMT) by increasing E-cadherin and ZO-1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm2, the expressions of EMT were compared at lower (6.25 dynes/cm2) and at higher (25 dynes/cm2) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.

Synthesis, structure, and mechanism of action of a unique mixed-ligand nickel (II)-complex of tetra-dentate phenol-based ligand with di-aquo co-ligands with significant pro-apoptotic and anti-metastatic effect against malignant human cancer cells

From the discovery of the anticancer activity of “cisplatin”, various type of numerous mononuclear platinum (II) complexes has been evaluated for antitumor activities, though therapeutic use is limited due to side effects and resistance. In this study, A unique mixed ligand mono nuclear octahedral Ni (II) complex [NiL(H2O)2].0·.5H2O (1) [H2L = N,Nʹ-dimethyl-N,Nʹ-bis (2-hydroxy-3,5-di methyl benzyl)-ethylenediamine] with tetra dentate phenol based ligand with N2O2 donor environment along with two labile water molecules was synthesised. The complex (1) is structurally characterized by spectroscopic tools including single-crystal X-ray diffractometer. Complex (1) crystallizes in monoclinic space group P21/n with a = 10.4871(17) Å, b = 20.860 (4) Å and c = 20.955(4) Å. The UV – visible spectra show two peaks around 507 nm and 367 nm due to spin-allowed 1A1g → 1A2g and 1A1g → 1B1g transitions respectively as expected for a square planar d8 system. Mixed ligand octahedral nickel (II) complex with facially coordinating tetra dentate phenol-based ligand (H2L) is in association with two water molecule as ancillary ligand. Two water molecules associated with coordination zone of nickel (II) centre is loosely bound. In this present study, we have evaluated the anti-cancer properties of Complex (1). We found that Complex (1) show potent cancer cell killing activity in case of poorly invasive mice and human cancer cell lines. Complex (1) trigger apoptosis chiefly via p53 dependent pathway. Complex (1) also inhibits cancer cell migration and epithelial to mesenchymal transition in case of metastatic breast cancer cells suggesting potent anti-cancer properties of complex (1).

P04 How fibroblasts and azathioprine prepare the soil for cutaneous squamous cell carcinoma

Abstract Introduction and aims DNA damage-inducing immunosuppressive drugs such as azathioprine (AZA) act synergistically with ultraviolet (UV)A radiation and photosensitize the skin of immunosuppressed individuals, such as organ transplant recipients. These individuals have an increased risk of developing cutaneous squamous cell carcinoma (cSCC). The specific combination of AZA and UVA causes oxidative DNA damage that leaves behind a characteristic mutational signature in tumour keratinocytes of patients treated with AZA. However, as UVA radiation can penetrate the dermis, the impact of AZA/UVA on cells of the tumour microenvironment, such as fibroblasts, also need to be addressed. Fibroblasts are crucial for cSCC development and progression as they can switch to a protumourigenic phenotype. Methods Cell viability and senescence assays were performed to investigate the impact of AZA in combination with or without UVA on neonatal (nonsun-exposed) and adult (sun-exposed) human dermal fibroblasts. In addition, the impact of AZA/UVA-treated fibroblasts on the clonal growth properties of different cSCC cell models was investigated using three-dimensional (co)culture models. Results We found that AZA and UVA synergistically reduce the viability of both UV-naïve neonatal and sun-exposed adult dermal fibroblasts. In addition, combined AZA and UVA treatments lead to an increased percentage of senescent fibroblasts. We hypothesize that the aberrant secretome of these senescent fibroblasts can impact the growth behaviour of tumour cells. In a soft agar assay, the more malignant cSCC cells (MET-1) formed more and larger clonal spheroids and were less dependent on growth factors compared with spheroids formed by premalignant (PM-1) keratinocytes. Conclusions AZA and UVA act synergistically and potentiate a UVA-induced senescent fibroblast phenotype. The changed characteristics of these fibroblasts can impact the stem cell-like properties from premalignant and malignant keratinocytes. Combining keratinocyte and fibroblast culture models enables us to study how AZA/UVA promote the initiation and progression of cSCC.

A prognostic neural epigenetic signature in high-grade glioma.

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.

Spinal Trauma Revealing a Metastatic Medullary Lesion: A Case Report

Introduction and Importance: Intramedullary spinal cord metastases (ISCM) are a rare and devastating complication of malignant disease with a poor prognosis. Prompt and accurate diagnosis is necessary for effective treatment, and magnetic resonance imaging (MRI) is the preferred imaging technique. In this article, a rare case of an ISCM presenting with motor weakness after trauma is described. Case Presentation: The patient showed progressive severe paraplegia and urinary retention, and a thoraco-abdomino-pelvic scan showed a mediastinal pulmonary process and mediastinal adenopathies with adrenal lesions. He was admitted and a total resection of the processus was performed. After surgery, the patient showed partial neurological improvement, but two weeks later, he had a consciousness impairment. A cerebral CT scan showed multiple round lesions, with perilesional edema, and the patient died one month later. Discussion: The article discusses the pathogenic mechanisms of ISCM and its diagnosis, treatment, and management, which are controversial due to the multitude of clinical circumstances and the lack of controlled studies on the efficacy of the different therapeutic approaches. Conclusion: In conclusion, this rare case of Intramedullary Spinal Cord Metastases (ISCM) offers several important take-away lessons for clinicians and researchers alike.

Assessment of CXCL13 plasma level in chronic lymphocytic leukemia and its relation to other prognostic markers

Abstract: BACKGROUND: Chronic lymphocytic leukemia is a mature B-cell malignancy where there is a progressive accumulation of leukemic cells with a distinctive immunophenotype as consequence to defective apoptosis and survival signals derived from the microenvironment. CXC chemokine ligand 13 (CXCL13) chemokines have recently emerged as crucial orchestrators for lymphocyte trafficking and activation. These secreted polypeptides exert their function by binding to specific cell surface receptors and can be divided into two categories: homeostatic and inflammatory. The CXCL13 is an efficacious attractant of naive B-cells in vitro and has been shown to be produced constitutively by stromal cells in lymphoid follicles of human lymph nodes. The CXCL13-CXCR5 axis has been previously shown to contribute to the progression of several malignancies and possibly CLL relapse. OBJECTIVE: The aim of this study to compare the plasma level of CXCL13 in a patient with CLL with healthy normal control and to correlate the plasma level of CXCL13 to beta-2 microglobulin (β2 M) and other hematological parameters in CLL. PATIENTS, MATERIALS AND METHODS: This cross-sectional study was conducted on 50 CLL patients who were newly diagnosed. A total of 30 healthy individuals were included in this study as a control group. Measurement of plasma CXCL13 and beta-2 microglobulin levels was done by the enzyme-linked immunosorbent assay. RESULTS: Fifty CLL patients were studied and compared with thirty control group of healthy individuals. The mean level of CXCL13 was 67.48 pg/ml in CLL patients while it was 69.2 pg/ml in control, so it is statistically not significant (P = 0.363). The mean level of β2 M was 50.89 ug/ml in CLL patients while it was 50.59 ug/ml in control, so it is statistically not significant (P = 0.702). The percentage of stage A of CLL patients was 22.44%, stage B was18.36%, and stage C was 10.20%. The percentages of lymphadenopathy, splenomegaly, and hepatomegaly were 66%, 32%, and 16%, respectively. The mean of malignant cell percentage in stage A was 55.18%; in stage B, it was 69.28%; and in stage C, it was 81%, so it is statistically significant (P < 0.001). CXCL13 shows no statistically significant between Cd38+ and CD38− and P value was 0.950. CONCLUSIONS: There was no correlation in level of CXCL13 between the CLL group and the control group. There was no correlation in level of CXCL13 and β2 M in the CLL group.

Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer.

Cold plasma (CP) is an ionised gas containing excited molecules and ions, radicals, and free electrons, and which emits electric fields and UV radiation. CP is potently antimicrobial, and can be applied safely to biological tissue, birthing the field of plasma medicine. Reactive oxygen and nitrogen species (RONS) produced by CP affect biological processes directly or indirectly via the modification of cellular lipids, proteins, DNA, and intracellular signalling pathways. CP can be applied at lower levels for oxidative eustress to activate cell proliferation, motility, migration, and antioxidant production in normal cells, mainly potentiated by the unfolded protein response, the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-activated antioxidant response element, and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which also activates nuclear factor-kappa B (NFκB). At higher CP exposures, inactivation, apoptosis, and autophagy of malignant cells can occur via the degradation of the PI3K/Akt and mitogen-activated protein kinase (MAPK)-dependent and -independent activation of the master tumour suppressor p53, leading to caspase-mediated cell death. These opposing responses validate a hormesis approach to plasma medicine. Clinical applications of CP are becoming increasingly realised in wound healing, while clinical effectiveness in tumours is currently coming to light. This review will outline advances in plasma medicine and compare the main redox and intracellular signalling responses to CP in wound healing and cancer.

Navigating diagnostic challenges—distinguishing malignant melanoma and clear cell sarcoma of soft tissues: a case report and review of the literature

BackgroundWithin the spectrum of melanocytic-differentiated tumors, the challenge faced by pathologists is discerning accurate diagnoses, with clear cell sarcoma of soft tissues standing out as a rare and aggressive neoplasm originating from the neural crest. Accounting for 1% of all soft tissue sarcomas, clear cell sarcoma of soft tissues poses diagnostic complexities, often misidentified owing to its phenotypic resemblance to malignant melanoma. This chapter delves into the intricacies of clear cell sarcoma of soft tissues, its epidemiology, characteristic manifestations, and the imperative need for a comprehensive diagnostic approach involving immunohistochemical and molecular analyses.Case presentationA compelling case unfolds as a 25-year-old male from Morocco, initially misdiagnosed with malignant melanoma, experiences tumor recurrence on the second toe. With no history of trauma or familial neoplasia, the patient’s clinical journey is explored, emphasizing the importance of detailed clinical examinations and radiological assessments. The chapter elucidates the histopathological findings, immunohistochemical spectrum, and the correlation between clinical parameters and diagnostic inference, ultimately leading to metatarsal amputation. This clinical vignette highlights the multidimensional diagnostic process in soft tissue neoplasms, emphasizing the synergistic role of clinical, radiological, and histopathological insights.ConclusionThe diagnostic challenges inherent in melanocytic-differentiated tumors, exemplified by the rarity of soft tissue clear cell sarcoma, underscore the essential role of an integrated diagnostic approach. This concluding chapter emphasizes the perpetual collaboration required across pathology, clinical medicine, and radiology for nuanced diagnostic precision and tailored therapeutic strategies. The rarity of these soft tissue malignancies necessitates ongoing interdisciplinary engagement, ensuring the optimization of prognosis and treatment modalities through a comprehensive understanding of the diagnostic intricacies presented by clear cell sarcoma of soft tissues.

ALL THE ROADS LEAD TO THE MYSTERIOUS DISEASE

Abstract A 58–year–old man with familiarity for sudden cardiac death was accepted to the hospital for dyspnea. Two years before he underwent cardiac angiography which showed a significative lesion of the descending artery which was treated with the placement of a drug eluting stent. For the appearance of an atrio–ventricular block 2:1, a permanent pacemaker was implanted. A transthoracic echocardiogram demonstrated: mildly dilated left ventricle with a reduced global systolic function (calculated ejection fraction was of 25%). Computed tomography with intravenous contrast of the chest showed upper, mid and lower multifocal nodularity with irregular margins with predominantly peri –bronchial distribution. The patient underwent bronchoscopy with endotracheal ultrasound and multiple transbronchial biopsies. Bronchoalveolar lavage (BAL) was negative for fungi infections, bacteria (including Mycobacterium Complex), and malignant cells. Endobronchial biopsies revealed non–necrotizing, well–formed granulomas embedded in dense hyaline sclerosis. Also the ratio of CD4+/CD8+ cells was within limits. FDG PET–TC scan showed: multiple enhancing areas in the lungs and lymph nodes probably of an inflammatory nature and therefore compatible with pulmonary sarcoidosis. A high dosage cortisone therapy was started, the patient was transferred to undergo endomyocardial biopsy, subsequently tested positive for multisystemic disease. Sarcoidosis is a rare disease with extremely heterogeneous clinical presentations. Actually, it is characterized by non–necrotizing granulomas, aggregates of epithelial cells, macrophages, multinucleated giant cells and CD4+ T lymphocytes, which infiltrate different tissues. When symptomatic, cardiac sarcoidosis includes conduction abnormalities, arrhythmias and ventricle dilation with hearth failure. Rhythm disorders, which rang from first to third degree, are the most common manifestation together with atrial fibrillation and ventricular tachyarrhythmias which can be explained with reentrant mechanisms from the granulomatous scar. Both atria–ventricular blocks and history of ventricular tachycardia elevate the risk for sudden cardiac death, which may be the first and unique manifestation of the disease. If myocardial involvement is extensive, cardiac sarcoidosis can present with hearth failure.

M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer

Tumor-associated macrophages of the M2 phenotype promote cancer initiation and progression. Importantly, M2 macrophage-derived exosomes play key roles in the malignancy of cancer cells. Here, we report that circTMCO3 is upregulated in ovarian cancer patients, and its high expression indicates poor survival. M2-derived exosomes promote proliferation, migration, and invasion in ovarian cancer, but these effects are abolished by knockdown of circTMCO3. Furthermore, circTMCO3 functions as a competing endogenous RNA for miR-515-5p to reduce its abundance, thus upregulating ITGA8 in ovarian cancer. miR-515-5p inhibits ovarian cancer malignancy via directly downregulating ITGA8. The decreased oncogenic activity of circTMCO3-silencing exosomes is reversed by miR-515-5p knockdown or ITGA8 overexpression. Exosomal circTMCO3 promotes ovarian cancer progression in nude mice. Thus, M2 macrophage-derived exosomes promote malignancy by delivering circTMCO3 and targeting the miR-515-5p/ITGA8 axis in ovarian cancer. Our findings not only provide mechanistic insights into ovarian cancer progression, but also suggest potential therapeutic targets.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.

Synthesis of Rhodamine-Conjugated Lupane Type Triterpenes of Enhanced Cytotoxicity.

Various conjugates with rhodamines were prepared by starting with betulinic acid (BA) and platanic acid (PA). The molecules homopiperazine and piperazine, which were identified in earlier research, served as linkers between the rhodamine and the triterpene. The pentacyclic triterpene's ring A was modified with two acetyloxy groups in order to possibly boost its cytotoxic activity. The SRB assays' cytotoxicity data showed that conjugates 13-22, derived from betulinic acid, had a significantly higher cytotoxicity. Of these hybrids, derivatives 19 (containing rhodamine B) and 22 (containing rhodamine 101) showed the best values with EC50 = 0.016 and 0.019 μM for A2780 ovarian carcinoma cells. Additionally, based on the ratio of EC50 values, these two compounds demonstrated the strongest selectivity between malignant A2780 cells and non-malignant NIH 3T3 fibroblasts. A375 melanoma cells were used in cell cycle investigations, which showed that the cells were halted in the G1/G0 phase. Annexin V/FITC/PI staining demonstrated that the tumor cells were affected by both necrosis and apoptosis.

Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component.

Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.