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Cancer Medicine Jul 2021Mesothelioma (MESO) is an infrequent tumor derived from mesothelial cells of pleura, peritoneum, pericardium, and tunica vaginalis testis. Despite advancement in...
Mesothelioma (MESO) is an infrequent tumor derived from mesothelial cells of pleura, peritoneum, pericardium, and tunica vaginalis testis. Despite advancement in technologies and better understanding of tumor progression mechanism, the prognosis of MESO remains poor. The role of alternative splicing events (ASEs) in the oncogenesis, tumor metastasis and drug resistance has been widely discussed in multiple cancers. But the prognosis and potential therapeutic value of ASEs in MESO were not clearly studied by now. We constructed a prognostic model using RNA sequencing data and matched ASE data of MESO patients obtained from the TCGA and TCGASpliceSeq database. A total of 3,993 ASEs were identified associated with overall survival using Cox regression analysis. Eight of them were finally figured out to institute the model by lasso regression analysis. The risk score of the model can predict the prognosis independently. Among the identified 390 splicing factors (SF), HSPA1A and DDX3Y was significantly associated with 43 OS-SEs. Among these OS-SEs, SNX5-58744-AT (p = 0.048) and SNX5-58745-AT (p = 0.048) were significantly associated with bone metastasis. Co-expression analysis of signal pathways and SNX5-58744-AT, SNX5-58745-AT was also depicted using GSVA. Finally, we proposed that splicing factor (SF) HSPA1A could regulate SNX5-58744-AT (R = -0.414) and SNX5-58745-AT (R = 0.414) through the pathway "Class I MHC mediated antigen processing and presentation" (R = 0.400). In this way, tumorigenesis and bone metastasis of MESO were controlled.
Topics: Alternative Splicing; Bone Neoplasms; DEAD-box RNA Helicases; Female; Gene Regulatory Networks; HSP70 Heat-Shock Proteins; Humans; Male; Mesothelioma; Minor Histocompatibility Antigens; Prognosis; Proportional Hazards Models; Risk Factors; Sequence Analysis, RNA; Sorting Nexins
PubMed: 34041868
DOI: 10.1002/cam4.3977 -
BMJ Case Reports Apr 2021Malignant mesotheliomas (MMs) are malignancies of the mesothelium, with primary deposits originating in the pleura, peritoneum, pericardium and the tunica vaginalis (ie,...
Malignant mesotheliomas (MMs) are malignancies of the mesothelium, with primary deposits originating in the pleura, peritoneum, pericardium and the tunica vaginalis (ie, testicular). Metastatic spread is commonly reported to affect the liver, adrenal glands, kidney and contralateral lung (in cases of malignant pleural mesothelioma). Metastases to distant sites are uncommon. Spread to the oral cavity in particular is very rare. A total of 23 cases of metastatic spread to the oral cavity have been reported in the literature to date; of those, 9 cases have been to the tongue. Given the rarity of the site of metastasis, the management remains challenging. This case highlights a rare site of metastasis in MM, discusses treatment options available and briefly talks about technical limitations in treating a mobile structure such as the tongue. Good palliative and supportive care is crucial in managing cases where no curative treatment is possible.
Topics: Humans; Male; Mesothelioma; Mesothelioma, Malignant; Pleura; Testis; Tongue
PubMed: 33846190
DOI: 10.1136/bcr-2020-241166 -
International Journal of Molecular... Mar 2021The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to... (Review)
Review
The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system.
Topics: Animals; Homeostasis; Humans; Immune System; Inflammation; Lymphocytes; Nanostructures; Peritoneal Cavity; Serous Membrane; Thoracic Cavity
PubMed: 33807632
DOI: 10.3390/ijms22052610 -
BBA Advances 2021Yes-associated protein (YAP) is involved in development, cell growth, cell size, and homeostasis and plays a key role in the progression of various cancers. Among them,...
Yes-associated protein (YAP) is involved in development, cell growth, cell size, and homeostasis and plays a key role in the progression of various cancers. Among them, constitutive activation of YAP can often be observed in malignant mesothelioma, which arises in the pleura, peritoneum, and pericardium because of inactivation of the Hippo pathway. To date, however, only less-effective treatments such as chemotherapy, radiation therapy, and surgery are available for patients with malignant mesothelioma. In this study, we identified narciclasine as a novel YAP inhibitor that prevents YAP from interacting with TEAD4 because it competes with TEAD4 for binding to YAP. Furthermore, narciclasine could perturb the cell growth and colony formation of malignant mesothelioma NCI-H290 cells in addition to inhibiting their growth in nude mice. Therefore, narciclasine might be a potential seed for a novel antitumor drug against malignant mesothelioma and other cancers in which hyperactivation and/or overexpression of YAP are observed.
PubMed: 37082014
DOI: 10.1016/j.bbadva.2021.100008 -
Journal For Immunotherapy of Cancer Feb 2021CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma....
BACKGROUND
CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.
METHODS
ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.
RESULTS
Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.
CONCLUSIONS
ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.
TRIAL REGISTRATION NUMBER
NCT02955251.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bispecific; Antineoplastic Agents, Immunological; CD40 Antigens; Female; France; Humans; Male; Maximum Tolerated Dose; Mesothelin; Middle Aged; Neoplasms; Progression-Free Survival; Time Factors; Tumor Microenvironment; United States
PubMed: 33608377
DOI: 10.1136/jitc-2020-002015 -
Frontiers in Veterinary Science 2020Mesothelioma is a rare lethal tumor of dogs and humans involving cavities of the body. Dogs are considered a model for new drugs and therapeutic methods since they...
Mesothelioma is a rare lethal tumor of dogs and humans involving cavities of the body. Dogs are considered a model for new drugs and therapeutic methods since they present spontaneous diseases similar to humans. Microfragmented adipose tissue (MFAT) uploaded by paclitaxel (PTX) is a drug delivery medium providing slow release of chemotherapic drugs. A dog affected by pleural, pericardial, and peritoneal mesothelioma was treated by 17 intracavitary ultrasound-guided injections of MFAT-PTX over 22 months. A long-lasting improvement of general conditions was observed, treatment was well-tolerated, and no toxicity or hypersensitivity was reported. Pharmacokinetic (PK) data indicated low drug localization in the circulatory system and a tendency to enter or remain in the extravascular compartments of the body. Indeed, low levels of free-circulating drugs for a short time produced low toxicity, whereas, a higher intracavitary PTX concentration can have major pharmacological efficacy. To our knowledge, this is the first time that mesothelioma has been treated using such a procedure, and this should be considered as a novel therapeutic approach. The low systemic absorption suggests the possible role of MFAT-PTX for loco-regional/intratumoral therapy also useful in other types of tumors, and further investigation is warranted.
PubMed: 33569396
DOI: 10.3389/fvets.2020.585427 -
Cancers Feb 2021Malignant mesothelioma (MM) is a rare but highly aggressive cancer that primarily originates from the pleura, peritoneum or pericardium. There is a well-established link...
Malignant mesothelioma (MM) is a rare but highly aggressive cancer that primarily originates from the pleura, peritoneum or pericardium. There is a well-established link between asbestos exposure and progression of MM. Direct invasion of the surrounding tissues is the main feature of MM, which is dependent on dysregulated communication between the mesothelium and the microenvironment. This communication is dependent on the dynamic organization of the cytoskeleton. We have analyzed the organization and function of key cytoskeletal components in MM cell lines of increasing malignancies measured as migratory and invasive properties, and we show that highly malignant and invasive MM cells have an organization of the actin filament and vimentin systems that is distinct from the less malignant MM cell lines. In addition, the Hippo tumor suppressor pathway was inactivated in the invasive MM cells, which was seen as increased YAP nuclear localization.
PubMed: 33567673
DOI: 10.3390/cancers13040685 -
Advances in Radiation Oncology 2021
PubMed: 33490725
DOI: 10.1016/j.adro.2020.09.002 -
Cureus Dec 2020Malignant pericardial sarcomatoid mesothelioma is a massively rare tumor accounting for 0.8% of all cases of mesothelioma. Superior vena cava syndrome (SVCS) occurs due...
Malignant pericardial sarcomatoid mesothelioma is a massively rare tumor accounting for 0.8% of all cases of mesothelioma. Superior vena cava syndrome (SVCS) occurs due to a partial obstruction or compression to the superior vena cava, which hinders the blood outflow to the upper body. It can be caused by an intrinsic factor such as thrombosis, or by an extrinsic factor such as tumors. Clinical presentation includes edema of the face and upper limbs, plethora, dyspnea, dysphagia, stridor and cough. we are reporting a case of a 56-year-old female, who is a known case of hypertension on angiotensin-converting enzyme inhibitors (ACEIs). Presented to the emergency department with intermittent facial swelling and dyspnea. Imaging and pathology reports confirmed the diagnosis of intermittent SVCS secondary to pericardial sarcomatoid mesothelioma with pericardial effusion. What makes our case unique is that both the etiology and the presenting complaint are rare entities, as most SVCS cases are continuously symptomatic throughout the disease course, and are usually caused by a lung cancer or lymphoma.
PubMed: 33489524
DOI: 10.7759/cureus.12107 -
Oncotarget Dec 2020Malignant mesotheliomas (MMs) are highly aggressive mesenchymal tumors that originate from mesothelial cells lining serosal cavities; i.e., the pleura, peritoneum, and...
Malignant mesotheliomas (MMs) are highly aggressive mesenchymal tumors that originate from mesothelial cells lining serosal cavities; i.e., the pleura, peritoneum, and pericardium. Classically, there is a well-established link between asbestos exposure, oxidative stress, release of reactive oxygen species, and chronic inflammatory mediators that leads to progression of MMs. MMs have an intermediate phenotype, with co-expression of mesenchymal and epithelial markers and dysregulated communication between the mesothelium and the microenvironment. We have previously shown that the organization and function of key cytoskeletal components can distinguish highly invasive cell lines from those more indolent. Here, we used these tools to study three different types of small-molecule inhibitors, where their common feature is their influence on production of reactive oxygen species. One of these, imipramine blue, was particularly effective in counteracting some key malignant properties of highly invasive MM cells. This opens a new possibility for targeted inhibition of MMs based on well-established molecular mechanisms.
PubMed: 33400741
DOI: 10.18632/oncotarget.27843