MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. RESULTS: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. CONCLUSION: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

Expression of PD-L1 on regulatory B cells in patients with acute myeloid leukaemia and its effect on prognosis.

Programmed death-ligand 1 (PD-L1) is involved in immunosuppression in variety of tumours. Regulatory B cells (Bregs) are critical immune regulatory cells, and it has been demonstrated that the number of regulatory B cells in patients with acute myeloid leukaemia (AML) is much higher than that in healthy donors (HDs), which is linked to a poor prognosis. This study aimed to determine whether increased expression of PD-L1, including in Bregs, is associated with a worse prognosis in individuals with AML. The proportion of Bregs, PD-L1 expression in Bregs and PD-1 expression in T cells were determined using flow cytometry using patient samples from 21 newly diagnosed AML patients at different stages of treatment and 25 HDs. We confirmed PD-L1 expression in Bregs, and PD-1 expression in CD3+ CD4+ T cells in bone marrow and peripheral blood samples from AML patients was higher than that in samples from HDs. The complete remission (CR) and progression-free survival (PFS) of Bregs with high PD-L1 expression were significantly decreased following induction chemotherapy. PD-L1 expression is indeed increased in Bregs from individuals with AML, and high PD-L1 expression is related to a poor prognosis.

Splenic infarction associated with obstructive sleep apnoea/hypopnoea syndrome: a case report.

Splenic infarction is rare, resulting from occlusion of the splenic artery or its branches. Its aetiology is complex and multifactorial involving various vascular and thrombotic diseases, thus, misdiagnosis or missed diagnosis is common. Here, the case of a 45-year old male patient diagnosed with splenic infarction caused by secondary erythrocytosis associated with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is reported. The patient presented with 10 days of abdominal distension and pain that worsened after eating, and had developed to include nausea, vomiting and fever. The patient had a history of night snoring for over 10 years without treatment, a diagnosis of chronic pulmonary heart disease and secondary polycythaemia 5 years previously, and diagnosis of OSAHS 1 year previously. He had not received previous non-invasive ventilation or oxygen therapy. Enhanced upper abdomen computed tomography (CT) showed splenic infarction, bone marrow cytology suggested secondary polycythaemia, and sleep polysomnography revealed severe OSAHS. Low molecular-weight heparin, ceftriaxone, fluid and oxygen treatment gradually relieved abdominal distension and pain. Enhanced CT showed splenic infarction improvement. The present case highlights that splenic embolism should not be ignored as a potential complication of OSAHS.

Sleep apnea-hypopnea syndrome caused by ankylosing spondylitis: A case report.

INTRODUCTION: Sleep apnea-hypopnea syndrome (SAHS) is a multifactorial disease characterized by recurrent hypopnea or respiratory interruption during sleep, which causes intermittent hypoxemia, hypercapnia, and sleep structure disturbances. An association between ankylosing spondylitis (AS) and the type of SAHS has rarely been reported in the literature. Here, we present a case of SAHS in a patient with AS and discuss the possible mechanism underlying the type of SAHS. PATIENT CONCERNS: A 46-year-old man presented with a 15-year history of AS. He had been receiving sulfasalazine for symptomatic relief and had never been on immunosuppressive therapy. DIAGNOSIS: The patient was diagnosed with SAHS in addition to AS. INTERVENTIONS: We instituted treatment with methylprednisolone (5 mg, oral, daily), leflumomide (20 mg, oral, daily), bicyclol tablets (25 mg, oral, 3 times a day), and ursodeoxycholic acid tablets (10 mg/kg, oral, daily). The patient received etanercept (50 mg, sc, once a week) as his condition deteriorated. In addition, for management of SAHS symptoms, the patient received nasal continuous positive airway pressure (CPAP) during sleep. OUTCOMES: Six months after commencement of the treatment, the clinical manifestations of SAHS and AS had significantly improved. CONCLUSIONS: We hypothesize that patients with AS are prone to sleep apnea due to airway compression, central depression of respiration, abnormal inflammatory responses. Hence, careful assessment toward potential SAHS symptoms should be considered especially in patients with AS.

Diagnostic Accuracy of Interleukin-27 in Bronchoalveolar Lavage Fluids for Pulmonary Tuberculosis.

BACKGROUND: The World Health Organization states that China had 0.9 million cases of tuberculosis in 2017, accounting for 9% of cases globally. Despite a decrease in the incidence and mortality of tuberculosis in China over time, development in choosing the appropriate prevention and control of TB is required. PURPOSE: The aim of this study was to evaluate the diagnostic significance of interleukin-27 in bronchoalveolar lavage fluids for pulmonary tuberculosis. MATERIALS AND METHODS: Eventually, 107 bronchoalveolar lavage fluids from patients were included in this study. The concentrations of interleukin-27 and adenosine deaminase were determined in bronchoalveolar lavage fluids using enzyme-linked immunosorbent assay. RESULTS: It was found that the concentrations of interleukin-27 in bronchoalveolar lavage fluids of sputum-positive pulmonary tuberculosis group were significantly higher than those in sputum-negative pulmonary tuberculosis, lung cancer, and previous pulmonary tuberculosis groups, respectively (all P<0.001). Interleukin-27 levels in bronchoalveolar lavage fluids could be used for diagnostic purpose for pulmonary tuberculosis, with the cutoff value of 7.867 pg/mL; interleukin-27 had a sensitivity of 68.8% and specificity of 100% for the differential diagnosis of pulmonary tuberculosis (sputum-negative and sputum-positive PTB) from lung cancer. And with the cutoff value of 6.012 pg/mL, IL-27 had sensitivity and specificity of both 100% for the differential diagnosis of PTB from previous PTB. The risk of pulmonary tuberculosis was positively associated with the concentrations of interleukin-27 and adenosine deaminase in bronchoalveolar lavage fluids. CONCLUSION: Interleukin-27 in bronchoalveolar lavage fluids is a sensitive and specific biomarker for the differential diagnosis of pulmonary tuberculosis from lung cancer and previous pulmonary tuberculosis.

Pulmonary embolism caused by myasthenia gravis: A case report.

RATIONALE: Pulmonary embolism (PE) is a relatively common disease; however, myasthenia gravis leading to PE has been rarely reported in the literature. We report a case of PE in a patient with myasthenia gravis and discuss the possible mechanism underlying the development of PE. We hypothesize that inflammatory mediators may lead to endothelial injury, resulting in PE or deep venous thrombosis (DVT) in patients with myasthenia gravis. PATIENT CONCERNS: A 45-year-old woman had a 9-year history of myasthenia gravis. She was receiving neostigmine bromide for symptomatic relief and had never been on immunosuppressive therapy. DIAGNOSES: Myasthenia gravis and pulmonary embolism. INTERVENTIONS: Our patient was treated with low-molecular-weight heparin immediately after hospital admission. Thrombolytic therapy was later initiated as her condition deteriorated. OUTCOMES: After 2 weeks, the pulmonary artery systolic pressure on echocardiography reduced to 60 mm Hg, and venous ultrasonography showed no evidence of DVT. Her computed tomography pulmonary angiogram revealed a mural thrombus in both the main pulmonary arteries. She refused to undergo immunosuppressive therapy; hence, she was discharged on neostigmine bromide and warfarin. There was no recurrence of PE or DVT at 3- and 6-month follow-ups. LESSONS: Patients with an autoimmune-mediated disease may have an increased risk of DVT and PE. We hypothesize that the risk may increase in the absence of immunosuppressive therapy. Hence, anticoagulant therapy may be administered early to reduce mortality from acute PE.

Left lung hypoplasia with a right tuberculous pleural effusion after childbirth: A case report.

RATIONALE: Unilateral hypoplasia of the lung is a rare congenital condition, the mechanism of which is poorly understood. Primary pulmonary hypoplasia occurring in an adult is extremely rare and we present what is probably the first case of a link to a tuberculous pleural effusion in a young woman after childbirth. PATIENT CONCERNS: Herein, we describe a 31-year-old woman with left lung hypoplasia, and she not only survived to adulthood without problems, but was able to deliver a baby in natural labor. DIAGNOSES: Left lung hypoplasia, right tuberculous pleural effusion. INTERVENTIONS: We initiated an anti-tuberculosis treatment for this patient with dose adjustments to her weight of isoniazid (0.3 g/day), rifampicin (0.45 g/day), pyrazinamide (1.5 g/day), and ethambutol (0.75 g/day) for 2 months then isoniazid and rifampicin for another 4 months. OUTCOMES: Ten days later after beginning therapy, she became afebrile and the pleural effusion resolved. No recurrence was observed during a 6-month follow-up period. LESSONS: In clinical practice, if one sees a chest x-ray revealing complete or incomplete opacification of a hemithorax with volume loss and history of repeated respiratory infections, one should consider the possibility of unilateral pulmonary hypoplasia. In such cases, regular close follow-up is important to minimize infections and to prevent development of cor pulmonale or respiratory failure.