Chao Cheng

Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein

Besides targeting the well‐known oncogenic c‐Met, crizotinib is the first oral tyrosine kinase inhibitor inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non‐small cell lung cancer. Here, we assessed the possible reversal of multidrug resistance (MDR) by crizotinib in vitro and in vivo.

Axitinib Targeted Cancer Stemlike Cells to Enhance Efficacy of Chemotherapeutic Drugs via Inhibiting the Drug Transport Function of ABCG2

Stemlike cells have been isolated by their ability to efflux Hoechst 33342 dye and are called the side population (SP). We evaluated the effect of axitinib on targeting cancer stemlike cells and enhancing the efficacy of chemotherapeutical agents. We found that axitinib enhanced the cytotoxicity of topotecan and mitoxantrone in SP cells sorted from human lung cancer A549 cells and increased cell apoptosis induced by chemotherapeutical agents. Moreover, axitinib particularly inhibited the function of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) and reversed ABCG2-mediated multidrug resistance (MDR) in vitro. However, no significant reversal effect was observed in ABCB1-, ABCC1- or lung resistance-related protein (LRP)-mediated MDR. Furthermore, in both sensitive and MDR cancer cells axitinib neither altered the expression of ABCG2 at the mRNA or protein levels nor blocked the phosphorylation of AKT and extracellular signal-regulated kinase (ERK)l/2. In nude mice bearing ABCG2-overexpressing Sl-Ml-80 xenografts, axitinib significantly enhanced the antitumor activity of topotecan without causing additional toxicity. Taken together, these data suggest that axitinib particularly targets cancer stemlike cells and reverses ABCG2-mediated drug resistance by inhibiting the transporter activity of ABCG2.

Extended Transsternal Thymectomy for the Treatment of Ocular Myasthenia Gravis

BACKGROUNDnThe optimal treatment for ocular myasthenia gravis (OMG) remains controversial. We conducted a review of the long-term clinical outcomes of Chinese patients with OMG after extended transsternal thymectomy (ETT) to determine the efficacy of this procedure as a treatment for OMG.nnnMETHODSnWe reviewed the cases of 115 consecutive patients with OMG who underwent ETT at our Myasthenia Gravis Research Center between January 2006 and December 2008. Extended transsternal thymectomy was done in patients who had thymoma, resistance to pyridostigmine therapy, or relapse after immunosuppressive therapy. The patients postoperative responses were defined as strict complete remission (SCR), consisting of an asymptomatic status without medication for more than 12 months; general complete remission (GCR), consisting of an asymptomatic status with low-dose single-drug therapy or without medication for more than 12 months; or improvement, consisting of fewer symptoms or less of a need for medication than before surgery.nnnRESULTSnThe overall complication rate was 7.8%. None of the patients experienced a myasthenic crisis, progression to generalized myasthenia gravis, or mortality. Hyperplasia of the thymus was present in 106 of the 115 patients (92.2%). Among 110 patients on whom follow-up was done postoperatively, 29 (26.4%) were in SCR, 64 (58.2%) showed improvement, 7 (6.4%) remained unchanged, and 10 (9.1%) had a worsening of their conditions. Kaplan-Meier analysis revealed rates of GCR of 41.8% at 24 months and 47.3% at 48 months after surgery, and rates of SCR of 24.5% at 24 months and 26.4% at 48 months. Both univariate analysis and multivariate Cox regression analysis revealed that only preoperative duration of illness was positively associated with GCR (p < 0.001).nnnCONCLUSIONSnThe results of the review indicate that ETT is a safe and effective treatment for OMG, especially in patients with illness of shorter duration.

Enhancing chemosensitivity in ABCB1- and ABCG2-overexpressing cells and cancer stem-like cells by an Aurora kinase inhibitor CCT129202.

Imidazopyridine CCT129202 is an inhibitor of Aurora kinase activity and displays a favorable antineoplastic effect in preclinical studies. Here, we investigated the enhanced effect of CCT129202 on the cytotoxicity of chemotherapeutic drugs in multidrug resistant (MDR) cells with overexpression of ATP-binding cassette (ABC) transporters and cancer stem-like cells. CCT129202 of more than 90% cell survival concentration significantly enhanced the cytotoxicity of substrate drugs and increased the intracellular accumulations of doxorubicin and rhodamine 123 in ABCB1 and ABCG2 overexpressing cells, while no effect was found on parental sensitive cells. Interestingly, CCT129202 also potentiated the sensitivity of cancer stem-like cells to doxorubicin. Importantly, CCT129202 increased the inhibitory effect of vincristine and paclitaxel on ABCB1 overexpressing KBv200 cell xenografts in nude mice and human esophageal cancer tissue overexpressing ABCB1 ex vivo, respectively. Furthermore, the ATPase activity of ABCB1 was inhibited by CCT129202. Homology modeling predicted the binding conformation of CCT129202 within the large hydrophobic cavity of ABCB1. On the other hand, CCT129202 neither apparently altered the expression levels of ABCB1 and ABCG2 nor inhibited the activity of Aurora kinases in MDR cells under the concentration of reversal MDR. In conclusion, CCT129202 significantly reversed ABCB1- and ABCG2-mediated MDR in vitro, in vivo and ex vivo by inhibiting the function of their transporters and enhanced the eradication of cancer stem-like cells by chemotherapeutic agents. CCT129202 may be a candidate as MDR reversal agent for antineoplastic combination therapy and merits further clinical investigation.

Clinical Outcome of Juvenile Myasthenia Gravis After Extended Transsternal Thymectomy in a Chinese Cohort

BACKGROUNDnThe role of surgical treatment for juvenile myasthenia gravis (MG) remains unclear. Here, we performed a retrospective study to evaluate the predictors of clinical outcome of juvenile MG treated with extended transsternal thymectomy.nnnMETHODSnA total of 141 consecutive juvenile MG patients underwent extended transsternal thymectomy at an academic hospital over a 20-year period were reviewed. Thymectomy was performed in patients resistant to pyridostigmine therapy, with generalized symptoms or ocular MG with partial response to pyridostigmine for more than 2 years. Variables potentially affecting responses to extended transsternal thymectomy were evaluated using Kaplan-Meier analysis and Cox regression modeling. Complete stable remission (CSR) is defined as asymptomatic without medication for more than 12 months.nnnRESULTSnThere were 96 patients with ocular MG and 45 generalized MG, the median age at disease onset was 6 years and that at operation was 12 years. Among 135 patients with complete postoperative follow-up, 34 (25.2%) achieved CSR, 28 (20.7%) experienced pharmacologic remission, 61 (45.2%) improved, 5 (3.7%) remained stable, and 7 (5.2%) deteriorated. The results indicated the disease-onset age greater than 6 years and age at operation greater than 12 years were both positively associated with CSR responses. Postoperative steroid treatments in ocular MG and preoperative disease duration in generalized MG (>12 months) were negatively associated with CSR responses.nnnCONCLUSIONSnExtended transsternal thymectomy for Chinese juvenile MG patients has an efficacy comparable with reports from other ethnicities. Juvenile patients with disease-onset age greater than 6 years, age at operation greater than 12 years, and shorter disease duration of generalized MG are associated with favorable clinical outcomes.

Predictors of extubation outcomes following myasthenic crisis.

Objective Myasthenic crisis (MC) is considered the most severe adverse event in patients with myasthenia gravis. The present retrospective study was performed to evaluate the predictors of clinical outcomes in patients with MC. Methods The medical charts of 33 patients (19 women, 14 men) with 76 MC attacks from 2002 to 2014 were retrospectively reviewed. Early extubation (≤7 days) and prolonged ventilation (>15 days) during the MC were used to assess patient outcomes. Results Among the 33 patients, 24 (72.7%) had positive acetylcholine receptor antibody test results and 20 (60.6%) experienced recurrent MC attacks (≥2 episodes) during follow-up (median 83.6 months, range 1.5–177 months). Plasma exchange during an MC was significantly associated with early extubation. Male sex, older age (>50 years), atelectasis, and ventilator-associated pneumonia significantly contributed to prolonged ventilation. In 22 patients who underwent thymectomy, both the duration between MC attacks and the mean number of MC attacks were significantly reduced after surgery. Conclusions Plasma exchange during MC attacks was found to be important for early extubation; older patients and those with atelectasis or ventilator-associated pneumonia were more vulnerable to prolonged ventilation. Thymectomy may be useful to prevent recurrence of MC.

Bilateral pulmonary artery aneurysms, coronary artery aneurysm, and ventricular pseudoaneurysm in Behçet disease.

Massive hemoptysis in Behçet disease (BD) is rare but often fatal. This report presents a 28-year-old man with recurrent massive hemoptysis. He was diagnosed with bilateral multiple pulmonary artery aneurysms (PAAs), coronary artery aneurysm, and ventricular pseudoaneurysm from BD. The patient underwent emergency right lower lobectomy with no obvious complications. No hemoptysis recurred during an 18-month follow-up. This report also reviews the occurrence of PAAs in BD, with an emphasis on the treatment approaches.

Pulmonary well-differentiated fetal adenocarcinoma with platelet-derived growth factor receptor (PDGFR)α expression.

Well-differentiated fetal adenocarcinoma (WDFA) is a rare pulmonary malignancy. Biomarkers of tumor biology has rarely been studied in WDFA. Here, we report two WDFA patients. Both patients had blood-streaked sputum or mild hemoptysis at presentation. They underwent lobectomy and systematic mediastinal lymphadenectomy. Expression of PDGFRα on the plasma membrane was demonstrated by immunohistochemistry (IHC) in the resected tumor specimens. Further IHC examination showed intense immunostaining of β-catenin in both patients but negative staining for TP53, CEA, CD56, EGFR, CK5/6, HER2, S-100, ER, PR, BCL2, and NSE. Both patients had no recurrence to date after more than 3 years of follow up. Herein, we reviewed this rare disease with special emphasis on the clinico-pathological features, treatment and potential role of PDGFRα.

Increased Numb protein expression predicts poor clinical outcomes in esophageal squamous cell carcinoma patients

ABSTRACT Numb is a protein whose asymmetric segregation during cell division determines cell fate and has numerous functions relevant to multiple fields of study, including developmental neurobiology and cancer biology. Little is known about the role of Numb in esophageal squamous cell carcinoma (ESCC), the predominant histological esophageal carcinoma in Asian populations. In this study, we focused on the expression and biologic functions of Numb in the context of ESCC. From analysis of tissue microarrays with 212 patients, it was found that Numb was significantly upregulated in ESCC tissues compared with corresponding non-cancerous tissues. Kaplan-Meier survival analysis suggests that higher expression of Numb was significantly associated with a high tumor recurrence (p = 0.015) and poor overall post-surgical survival (p = 0.016). Using multiple Cox regression, the expression of Numb was determined to be an independent predictor of poor prognosis. When siRNA was used to knockdown Numb in ESCC cell lines, there was a consistent increase in caspase-3 dependent apoptosis and inhibition of cellular proliferation, as well as downregulation of expression of the cancer stem cell markers Oct-4, SOX-2 and Nanog. In addition, downregulated Numb expression was not significantly associated with the migration of ESCC cells. These results indicate that Numb acts as an oncoprotein and has potential as a novel prognostic biomarker and therapeutic target in ESCC patients.

Cardiac arrest without physical cardiac injury during Nuss repair of pectus excavatum

BackgroundCardiac arrest is a lethal complication of Nuss repair of pectus excavatum which is strongly related to heart or big vessels injury. A rare case developed cardiac arrest without direct cardiac injury during Nuss procedure is presented in this article.Case PresentationIn July 2015, a previously healthy 18-year-old man undergoing Nuss repair for pectus excavatum developed cardiac arrest while the Nuss bar was being inserted into the chest. After successful resuscitation and exclusion of direct cardiac injury, the Nuss procedure was continued. The patient suffered a second cardiac arrest during rotation of the Nuss bar. This time, the patient had poor initial response to resuscitation and defibrillation until the retrosternal bar was removed. He ultimately recovered well from the episodes of cardiac arrest, but was unable to receive surgical correction of his pectus excavatum deformity.ConclusionsThe possible mechanisms of cardiac arrest and lessons we can learn from this complication are discussed.