ABSTRACT
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Karyopherins/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Animals , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Heterografts , Humans , Mice , Neoplasm Invasiveness , Survival Rate , Treatment Outcome , Exportin 1 ProteinABSTRACT
Hashimoto thyroiditis (HT), which is an autoimmune disease of thyroid gland, has been declared to present with concomitant several systemic diseases. In this study, the coexistence of the Hashimoto disease with the sleep apnea syndrome has been examined. Seven female patients (33-66 year of age) with Hashimoto thyroiditis were evaluated for sleep apnea syndrome. The diagnosis of Hashimoto disease was based on the high titers of anti-thyroid antibodies and histological findings. None of the patients had any complaints of sleep disturbances. Seven healthy subjects with similar age and sex characteristics were taken as the control group. All the patients and the control subjects were undertaken a full polysomnography (PSG). Five patients with HT showed the characteristics of obstructive sleep apnea syndrome (one severe, one moderate and three mild OSAS), whereas no sleep breathing disturbance was found in the control group. These findings suggest that sleep related breathing problems may develop in the patients with autoimmune thyroiditis even if they are euthyroid.
Subject(s)
Sleep Apnea, Obstructive/etiology , Thyroiditis, Autoimmune/complications , Adult , Aged , Female , Humans , Middle Aged , Sleep Apnea, Obstructive/physiopathologyABSTRACT
During coronary angiography in 24 chronic smokers with coronary heart disease, cardiac function measurements were taken and correlated with respiratory function tests. Fourteen patients had evidence of chronic obstructive pulmonary disease. Cardiac output had a direct correlation with vital capacity, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and velocity at 25% of FVC (V(max)25). Pulmonary artery resistance was inversely correlated with FEV1/FVC, while pulmonary artery oxygen saturation weakly correlated with FEV1 and V(max)25. The pulmonary artery pressure had a weak correlation with the pulmonary artery resistance and an intermediate correlation with the right atrium and the right ventricular pressures. Early diagnosis and therapy of chronic obstructive pulmonary disease in smokers may be possible without using invasive methods.
Subject(s)
Atrial Function, Right , Coronary Disease/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiratory Function Tests/standards , Smoking/physiopathology , Ventricular Function, Right , Aged , Cardiac Catheterization , Cardiac Output , Chronic Disease , Coronary Angiography , Coronary Disease/complications , Coronary Disease/diagnosis , Female , Forced Expiratory Volume , Humans , Linear Models , Male , Middle Aged , Predictive Value of Tests , Pulmonary Circulation , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Wedge Pressure , Regression Analysis , Respiratory Function Tests/methods , Smoking/adverse effects , Vascular Resistance , Ventricular Pressure , Vital CapacityABSTRACT
During coronary angiography in 24 chronic smokers with coronary heart disease, cardiac function measurements were taken and correlated with respiratory function tests. Fourteen patients had evidence of chronic obstructive pulmonary disease. Cardiac output had a direct correlation with vital capacity, forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and velocity at 25% of FVC [V[max]25]. Pulmonary artery resistance was inversely correlated with FEV1/FVC, while pulmonary artery oxygen saturation weakly correlated with FEV1 and V[max]25. The pulmonary artery pressure had a weak correlation with the pulmonary artery resistance and an intermediate correlation with the right atrium and the right ventricular pressures. Early diagnosis and therapy of chronic obstructive pulmonary disease in smokers may be possible without using invasive methods
Subject(s)
Cardiac Output , Chronic Disease , Coronary Angiography , Forced Expiratory Volume , Cardiac Catheterization , Linear Models , Atrial Function, RightABSTRACT
Although interferon has not been classified in the pathogenesis of sarcoidosis, it may rarely lead to this disease during treatment of chronic hepatitis C. The case of a 36-year-old woman with chronic hepatitis C who developed sarcoidosis within 10 weeks of treatment with recombinant interferon-alpha2a and ribavirin is described and all seven similar cases published in English from 1989 to 2001 are discussed.
Subject(s)
Antiviral Agents/adverse effects , Hepatitis C, Chronic/drug therapy , Interferon-alpha/adverse effects , Sarcoidosis, Pulmonary/chemically induced , Adult , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Female , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Recombinant Proteins , Ribavirin/adverse effects , Ribavirin/therapeutic useABSTRACT
BACKGROUND/AIM: Both p16INK4a and p53 proteins are negative regulators of the cell cycle. In human hepatocellular carcinomas (HCC), the loss of function of p53, retinoblastoma (pRb) and pl6INK4a genes by different mechanisms has been largely documented, but their hepatocellular effects are poorly known. We compared the growth-inhibitory effects of p16INK4a and p53 proteins in Hep3B cell line-derived clones. METHODS: Cells were transfected with inducible p16INK4a and p53 expression vectors, and stable clones were analyzed for transgene expression by Western blotting and immunoperoxidase staining. Effects on cell growth were analyzed by in vitro growth assay, thymidine incorporation and flow cytometry. Biochemical effects of p53 were tested by Northern blotting of p21Cip1 transcripts and by Western blotting of p21Cip1, mdm-2, bax, cyclin-dependent kinase 2 and cyclin E proteins. The pRb protein was studied by Western blotting and immunoprecipitation assays. RESULTS: The induction of p16INK4a protein expression did not affect in vitro growth of cells. In contrast, p53 protein in its wild-type conformation provoked a growth arrest accompanied by transactivation of p21Cip1 gene and accumulation of p21Cip1, bax and mdm-2 proteins. p53-induced growth arrest was due to a cell cycle arrest at the G1/S transition, probably mediated by p21Cip1 protein, which inhibits cyclin-dependent kinase 2/cyclin E complexes. CONCLUSIONS: The lack of detectable pRb protein and resistance of cells to p16TNK4a strongly suggest that p53 is able to arrest the growth of HCC cells by a mechanism independent of "p53-retinoblastoma pathway". These findings are applicable to HCC with abberrations of both p53 and pRb genes, and may not represent the universal effects of p53 in hepatic cells.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carrier Proteins/genetics , Gene Expression Regulation, Neoplastic , Genes, p53 , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Retinoblastoma Protein/genetics , Cell Division/genetics , Cyclin-Dependent Kinase Inhibitor p16 , Genes, Tumor Suppressor , Humans , Tumor Cells, CulturedABSTRACT
Patients with tracheal or major airway obstruction due to inoperable carcinomas are at a high risk of developing respiratory failure or post-obstructive pneumonia, or both. This often leads to death in days or weeks. In such cases there is usually an urgent need to restore the airway. This report details the short-term results and techniques used for the treatment of airway obstruction by direct intratumoural injection of several anti-cancer drugs. A total of 93 patients with nearly complete extrinsic obstruction of at least one major airway were treated by injection of anti-cancer drugs directly into the endobronchial tumours or infiltrated bronchial mucosa through a flexible fiber-optic bronchoscope. At every session of treatment 1-3 ml each of 50 mg/ml 5-fluorouracil, 1 mg/ ml mitomycin, 5 mg/ml methotrexate, 10 mg/ml bleomycin and 2 mg/ml mitoxantrone were injected separately at different sites without pre-mixing. Local intratumoural chemotherapy relieved the obstruction in 81 of the 93 patients. Endoscopically visible tumours were reduced in size, and infiltrative changes were also improved. Obstruction was not relieved in 12 patients. The therapy was well tolerated and had no systemic side-effects, and no serious complications. Intratumoural chemotherapy can be considered a new life-saving palliative method in patients with life-threatening airway obstruction.
