ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line

PURPOSE: This study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2). METHODS: Western blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase-related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases. RESULTS: Cell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT-737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment. CONCLUSION: Combination of ABT-737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2.

Combination Technique with Ultrasonography and Electromyography for Botulinum Injection in the Cricopharyngeal Muscle: A Case Report / 대한연하장애학회지

Cricopharygeal dysfunction (CPD) may lead to a range of symptoms including dysphagia and aspiration. Treatments for CPD have included mechanical dilation, myotomy and botulinum injection. Recently, the use of botulinum toxin injection has been reported to be safe and effective for the treatment of CPD. Ultrasonography guided technique, however, is not well established. A 55-year-old woman visited the hospital with a left cerebellar, lateral medullary, and pons infarct 4 years ago. A three-year conventional dysphagia therapy had not improved the patient's condition. Nutrition had been provided via a percutaneous endoscopic gastrostomy (PEG) tube. Videofluoroscopic swallowing study (VFSS) showed CPD. Ultrasonography and elelctromyography-guided injection of 20 units of botulinum (Meditoxin®) in left cricopharyngeal muscle. One month after injection, the VFSS showed improvement in relaxation of the upper esophageal sphincter. The patient could eat semisolid food and a soft diet at 1,200 kcal/day orally; the treatment was a success.

Treatment Adherence of Osmotic-Controlled Release Oral Delivery System Methylphenidate in Korean Children and Adolescents with Attention-Deficit Hyperactivity Disorder

OBJECTIVES: The objective of this study was to evaluate the treatment duration and adherence of osmotic-controlled release oral delivery system (OROS) methylphenidate for treatment of attention-deficit hyperactivity disorder (ADHD). METHODS: A total of 843 children with ADHD were recruited : 213 children (25.3%) who had previously taken medications for ADHD and 630 drug-naive children (74.7%) were recruited. The dosage was adjusted according to the clinician's judgment. The primary efficacy endpoint of this study was treatment retention rate, which was estimated at Week 12 and Week 20 using the Kaplan-Meier curve. The Swanson, Nolan and Pelham-IV (SNAP-IV), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement, and the side effect rating scale were measured at every visit. Remission rates were presented based on SNAP-IV and CGI-S, respectively. RESULTS: The treatment retention rate at 12 weeks and at 20 weeks was 76.2% and 66.8%, respectively. Divided according to 6-8, 9-11, 12-14 and 15-18 years of age, younger children tended to show a statistically higher treatment retention rate (p=.02). Based on SNAP-IV and CGI scores, children with better response to medication showed tendencies of statistically higher treatment retention rate. The most common adverse events included loss of appetite (7.1%) and insomnia (3.3%). There was no serious adverse event related to the treatment, such as death. CONCLUSION: The use of OROS methylphenidate for treatment of ADHD was safe and tolerable for children. In this study, lower age and better treatment response showed a statistically significant relationship with higher treatment adherence. Boys showed a trend of high treatment adherence. The treatment adherence at 20 weeks was satisfactory, however, the treatment adherence after 20 weeks showed a sharp decrease. Therefore, treatment persistence for six months after the beginning of ADHD treatment is important. In addition, the positive role of psycho-education for children and parents is necessary for increasing treatment adherence.

Measurement of Corpus Callosal Area in Schizophrenic Patients Using Magnetic Resonance Imaging / 신경정신의학

OBJECTIVES: This study was performed to determine whether the corpus callosum is involved in pathophysiology of schizophrenia and measured corpus callosal areas of first episode, chronic schizophrenic patients and controls. METHODS: We obtained the brain magnetic resonance imaging of 23 schizophrenic inpatients(15 males, 8 females)and 23 controls(11 males, 12 females)with simple headache or dizziness. Among the schizophrenic group, first episode patients were 13, chronic patients were 10. In mid-sagittal plane, the corpus callosum was divided into 7 areas and the cerebral area was measured. This data was analyzed with NIH image 1.60 software. We compared the corpus callosal areas of schizophrenics with controls by t-test and by ANOVA according to sex. Thereafter, ANCOVA was performed with mid-sagittal cerebral area as covariant. Comparison of first episode, chronic schizophrenics and controls was carried out by MANCOVA that was adjusted with age and mid-sagittal cerebral area. RESULTS: The schizophrenics, compared with controls, had smaller corpus callosal areas except for the 3rd, 6th callosal area, but statistical significance was absent. According to sex, male schizophrenics had insignificantly smaller total callosal areas than male controls and female schizophrenics had larger ones. In comparision of first episode, chronic schizophrenic patients and controls, first episode patients had smaller every corpus callosal areas than chronic ones, chronic ones had larger total callosal area than controls and first episode ones had smaller total area than controls, but statistical significances were absent also. CONCLUSION: Our study did not reveal the structural abnormality of corpus callosum in schizophrenic patients, but many controversial results have been reported in other studies. This inter-study inconsistency could be explained by the hypotheses of not only clinical but also biological different phenotypes within the schizophrenia.

Signal Hyperintensities on Brain Magnetic Resonance Imaging in Late-life Depressive Patients

OBJECTIVES: This study was performed to investigate the relationship between age of onset in late-life depression and T2 hyperintensities observed in the brain MRI, we tried to see part of pathophysiology of late-life depression. METHOD: The subjects consisted of 18 patients whose first depressive episode occurred before age 50, and 20 patients whose first depressive episode occurred after age 50 years, and 20 agematched controls. Depressive patients were diagnosed according to DSM-IV. Established hyperintensity rating systems were used to analyse the T2 weighted images and blood pressure, cholesterol level, DM, EKG were measured to compare the relationships. RESULTS: 1) Signal hyperintensities on T2 weighted image were more severe in late-life depressive patients whose first depressive episode after age 50 (p<0.05) and there is no significant difference between patients whose first episode before age 50 and age-matched control subjects. 2) Mild signal hyperintensities were observed in all elderly depressed patients and control subjects, but severe hyperintensities were observed in late-onset depression. 3) Signal hyperintensities were related to age, hypertension, blood cholesterol level (p<0.05). CONCLUSION: The late onset depressive patients had more white matter hyperintensities on T2 weighted image than early onset depressive patients. this results support previous hypothesis that white matter change is the important biological factor of late-onset elderly depression and old age, hypertension, hypercholesterolemia may be associated with signal hyperintensities.