ABSTRACT
BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. METHODS: The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. RESULTS: Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. CONCLUSION: Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.
Subject(s)
Inflammatory Breast Neoplasms/metabolism , Inflammatory Breast Neoplasms/therapy , Transcription Factors/antagonists & inhibitors , Transcription Factors/biosynthesis , Apoptosis/drug effects , Apoptosis/genetics , Cell Growth Processes/drug effects , Cell Growth Processes/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Female , Gene Expression Profiling , Humans , Inflammatory Breast Neoplasms/genetics , Inflammatory Breast Neoplasms/pathology , Molecular Targeted Therapy/methods , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Transcription Factors/genetics , Zinc Finger Protein GLI1ABSTRACT
We examined the ability to produce, repeat, and comprehend emotional prosody in 20 patients with Alzheimer's disease (AD) and in 11 elderly normal control subjects. In addition, caregivers of AD patients completed affective and behavioral measures with reference to the patient. Relative to control subjects, comprehension of emotional prosody was marginally impaired in mildly demented AD patients, whereas production, comprehension, and repetition of emotional prosody were significantly impaired in moderately demented AD patients. The moderately demented patients performed significantly poorer than the mildly demented patients on the production and repetition tasks. In contrast, there was no significance difference between the two groups on the prosody comprehension task. Additional analyses revealed an inverse relationship between the ability to correctly produce and repeat emotional prosody and the frequency of agitated behaviors and depressive symptomatology in moderately demented patients. This latter findings suggests that the inability to communicate emotional message is associated with disturbances in mood and behavior in AD patients. Implications for the management of disruptive behavior in agitated and aprosodic AD patients include the development of caregiver sensitivity to unexpressed emotion and caregiver assistance with emotional expression.
Subject(s)
Alzheimer Disease/psychology , Speech Perception/physiology , Aged , Alzheimer Disease/physiopathology , Analysis of Variance , Emotions/physiology , Humans , Middle Aged , Neuropsychological TestsABSTRACT
The clinical course of early-onset, dominantly inherited, familial Alzheimer's disease (FAD) was contrasted with late-onset, sporadic Alzheimer's disease (AD). Eight FAD and 23 sporadic AD patients were followed over a mean of 63 months from estimated disease onset. The two groups did not differ notably in duration of symptoms from onset, global disease severity, or degree of cognitive deficits on initial evaluation. The Kaplan-Meier lifetable method was used to assess time from estimated disease onset to dependence in self-care, institutionalization, and death. A greater percentage of FAD patients became dependent in self-care and died earlier than did sporadic AD patients. The lifetable results suggest that FAD may have a more rapid course than dose late-onset sporadic AD.
Subject(s)
Activities of Daily Living/classification , Alzheimer Disease/genetics , Genes, Dominant/genetics , Neuropsychological Tests/statistics & numerical data , Activities of Daily Living/psychology , Adult , Aged , Alzheimer Disease/diagnosis , Alzheimer Disease/mortality , Alzheimer Disease/psychology , Female , Follow-Up Studies , Geriatric Assessment/statistics & numerical data , Humans , Institutionalization , Life Tables , Male , Middle Aged , Pedigree , Survival RateABSTRACT
A consecutive sample of 500 adults undergoing cardiac surgery was randomly allocated to extracorporeal circulation with either a Bard bubble oxygenator H1700 or a Bard membrane oxygenator HF5700 (Bard Ltd, Crawley, UK). Alveolar-arterial oxygen tension gradient (AaDO2) was calculated prebypass, then 20, 90, 180, and 420 minutes postbypass. Preoperative, initial postoperative, and first-day postoperative chest x-rays were assigned an extravascular lung water (EVLW) score and an atelectasis score. There was a comparable increase in AaDO2 after bypass in each group. The increase in EVLW score was significantly greater in the bubble group (mean 2.91, 95% CI 2.28-3.54) than the membrane group (mean 2.06, 95% CI 1.43-2.69) for the initial postoperative x-rays (P < 0.01) and also for the x-rays on the first postoperative day (P < 0.01). The increase in atelectasis score was significantly greater in the bubble group (mean 1.06, 95% CI 0.94-1.18) than the membrane group (mean 0.86, 95% CI 0.74-0.98) for the initial postoperative x-rays (P < 0.01) but not for the x-rays on the first postoperative day. There was no difference in duration of ventilation, intensive care, hospital stay, or hospital mortality between bubble and membrane groups. Although there was a statistically significant difference in x-ray scores between oxygenator groups, neither intrapulmonary shunting nor clinical outcome was influenced by the type of oxygenator used during bypass.
Subject(s)
Cardiopulmonary Bypass/instrumentation , Oxygenators, Membrane , Oxygenators , Respiration/physiology , Adult , Critical Care , Extravascular Lung Water/physiology , Female , Humans , Length of Stay , Lung/diagnostic imaging , Male , Middle Aged , Oxygen/blood , Pulmonary Atelectasis/physiopathology , Pulmonary Gas Exchange/physiology , Radiography , Respiration, Artificial , Survival Rate , Time FactorsABSTRACT
The distribution of cholecystokinin (CCK) mRNA in the rat brain was determined by means of in situ hybridization histochemistry. Our results demonstrate a widespread distribution of neurons containing CCK mRNA throughout the rat brain. Hybridization-positive neurons were distributed throughout the neocortex, olfactory bulb, claustrum, amygdala, the dentate gyrus and hippocampus proper, and several subnuclei of the thalamus and the hypothalamus. The most abundant and most heavily labeled neurons were found in the endopiriform/piriform cortex, tenia tecta, and the ventral tegmental area. The distribution of neurons positive for CCK mRNA paralleled that of CCK-like immunoreactive neurons. These results detail the distribution of CCK mRNA and clearly identify the existence of CCK-synthesizing neurons in regions such as the paraventricular and supraoptic nuclei of the hypothalamus, where the presence of CCK cell bodies was previously uncertain.
