HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA.

BACKGROUND: Although histone deacetylase inhibitors (HDACi) are promising cancer therapeutics regulating proliferation, differentiation and apoptosis, molecular pathways engaged by specific HDAC isoenzymes in cancer are ill defined. RESULTS: In this study we demonstrate that HDAC2 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), especially in undifferentiated tumours. We show that HDAC2, but not HDAC1, confers resistance towards the topoisomerase II inhibitor etoposide in PDAC cells. Correspondingly, the class I selective HDACi valproic acid (VPA) synergises with etoposide to induce apoptosis of PDAC cells. Transcriptome profiling of HDAC2-depleted PDAC cells revealed upregulation of the BH3-only protein NOXA. We show that the epigenetically silenced NOXA gene locus is opened after HDAC2 depletion and that NOXA upregulation is sufficient to sensitise PDAC cells towards etoposide-induced apoptosis. CONCLUSIONS: In summary, our data characterise a novel molecular mechanism that links the epigenetic regulator HDAC2 to the regulation of the pro-apoptotic BH3-only protein NOXA in PDAC. Targeting HDAC2 will therefore be a promising strategy to overcome therapeutic resistance of PDAC against chemotherapeutics that induce DNA damage.

Age-related decline of brain monoamines in mice is reversed to young level by Japanese herbal medicine.

Young (3-month-old) and aged mice (18-month-old) were fed a diet containing Japanese herbal medicine (TJ-41 or TJ-48) for 5 months, and the effect of the herbal medicines were examined in terms of levels of monoamines and their metabolites in the brain of young and aged mice. In the aged mice, the levels of norepinepherine, serotonin and their metabolites in the brain were decreased in the cortex, hippocampus and hypothalamus. Feeding of diet containing TJ-48, but not TJ-41, enhanced the levels of some monoamines and their metabolites in the brains of aged mice, comparable to those of young mice. The results indicated that the improvement of levels of monoamines by Japanese herbal medicine was observed only in the aged mice, not in the young mice. The data have suggested the importance of the aged animals to see the effect of medicine on the functions of organs or systems.

Differential expression and regulation of Na(+)/H(+) exchanger isoforms in rabbit parietal and mucous cells.

Several Na(+)/H(+) exchanger (NHE) isoforms are expressed in the stomach, and NHE1 and NHE2 knockout mice display gastric mucosal atrophy. This study investigated the cellular distribution of the NHE isoforms NHE1, NHE2, NHE3, and NHE4 in rabbit gastric epithelial cells and their regulation by intracellular pH (pH(i)), hyperosmolarity, and an increase in cAMP. Semiquantitative RT-PCR and Northern blot experiments showed high NHE1 and NHE2 mRNA levels in mucous cells and high NHE4 mRNA levels in parietal and chief cells. Fluorescence optical measurements in cultured rabbit parietal and mucous cells using the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein and NHE isoform-specific inhibitors demonstrated that in both cell types, intracellular acidification activates NHE1 and NHE2, whereas hyperosmolarity activates NHE1 and NHE4. The relative contribution of the different isoforms to pH(i)- and hyperosmolarity-activated Na(+)/H(+) exchange in the different cell types paralleled their relative expression levels. cAMP elevation also stimulated NHE4, whereas an increase in osmolarity above a certain threshold further increased NHE1 and not NHE4 activity. We conclude that in rabbit gastric epithelium, NHE1 and NHE4 regulate cell volume and NHE1 and NHE2 regulate pH(i). The high NHE1 and NHE2 expression levels in mucous cells may reflect their special need for pH(i) regulation during high gastric acidity. NHE4 is likely involved in volume regulation during acid secretion.

[Surgical treatment of temporomandibular joint ankylosis]. / Kirurgisk behandling af kaebeledsankylose.

Surgical treatment of temporo-mandibular joint (TMJ) ankylosis may be a particularly difficult procedure due to unfavourable anatomic configurations and the proximity of vital structures. Postoperatively, it is followed by an often long and painful period of physiotherapy. The results of treatment of eight patients with TMJ ankylosis are reported. Different methods were used according to age of the patient and the extent of the ankylotic changes. The importance of early treatment is emphasized. This results in less extensive surgery and reduces secondary growth anomalies of the jaws.

Facial growth and oral function in a case of juvenile rheumatoid arthritis during an 8-year period.

The present report is a detailed analysis of facial growth and oral function in a girl with juvenile rheumatoid arthritis of the temporomandibular joints. She was followed from 9 to 17 years of age prior to and after orthognathic surgery. Facial growth was assessed by facial photographs, dental casts, and roentgencephalometry, and oral function was assessed clinically by electromyography, kinesiography, and bite force. In addition, histological and histochemical analysis was performed on biopsy material from her masseter muscle obtained at the time of surgery. The study showed a clear relationship between facial growth and oral function. Dysplastic growth of the mandible led to an increasingly unstable occlusion with poor working conditions for the masticatory muscles. The muscles became weak, and even revealed marked structural histological and histochemical changes. Based on these observations it is suggested that the conventional treatment strategy with postponement of orthodontic or orthognathic surgical treatment until cessation of growth is abandoned and that early treatment should be undertaken to maintain occlusal stability throughout the growth period.

[Occurrence of muscle contraction headache in children with abnormal incisor occlusion]. / Forekomst af muskel-spaendingshovedpine hos born med afvigende fortandsokklusion.

The principal result of the investigation indicates that children with abnormal incisor occlusion must be regarded as a risk group concerning muscle contraction headache (MCH). The need for orthodontic treatment of children with abnormal incisor occlusion is usually by layman regarded as being based upon psychosocial considerations. These considerations shall not be underestimated. For children as well as for grown up persons an appearance dominated by a visible abnormal incisor occlusion will be loading in contact with other people. From a professional point of view need for orthodontic treatment of children with abnormal incisor occlusion has usually been defined from the demand for stability. Grown up people with abnormal incisor relations are frequently referred to orthodontic specialists because of problems, such as migration of the incisors, extreme attrition or functional disturbances in the masticatory system. These problems are closely related to the abnormal incisor occlusion. With our present knowledge of the importance of the incisor relation for the function of the masticatory system, this condition must have high priority in the evaluation of need for orthodontic treatment of children. The treatment will, by improving the functional condition of the masticatory system and normalizing the function, have importance as prophylaxis and/or early treatment of a risk group concerning muscle contraction headache.