Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of DCK.

The anti-tumor activity of gemcitabine (GEM) has been clinically proven in several solid tumors, including pancreatic cancer, biliary tract cancer, urinary bladder cancer, and non-small cell lung cancer. However, problems remain with issues such as acquisition of chemoresistance against GEM. GEM is activated after phosphorylation by deoxycytidine kinase (DCK) inside of the cell; thus, DCK inactivation is one of the important mechanisms for acquisition of GEM resistance. We previously investigated the DCK gene in multiple GEM resistant cancer cell lines and identified frequent inactivating mutations. In this study, we identified two crucial genetic alteration in DCK. (1) A total deletion of DCK in RTGBC1-TKB, an acquired GEM resistant cell line derived from a gall bladder cancer cell line TGBC1-TKB. (2) An E197K missense alteration of DCK in MKN28, a gastric cancer cell line; its acquired GEM resistant cancer cell line, RMKN28, showed a loss of the normal E197 allele. We introduced either normal DCK or altered DCK_E197K into RMKN28 and proved that only the introduction of normal DCK restored GEM sensitivity. Furthermore, we analyzed 104 healthy volunteers and found that none of them carried the same base substitution observed in MKN28. These results strongly suggest that (1) the E197K alteration in DCK causes inactivation of DCK, and that (2) loss of the normal E197 allele is the crucial mechanism in acquisition of GEM resistance in RMKN28.

Somatic symptoms most often associated with depression in an urban hospital medical setting in Japan.

Somatic symptoms are known to be a prominent characteristic in patients with depression. The aim of the present study was to investigate the major somatic and psychiatric symptoms associated with depression in each sex. Patients with a DSM-IV diagnosis of depressive disorders (n=335) and comparison patients without depression (n=423) among new outpatients in an urban hospital medical setting were eligible for study. The relationship between the the most distressing subjective symptoms at first visit, confirmed by the patient's description on a health questionnaire and the admitting physician's interview, and depression was investigated in each sex. Most (73.5%) of the complaints in patients with depression were somatic. In a simple logistic regression analysis, diarrhea, excessive sweating and psychomotor retardation in men and headache, depressed mood and grief in women were associated with depression. In multiple logistic regression analysis, diarrhea, excessive sweating and weight loss in men, and headache, dysesthesia and grief in women, as well as sleep disturbance, loss of appetite, general fatigue loss on interest and agitation in both sexes, were significantly associated with depression. Fever in men was also associated with depression by Fisher's exact test.