A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia

p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.

A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia.

p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.

Studies on enhancing embryo quantity and quality by immunization against inhibin in repeatedly superovulated Holstein heifers and the associated endocrine mechanisms.

To investigate the feasibility of improving embryo production in cattle by immunization against inhibin, both in vivo and in vitro experiments were conducted. In two experiments conducted in two autumns, 14 animals aged 14 months were immunized with a recombinant inhibin α subunit protein antigen for four times at monthly intervals, with another 14 animals of the same age served as the controls. Starting from the second immunization, all the heifers received standard superovulation treatment for three sessions, one session per month, each starting 10 days after every antigen administration. Immunization against inhibin increased number of transferable embryos (P<0.05), and high quality Grade A embryos (P<0.01) in each superovulation. Blood concentrations of FSH, estradiol, activin, and also ratio of activin to follistatin concentrations were greater in inhibin immunized than in control animals during the period of superovulatory FSH administration and animal estrous expression. Heifers immunized with inhibin also had greater concentrations of progesterone in the later diestrus period. In the second experiment, the inclusion of anti-inhibin antibody in oocyte IVM medium increased oocyte maturation rate and cleavage rate following IVF (P<0.05). These results demonstrated that inhibition of the adverse effects of inhibin on ovarian follicular development and oocyte maturation improved embryo yield, in both quantity and quality, following superovulation. These results also demonstrate that active immunization against inhibin, in conjunction with the conventional superovulation protocol, can constitute a new technique for consistent improvement of bovine embryo production in vivo; while passive immunization with anti-inhibin antibody can improve embryo production in vitro.

Bortezomib-dexamethasone or vincristine-doxorubicin-dexamethasone as induction therapy followed by thalidomide as maintenance therapy in untreated multiple myeloma patients.

This randomized, retrospective study evaluated the effect of thalidomide combined with bortezomib-dexamethasone (TBD) or vincristine-doxorubicin-dexamethasone (T-VAD) on 46 patients with multiple myeloma. Newly diagnosed patients were randomly allocated to receive TBD (n = 24) or T-VAD (n = 22). The high-quality response rate (complete response plus very good partial response) was 62.5% in the TBD group and 45.4% for T-VAD. The complete response rate was 29.2% for TBD and 13.6% for T-VAD. Overall survival at 2 and 3 years, respectively, was 91.7% and 62.5% for TBD versus 86.4% and 54.5% for T-VAD. Most of the toxic effects of treatment were well tolerated. Both regimens were effective in the treatment of newly diagnosed multiple myeloma patients. Further studies are required to determine the role of thalidomide in these two regimens.

A role for the noncatalytic N terminus in the function of Cdc25, a Saccharomyces cerevisiae Ras-guanine nucleotide exchange factor.

The Saccharomyces cerevisiae CDC25 gene encodes a guanine nucleotide exchange factor (GEF) for Ras proteins. Its catalytic domain is highly homologous to Ras-GEFs from all eukaryotes. Even though Cdc25 is the first Ras-GEF identified in any organism, we still know very little about how its function is regulated in yeast. In this work we provide evidence for the involvement of the N terminus of Cdc25 in the regulation of its activity. A truncated CDC25 lacking the noncatalytic C-terminal coding sequence was identified in a screen of high-copy suppressors of the heat-shock-sensitive phenotype of strains in which the Ras pathway is hyper-activated. The truncated gene acts as a dominant-negative mutant because it only suppresses the heat-shock sensitivity of strains that require the function of CDC25. Our two-hybrid assays and immunoprecipitation analyses show interactions between the N terminus of Cdc25 and itself, the C terminus, and the full-length protein. These results suggest that the dominant-negative effect may be a result of oligomerization with endogenous Cdc25. Further evidence of the role of the N terminus of Cdc25 in the regulation of its activity is provided by the mapping of the activating mutation of CDC25HS20 to the serine residue at position 365 in the noncatalytic N-terminal domain. This mutation induces a phenotype similar to activating mutants of other genes in the Ras pathway in yeast. Hence, the N terminus may exert a negative control on the catalytic activity of the protein. Taken together these results suggest that the N terminus plays a crucial role in regulating Cdc25 and consequently Ras activity, which in S. cerevisiae is essential for cell cycle progression.

An international study of patient compliance with hemodialysis.

CONTEXT: International differences in compliance of patients undergoing hemodialysis are poorly characterized and could contribute to international survival differences. OBJECTIVE: To compare international differences in patient compliance with hemodialysis treatments. DESIGN: A prospective observational study of patients undergoing hemodialysis in 1995 and a cross-sectional survey of health care professionals caring for hemodialyzed patients in 1996. SETTING AND PATIENTS: Four dialysis centers in the southeastern United States with 415 patients undergoing hemodialysis, 1 center in Sweden with 84 patients, and 4 centers in Japan with 194 patients participated in the prospective observational study. In the cross-sectional survey, nurses and nephrologists from the United States (n = 49), Japan (n = 21), and Sweden (n = 16) responded to questions regarding the compliance of their patients undergoing hemodialysis. MAIN OUTCOME MEASURES: Percentage of patients who miss a dialysis treatment and number of missed dialysis treatments. RESULTS: Of 415 US patients, 147 missed 699 treatments over a 6-month period (28.1 missed treatments per 100 patient-months or 2.3% of all prescribed treatments). During a 3-month period, there were 0 missed treatments per 100 patient-months for patients from Japan and 0 missed treatments per 100 patient-months for patients from Sweden (P<.001). In the cross-sectional survey, the mean (SD) estimated percentage of patients missing a treatment per month was 4% (3%) for the United States, 0% for Japan, and 0.1% (3%) for Sweden (P<.001). CONCLUSIONS: Noncompliance is much more common in US patients undergoing hemodialysis than Swedish and Japanese patients. The implications of these results for international differences in survival deserve further study.

[Clinical study on treatment of male infertility with shengjing pill].

202 cases of male infertility were treated with Shengjing Pill. After treatment, quantity and quality of sperm were significantly improved (P < 0.001), levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were enhanced to normal in 96 patients (P < 0.001), levels of anti-sperm-antibody was reduced to normal in 45 cases (P < 0.001), of 148 follow-ups. Their 116 spouses became pregnant and have borne 108 well-developed babies.

Mortality among dust-exposed Chinese mine and pottery workers.

A cohort study of approximately 68,000 persons employed during 1972 to 1974 at metal mines and pottery factories in south central China was conducted to evaluate mortality from cancer and other diseases among workers exposed to different levels of silica and other dusts. A follow-up of subjects through December 31, 1989 revealed 6,192 deaths, a number close to that expected based on Chinese national mortality rates. There was, however, a nearly 6-fold increase in deaths from pulmonary heart disease (standard mortality ratio, 581; 95% confidence interval 538 to 626), and a 48% excess of mortality from nonmalignant respiratory diseases (standard mortality ratio, 148; 95% confidence interval, 139 to 158), primarily because of a more than 30-fold excess of pneumoconiosis. Pulmonary heart disease and noncancerous respiratory disease rates rose in proportion to dust exposure. Cancer mortality overall was not increased among the miners or pottery workers. There was no increased risk of lung cancer, except among tin miners, and trends in risk of this cancer with increasing level of dust exposure were not significant. Risks of lung cancer were 22% higher among workers with than without silicosis. The findings indicate that respiratory disease continues to be an occupational hazard among Chinese miners and pottery workers, but that cancer risks are not as yet strongly associated with work in these dusty trades.

A nested case-control study of lung cancer among silica exposed workers in China.

In an attempt to assess whether silica induces lung cancer, a nested case-control study of 316 male lung cancer cases and 1352 controls was carried out among pottery workers and tungsten, copper-iron, and tin miners from five provinces in south central China. Exposure to dust and silica for each study subject was evaluated quantitatively by cumulative exposure measures based on historical industrial hygiene records. Measurements on confounders such as inorganic arsenic, polycyclic aromatic hydrocarbons (PAHs), and radon were also collected from the worksites. Information on cigarette smoking was obtained by interviews of the subjects or their next of kin. A significant trend of increasing risk of lung cancer with exposure to silica was found for tin miners, but not for miners working in tungsten or copper-iron mines. Concomitant and highly correlated exposures to arsenic and PAHs among tin miners were also found. Risk of lung cancer among pottery workers was related to exposure to silica, although the dose-response gradient was not significant. Risks of lung cancer were significantly increased among silicotic subjects in iron-copper and tin mines, but not in pottery factories or tungsten mines. The results of this study provide only limited support for an aetiological association between silica and lung cancer.

A comparison of radiographic interpretation of silica exposed workers using the 1963 and the 1986 Chinese roentgenodiagnostic criteria of pneumoconioses.

As part of a larger study relating to silica exposure, silicosis, and lung cancer mortality in Chinese mine and factory workers, 1936 old posterior-anterior chest X-rays were re-interpreted according to the 1986 Chinese Roentgenodiagnostic Criteria of pneumoconioses. Each film was independently read by three individuals from a panel of eleven radiologists, and this reading was compared to the original one. Subsequent to the independent readings, a groups of three readers interpreted the films together, called the consensus readings. Comparisons were made by Chinese stage of pneumoconiosis. For the entire cohort, there was a crude agreement of 57.4% between the old and the new interpretations. Agreement within one step of full agreement was 92.5%. The interpretations done by median reading and by consensus were very similar. In general, there was a tendency for the old readings to be slightly higher compared to the new interpretations. This tendency was most marked in the tin mines, followed in decreasing order by the iron/copper mines, the potteries, and the tungsten mines. The agreement between the old and new interpretations is felt to be satisfactory.

A comparison of pneumoconiosis interpretation between Chinese and American readers and classifications.

As a preliminary step in joint Sino-American pneumoconiosis research efforts, a formal chest X-ray pneumoconiosis reading trial was conducted among Chinese and American radiologists. Twelve Chinese readers from different institutions located in south central China used the 1986 Chinese Roentgenodiagnostic Criteria of Pneumoconioses. Three American radiologists, centified as NIOSH "B" readers, used the International Labour Office Classification of Pneumoconioses. The chest X-ray study set consisted of 150 posterior-anterior films. One-half were Chinese X-rays of silica-exposed workers, and the other half were American films of variously exposed workers but primarily coal miners. All readings were done independently. The results showed that the inter-reader variability among the Chinese was similar to that of the American readers, both being in an acceptable range. In addition, there was general agreement between the Chinese and American interpretations. For small opacity profusion, the Chinese readers tended to read slightly more diseases than their American counterparts, although there was exact agreement as to the major category in two-thirds of the films. Agreement for film quality, and pleural disease was less, but was not different from reported variation among American "B" readers. Overall, the results suggest that despite the use of two different classification systems, a valid correspondence exists between the Chinese and American Interpretations, which is suitable for use in epidemiologic research.