Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis

The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.     

A generic model for the assessment of disease epidemiology: the computational basis of DisMod II

Reliable and comparable analysis of risks to health is key for preventing disease and injury. Causal attribution of morbidity and mortality to risk factors has traditionally been conducted in the context of methodological traditions of individual risk factors, often in a limited number of settings, restricting comparability.     

Population health metrics: crucial inputs to the development of evidence for health policy

Valid, reliable and comparable measures of the health states of individuals and of the health status of populations are critical components of the evidence base for health policy. We need to develop population health measurement strategies that coherently address the relationships between epidemiological measures (such as risk exposures, incidence, and mortality rates) and multi-domain measures of population health status, while ensuring validity and cross-population comparability.     

Unoprostone isopropyl ester darkens iris color in pigmented rabbits with sympathetic denervation

PURPOSE: Unoprostone isopropyl ester (unoprostone) -induced iris color darkening was evaluated in a rabbit model using a cyclooxygenase inhibitor, an alpha(1)-adrenergic antagonist, and sympathetic denervation. MATERIALS AND METHODS: Dutch-belted rabbits were divided into five groups based on type of surgery and eyedrop treatment to both eyes: (1) sham surgery (n = 7); (2) bilateral superior cervical ganglionectomy (SCGx, n = 7); (3) SCGx plus flurbiprofen 0.03% (n = 7); (4) SCGx plus thymoxamine 0.5% (n = 6); and (5) SCGx plus flurbiprofen and thymoxamine (n = 6). All rabbits were treated with unoprostone 0.12% to one eye and its vehicle to the contralateral eye twice daily for 43 weeks after SCGx. Periodic color photographs of paired eyes were scored for difference in eye color. Iris melanin and aqueous humor protein were measured at week 43. RESULTS: Twenty-three of the 26 rabbits with bilateral SCGx and unilateral unoprostone treatment demonstrated a darker iris color on the unoprostone-treated side. The average scores (demonstrating difference in iris color) comparing photographs of treated versus control eyes in the four SCGx groups were higher than those in the sham surgery group (P < 0.03), and higher than at week 0 (P < 0.001). The group pretreated with flurbiprofen and thymoxamine had the highest score of all groups. The aqueous humor protein in unoprostone-treated eyes was higher (P < or = 0.0001) than in vehicle-treated eyes. The melanin content of irides of the denervated groups was higher (P < or = 0.01) in unoprostone-treated than in vehicle-treated eyes. CONCLUSION: Unoprostone produced iris color darkening in pigmented rabbit eyes with sympathetic denervation. Pretreatment with flurbiprofen and thymoxamine appeared to enhance this effect but this was not statistically demonstrated by the study.     

Fixed-dose pegfilgrastim is safe and allows neutrophil recovery in patients with non-Hodgkin's lymphoma

Twenty-nine patients with non-Hodgkin's lymphoma received a single subcutaneous injection of 6 mg pegfilgrastim approximately 24 h after the start of CHOP chemotherapy. The safety of pegfilgrastim in this patient population was determined by reports of adverse events. The pharmacokinetics of pegfilgrastim were characterized and the duration of grade 4 neutropenia, time to absolute neutrophil count (ANC) recovery to > or = 2.0 x 10(9)/l, neutrophil nadir, and incidence of febrile neutropenia were determined in the first 21-day chemotherapy cycle. The incidence of grade 4 neutropenia in cycle 1 was 43% with a mean (SD) duration of grade 4 neutropenia value of 1.0 (1.4) day. No apparent relationship between the duration of grade 4 neutropenia and body weight was observed. The median [quartiles] time to ANC recovery was 10 [9, 11] days. The incidence of febrile neutropenia was 11%. No unexpected adverse events were reported and no patient developed antibodies to pegfilgrastim. Serum concentration of pegfilgrastim reached a maximum (median [quartiles]) of 128 [58, 159] ng/ml at approximately 24 h after administration, and was followed by a second smaller peak (median [quartiles]) of 10.6 [3.0, 20.5] ng/ml at the time of the neutrophil nadir. After the second peak, concentration of pegfilgrastim declined linearly with a median terminal half-life of approximately 42 h.     

Breast and cervical cancer survival: making sense of ‘league tables’

During 1998, the Department of Health proposed to use survival rates of cervical and breast cancer in the 1989/90 incidence cohort as indicators of care. Valid interpretation was of concern within Trent and the Trent Cancer Registry responded by performing additional analyses. Trent Cancer Registry registrations for 1989/90 were re-analysed and the stability of districts' ranks for that cohort was investigated using random simulation techniques. Stability of ranks across more recent cohorts was investigated and attempts made to use all available information.The Department of Health's analyses were confirmed by our re-analysis of the 1989/90 cohort: Rotherham residents appeared to have the "worst" survival for cervical cancer, and Sheffield residents for breast cancer, although not statistically significantly so. Random simulations indicated that ranks based on a single cohort are not stable: for example Sheffield (ranked tenth for 1-y breast cancer survival) was ranked third or better in 6% of randomisations. Ranks were also unstable across cohorts: for example Rotherham 1-y cervical cancer survival was ranked tenth for 1989/90, fifth for 1991/92 and tenth for 1993/94. Analysis of 3-y running averages provided better information than the league table approach. Most districts improved over time, to different degrees, and similar sized gaps remained between the "best" and the "worst" districts. This analysis illustrates the need to be circumspect when interpreting "league tables" based on a single year or cohort analysis. League tables are based on ranks: clearly a large difference in rank may reflect only trivial (ie medically unimportant) differences in actual outcome. Lack of a statistically significant difference in survival between two districts does not mean their survival is equivalent. Even for a common cancer, like breast cancer, rankings were unstable from cohort to cohort. At the Registry we propose to perform these trend analyses routinely in future, adjusting, when possible, for the effects of deprivation and stage at diagnosis.     

TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas

TP53 is a pivotal gene frequently mutated in diffuse gliomas and particularly in astrocytic tumors. The majority of studies dedicated to TP53 in gliomas were focused on mutational hotspots located in exons 5–8. Recent studies have suggested that TP53 is also mutated outside the classic mutational hotspots reported in gliomas. Therefore, we have sequenced all TP53 coding exons in a retrospective series of 61 low grade gliomas (LGG) using high throughput sequencing technology. In addition, TP53 mutational status was correlated with: (i) p53 expression, (ii) tumor type, (iii) chromosome arms 1p/19q status and (iv) clinical features of patients. The cohort included 32 oligodendrogliomas (O), 21 oligoastrocytomas (M) and 8 astrocytomas (A). TP53 mutation was detected in 52.4 % (32/61) of tumors (34 % of O, 71.4 % of M and 75 % of A). All mutations (38 mutations in 32 samples) were detected in exons 4, 5, 6, 7, 8 and 10. Missense and non-missense mutations, including seven novel mutations, were detected in 42.6 and 9.8 % of tumors respectively. TP53 mutations were almost mutually exclusive with 1p/19q co-deletion and were associated with: (i) astrocytic phenotype, (ii) younger age, (iii) p53 expression. Using a threshold of 10 % p53-positive tumor cells, p53 expression is an interesting surrogate marker for missense TP53 mutations (Se = 92 %; Sp = 79.4 %) but not for non-missense mutation (18.4 % of mutations). TP53 and p53 statuses were not prognostic in LGG. In conclusion, we have identified novel TP53 mutations in LGG. TP53 mutations outside exons 4–8 are rare. Although it remains imperfect, p53 expression with a threshold of 10 % is a good surrogate marker for missense TP53 mutations and appears helpful in the setting of LGG phenotype diagnosis.     

玻璃体切除术治疗外伤性眼内炎62例

0　引言　外伤性眼内炎是眼外伤的常见并发症 ,对视力及眼球威协极大 .由于病原体随致伤物直接进入眼内 ,在眼内和玻璃体繁殖 ,产生剧烈炎症反应 ,对眼内组织造成严重破坏 .如不及时而有效的控制 ,终使视力丧失 ,眼球萎缩 .近年随着现代玻璃体手术的发展 ,外伤性眼内炎的治愈率明显提高 .现将我科收治的 6 2例报告如下 .1　对象和方法1 .1　对象 1 996 - 0 6 / 1 998- 0 6我院连续收治 6 2例外伤性眼内炎 ,其中男 5 0例 ,女 1 2例 ,年龄 2～ 45岁 ,平均 1 6 .5岁 .1 4岁以下儿童 38例 ,占 6 1 .3% .以致伤原因分类 :角膜穿通伤30例 ,巩膜穿…     

52Fe for additional marrow ablation before bone marrow transplantation

The effectiveness of bone marrow transplantation (BMT) for malignant blood diseases remains limited by the inability of the preparative regimen to eliminate the disease without causing toxicity to normal organs. We have used 52Fe to deliver radiotherapy selectively to the BM. Fourteen patients with hematologic malignancies received 52Fe before a conventional BMT conditioning regimen. The median 52Fe dose was 58 mCi (range, 32 to 85 mCi). As evaluated by quantitative scanning, the median percentage of 52Fe taken up by the BM was 82% (range, 36% to 90%). This resulted in a median radiation-absorbed dose to the BM of 632 rad (range, 151 to 1,144 rad). The median uptake of 52Fe by the liver was 18% (range, 10% to 64%) and the median radiation- absorbed dose to the liver was 239 rad (range, 82 to 526 rad). The median whole body radiation-absorbed dose was 46 rad (range, 22 to 68 rad). No untoward effects were noted after the injections of 52Fe. The patients recovered hematopoiesis without toxicity in excess of that expected with conventional conditioning alone. The median follow-up was 8 months and three patients have relapsed. 52Fe should provide a way to boost the radiation dose to marrow-based diseases before marrow transplantation without increasing toxicity.