Chromosomes and causation of human cancer and leukemia. LIV. Near-tetraploidy in acute leukemia

Near-tetraploid cell populations were observed in a case of T-cell acute lymphoblastic leukemia (T-ALL) and in one of acute myeloblastic leukemia (AML). In the ALL case, hyperdiploid chromosomal changes, characterized by an isochromosome 17q [i(17q)], as well as other changes, were seen at the onset of the disease. At the first relapse, hypertetraploid cells appeared in about 10% of the mitoses in the bone marrow (BM), and by the second and third relapses, the hypertetraploidy was present in more than 90% of the mitoses in the BM. Even though karyotypic instability was evident, all abnormal karyotypes contained one or two i(17q) at every sampling. In spite of karyotypic instability at each relapse, karyotypic evolution was observed whenever relapse occurred. A normal female karyotype was confirmed in the BM of each period. Immunologic examinations performed at each sampling revealed no recognizable changes before and after the appearance of tetraploidy. In the AML case, which was classified as FAB M2, cytogenetic examination was performed at diagnosis and relapse. In both, hypotetraploid cells were observed in over 60% of the BM cells; the modal chromosome number was 90. Banding analysis was successful at relapse, and a pseudodiploid clone characterized by t(8;21) and a hypotetraploid clone with two t(8;21) and a loss of two Y chromosomes were observed in the same BM sample. A normal male karyotype was also observed in BM cells. In both cases, giant and bizarre blasts were seen in the BM. A close correlation between near-tetraploid mitoses and giant and bizarre blast cells in BM smears of the same samples was observed. Previously published tetraploid acute leukemia cases analyzed with banding methods were accumulated and compared with our two cases.     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

Dissecting Obesogenic Environments: The Development and Application of a Framework for Identifying and Prioritizing Environmental Interventions for Obesity

Background. The “obesogenicity” of modern environments is fueling the obesity pandemic. We describe a framework, known as ANGELO (analysis grid for environments linked to obesity), which is a conceptual model for understanding the obesogenicity of environments and a practical tool for prioritizing environmental elements for research and intervention.Methods: Development of the ANGELO framework. The basic framework is a 2 × 4 grid which dissects the environment into environmental size (micro and macro) by type: physical (what is available), economic (what are the costs), political (what are the “rules”), and sociocultural (what are the attitudes and beliefs). Within this grid, the elements which influence food intake and physical activity are characterized as obe sogenic or “leptogenic” (promoting leanness).Results: Application of the ANGELO framework. The ANGELO framework has been piloted at the population level (island communities) to prioritize the settings/sectors for intervention and at the setting level (fast food outlets) to prioritize research needs and interventions. Environmental elements were prioritized by rating their validity (evidence of impact), relevance (to the local context), and potential changeability.Conclusions. The ANGELO framework appears to be a flexible and robust instrument for the needs analysis and problem identification stages of reducing the obe sogenicity of modern environments.     

The potential role of bacterial toxins in Sudden Infant Death Syndrome (SIDS)

Summary Toxigenic bacteria have been implicated in some cases of Sudden Infant Death Syndrome (SIDS). Although there is not much evidence thatClostridia spp. are associated with SIDS in Britain, strains ofStaphylococcus aureus producing pyrogenic toxins have been isolated from significant numbers of these infants at autopsy. The pyrogenic toxins, produced by some strains of group AStreptococcus pyogenes as well as staphylococci, are powerful superantigens that have significant physiological effects including induction of fever > 38°C. In this article, interactions between genetic and environmental factors that might enhance colonization of epithelial surfaces by toxigenic staphylococci are analyzed: infant's expression of Lewis^a antigen which acts as a receptor for some microorganisms; viral infections; the effect of mother's smoking on susceptibility to respiratory infection. Based on epidemiological findings and laboratory investigations, a hypothesis is proposed to explain how bacteria producing pyrogenic toxins might contribute to some cot deaths.     

Some reasons for the lack of progress in the treatment of acute myelogenous leukemia: a review of three consecutive trials of the treatment of poor prognosis patients

The failure of three consecutive treatment protocols to significantly increase the complete remission rate for poor prognosis newly diagnosed patients with acute myelocytic leukemia led to a detailed investigation of the causes of treatment failure. In the majority of cases treatment failure was attributable to "clinical resistance" to therapy. Upon close examination two types of "clinical resistance" were discernible: the failure of chemotherapy to produce adequate cytotoxic effects ("classical" drug resistance), and treatment failure attributed to the rapid regrowth of leukemia cells subsequent to the substantial killing of leukemia cells by cytotoxic therapy ("biological" resistance). Each form of resistance accounted for one-half of the treatment failures.     

Early posttransplant lymphoproliferative disorder presenting with ureteric obstruction in en bloc kidneys

We describe a female patient who received double pediatric (en bloc) kidney transplants. She presented initially with fever of unknown origin 3 months after transplantation; 5 months after surgery, she presented with obstruction of one ureter followed by obstruction of the other. After 9 months she developed posttransplant lymphoproliferative disorder in both kidneys. To our knowledge, this is the first case report of this disorder occurring in en bloc kidneys and presenting with bilateral ureteric obstruction.     

Initial transforming event in myelodysplastic syndromes may be viral: case for cytomegalovirus

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders which begin in a pluripotential bone marrow (BM) stem cell. This early stem cell is believed to acquire a growth advantage over its neighbors as a result of an initial transforming event, the nature of which has remained obscure. In this paper, we propose that pathogens such as those belonging to the herpesvirus family of DNA viruses may play a role in the initial transformation of the stem cell. The case for cytomegalovirus (CMV) as a representative of this family of viruses is discussed at length and a molecular mechanism which may be involved in the oncogenic activity of CMV is proposed. No proof has been presented to implicate CMV directly in MDS, but circumstantial evidence which supports such a possibility is provided.     

Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients.

PURPOSE: Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent. PATIENTS AND METHODS: Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 microg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA). RESULTS: From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin. CONCLUSION: A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment.     

单核细胞增生李斯特菌L型对小鼠脾脏树突状细胞免疫调节作用影响的研究

  目的  研究单核细胞增生李斯特菌(Listeria monocytogenes, LM)感染对树突状细胞(dendritic cell, DC)免疫功能的影响,探讨细菌型(WT)和L型(L-form)LM对DC的免疫活化能力差异。  方法  将C57BL/6小鼠随机分为对照组、WT组、L-form组,3组小鼠分别经尾静脉感染PBS液、细菌型LM和L型LM,电镜观察脾脏DC超微结构特征;流式细胞术检测小鼠脾脏DC的数量、共刺激分子表达、胞内细胞因子分泌、脾脏T细胞亚群及其活化程度。  结果  透射电镜可观察到对照组小鼠脾脏DC表面有大量丝状伪足,胞浆均匀,细胞核大而偏于一侧;吞噬细菌后,表面丝状伪足减少,胞质内空泡增多;小鼠感染后第1天脾脏中DC绝对值无明显升高或降低(P>0.05),但成熟表型特征性分子表达上调(P < 0.05),L-form感染组DC表面CD80和CD86分子均高于WT组(P < 0.05);小鼠感染LM后TNF-α+DC比例明显升高,L-form感染组分泌TNF-α的DC高于WT组(P < 0.05);感染LM后第7天,3组小鼠脾脏CD4+T细胞和CD8+T细胞在淋巴细胞中所占比例差异均无统计学意义(P>0.05),但L-form组CD69+ T细胞比例高于WT组(P < 0.05)。  结论  L型LM可介导相对高水平的TNF-α,促进DC成熟以增强其抗原递呈的能力。     

A role for physicians in ethnopharmacology and drug discovery

Ethnopharmacology investigations classically involved traditional healers, botanists, anthropologists, chemists and pharmacologists. The role of some groups of researchers but not of physician has been highlighted and well defined in ethnopharmacological investigations. Historical data shows that discovery of several important modern drugs of herbal origin owe to the medical knowledge and clinical expertise of physicians. Current trends indicate negligible role of physicians in ethnopharmacological studies. Rising cost of modern drug development is attributed to the lack of classical ethnopharmacological approach. Physicians can play multiple roles in the ethnopharmacological studies to facilitate drug discovery as well as to rescue authentic traditional knowledge of use of medicinal plants. These include: (1) Ethnopharmacological field work which involves interviewing healers, interpreting traditional terminologies into their modern counterparts, examining patients consuming herbal remedies and identifying the disease for which an herbal remedy is used. (2) Interpretation of signs and symptoms mentioned in ancient texts and suggesting proper use of old traditional remedies in the light of modern medicine. (3) Clinical studies on herbs and their interaction with modern medicines. (4) Advising pharmacologists to carryout laboratory studies on herbs observed during field studies. (5) Work in collaboration with local healers to strengthen traditional system of medicine in a community. In conclusion, physician's involvement in ethnopharmacological studies will lead to more reliable information on traditional use of medicinal plants both from field and ancient texts, more focused and cheaper natural product based drug discovery, as well as bridge the gap between traditional and modern medicine.