IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.

Despite high remission rates after chemotherapy, only 30-40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. This extremely poor prognosis of AML is mainly caused by treatment failure due to chemotherapy resistance. Chemotherapy resistance can be caused by various features including activation of alternative signaling pathways, evasion of cell death or activation of receptor tyrosine kinases such as the insulin growth factor-1 receptor (IGF-1R). Here we have studied the role of the insulin-like growth factor-binding protein-7 (IGFBP7), a tumor suppressor and part of the IGF-1R axis, in AML. We report that IGFBP7 sensitizes AML cells to chemotherapy-induced cell death. Moreover, overexpression of IGFBP7 as well as addition of recombinant human IGFBP7 is able to reduce the survival of AML cells by the induction of a G2 cell cycle arrest and apoptosis. This effect is mainly independent from IGF-1R activation, activated Akt and activated Erk. Importantly, AML patients with high IGFBP7 expression have a better outcome than patients with low IGFBP7 expression, indicating a positive role for IGFBP7 in treatment and outcome of AML. Together, this suggests that the combination of IGFBP7 and chemotherapy might potentially overcome conventional AML drug resistance and thus might improve AML patient survival.

Estimating overall persistence and long-range transport potential of persistent organic pollutants: a comparison of seven multimedia mass balance models and atmospheric transport models.

Two different approaches to modeling the environmental fate of organic chemicals have been developed in recent years. The first approach is applied in multimedia box models, calculating average concentrations in homogeneous boxes which represent the different environmental media, based on intermedia partitioning, transport, and degradation processes. In the second approach, used in atmospheric transport models, the spatially and temporally variable atmospheric dynamics form the basis for calculating the environmental distribution of chemicals, from which also exchange processes to other environmental media are modeled. The main goal of the present study was to investigate if the multimedia mass balance models CliMoChem, SimpleBox, EVn-BETR, G-CIEMS, OECD Tool and the atmospheric transport models MSCE-POP and ADEPT predict the same rankings of the overall persistence (P(ov)) and long-range transport potential (LRTP) of POPs, and to explain differences and similarities between the rankings by the mass distributions and inter-compartment mass flows. The study was performed for a group of 14 reference chemicals. For P(ov), the models yield consistent results, owing to the large influence of phase partitioning parameters and degradation rate constants, which are used similarly by all models. Concerning LRTP, there are larger differences between the models than for P(ov), due to different LRTP calculation methods and spatial model resolutions. Between atmospheric transport models and multimedia fate models, no large differences in mass distributions and inter-compartment flows can be recognized. Deviations in mass flows are mainly caused by the geometrical design of the models.

Identification of a putative p53 binding sequence within the human mitochondrial genome.

A small fraction of the total cellular amount of nuclear transcription factor p53 seems to be located at and within mitochondria. Transcription factors of the steroid receptor superfamily that, like p53, lack a classical mitochondrial leader sequence are nonetheless imported into mitochondria where they regulate mtDNA transcription through binding to specific recognition sequences. Here, we examined seven candidate sequences from the human mitochondrial genome with similarity to the consensus p53 binding motif. Two imperfect half-sites at coordinate 1553 with homology to the nuclear IGF-BP3 box A binding sequence are demonstrated to confer responsivity to p53 and the p53 relatives p73alpha and beta in the context of the cell nucleus. Mitochondrial p53 may thus bind directly to mtDNA and, perhaps, be involved in the regulation of mitochondrial transcription/replication.

Microactuators based on conducting polymers.

In this contribution we report the use of polyaniline and polypyrrole for miniaturized actuators fabricated by microstructural and electrochemical technologies. The potential necessary to drive the actuator is typically less than 1 V, i.e. 2-3 orders of magnitude lower than that necessary for the widespread piezoelectric actuator devices. This low voltage is imperative for future application of actuators of micrometer dimensions. The volume variation of polymers substantially exceeds that of piezoelectric materials. Different contributions to the actuator characteristics are discussed and evaluated semi-quantitatively.

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse.

Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 microM resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation.

p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents.

The molecular basis for the sensitivity of tumor cells to chemopreventive natural food compounds and commonly used chemotherapeutic agents is not well understood, not least because studies are frequently confounded by the diversity among cell lines or rely on experimental protein overexpression. Here we investigated the effects of n-butyrate, a cancer-preventive short-chain fatty acid produced by anaerobic bacteria in the gastrointestinal tract, on the human wild-type p53 and p21 expressing HCT116 colon carcinoma cell line and on HCT116 cells with either p53 or p21 alleles inactivated by homologous recombination. The effects of n-butyrate were then compared with those elicited by cytotoxic drugs and the natural chemopreventive phytoalexin of wine and grapes, resveratrol. We document that physiological concentrations of n-butyrate stimulate p21 expression and induce apoptosis independently of p53, and that the absence of p21 increases apoptosis drastically. The apoptosis is mediated through the mitochondria and is accompanied by mitochondrial proliferation and membrane potential changes. Adriamycin, etoposide, cisplatinum, colcemid and resveratrol induce distinct cellular responses; however, absence of p21 favors apoptosis-induction by adriamycin, etoposide and colcemid. Thus, control of p21 expression may support chemoprevention and certain tumor therapies.

Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS.

We report the first described case of Arthrographis kalrae pansinusitis and meningitis in a patient with AIDS. The patient was initially diagnosed with Arthrographis kalrae pansinusitis by endoscopic biopsy and culture. The patient was treated with itraconazole for approximately 5 months and then died secondary to Pneumocytis carinii pneumonia. Postmortem examination revealed invasive fungal sinusitis that involved the sphenoid sinus and that extended through the cribiform plate into the inferior surfaces of the bilateral frontal lobes. There was also an associated fungal meningitis and vasculitis with fungal thrombosis and multiple recent infarcts that involved the frontal lobes, right caudate nucleus, and putamen. Post mortem cultures were positive for A. kalrae.

Social insurance for health service.

Implementation of social insurance for financing health services has yielded different patterns depending on a country's economic level and its government's political ideology. By the late 19th century, thousands of small sickness funds operated in Europe, and in 1883 Germany's Chancellor Bismarck led the enactment of a law mandating enrollment by low-income workers. Other countries followed, with France completing Western European coverage in 1928. The Russian Revolution in 1917 led to a National Health Service covering everyone from general revenues by 1937. New Zealand legislated universal population coverage in 1939. After World War II, Scandinavian countries extended coverage to everyone and Britain introduced its National Health Service covering everyone with comprehensive care and financed by general revenues in 1948. Outside of Europe Japan adopted health insurance in 1922, covering everyone in 1946. Chile was the first developing country to enact statutory health insurance in 1924 for industrial workers, with extension to all low-income people with its "Servicio Nacional de Salud" in 1952. India covered 3.5 percent of its large population with the Employees' State Insurance Corporation in 1948, and China after its 1949 revolution developed four types of health insurance for designated groups of workers and dependents. Sub-Saharan African countries took limited health insurance actions in the late 1960s and 1970s. By 1980, some 85 countries had enacted social security programs to finance or deliver health services or both.

Recent health system development in Poland and Hungary.

Before 1989, the health systems of both Poland and Hungary were fully socialist, with all resources being governmental. The total populations of these countries were entitled to comprehensive health services from regionalized networks of hospitals, polyclinics, and primary health stations. Preventive environmental and epidemiological services were provided through special small facilities. Since the termination of socialism in 1989, the Polish system has been largely unchanged, except for greater emphasis on primary health care. About 5 percent of polyclinics have been privatized. In Hungary, financing has been transferred to a Social Security Fund. Polyclinics have been absorbed by hospital outpatient departments, and patients may use them only on referral by a family doctor. Public health officers have a wider scope of responsibilities in their districts. Both health systems still stress equitable distribution of services to everyone.

The meanings of social medicine and public health.

The term "social medicine" has been marked by a great deal of confusion in the medical literature, in medical education, and in discussion of systems of health care. It has occupied diverse relationships to the term "public health", which this article will explore.

Public health principles and methods.

Author presents his views on the past and present problems of public health. Special attention is given to the differences in public health goals of industrialized and developing countries.