PubMed Health⌕ Search

Biomedical subjects

Alfred Sommer

Publications and source records attributed to Alfred Sommer.

14 recordsLinked to original sources
PubMed2004

The erythropoietin-receptor pathway modulates survival of cancer cells.

Anemia in cancer patients is associated with reduced quality of life and local failure after radiation treatment. However, the use of erythropoietin to correct cancer anemia and to improve radiation efficacy was disappointing. Erythropoietin-receptor signaling mainly acts via activation of STAT 5, but also crossactivates the antiapoptotic transcription factor NF-kappaB. This causes neuroprotection against oxidative stress and implies radioprotection. In order to investigate possible radioprotective effects of erythropoietin-receptor signaling, we used an in vitro model system employing HeLa TetOff cells, stably transfected with an expression vector for the erythropoietin-receptor gene. Using electrophoretic mobility shift assays, we could demonstrate strong activation of NF-kappaB by erythropoietin-receptor signaling in HeLa cells. Activation of NF-kappaB did not require degradation of IkappaBalpha and was not prevented by proteasome inhibition. Furthermore, stimulation with erythropoietin resulted in a 50% increased clonogenicity of erythropoietin-receptor-expressing cells but did not alter radiation sensitivity itself. As most human tumors express erythropoietin receptor, we advocate a restricted use erythropoietin to patients suffering from erythropoietin-receptor-expressing cancers.

Apoptosis↗
PubMed2003

Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial.

OBJECTIVE: To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women. DESIGN: Double blind cluster randomised controlled trial. SETTING: Rural community in south eastern Nepal. PARTICIPANTS: 4926 pregnant women and 4130 live born infants. INTERVENTIONS: 426 communities were randomised to five regimens in which pregnant women received daily supplements of folic acid, folic acid-iron, folic acid-iron-zinc, or multiple micronutrients all given with vitamin A, or vitamin A alone (control). MAIN OUTCOME MEASURES: Birth weight, length, and head and chest circumference assessed within 72 hours of birth. Low birth weight was defined <2500 g. RESULTS: Supplementation with maternal folic acid alone had no effect on birth size. Folic acid-iron increased mean birth weight by 37 g (95% confidence interval -16 g to 90 g) and reduced the percentage of low birthweight babies (<2500 g) from 43% to 34% (16%; relative risk=0.84, 0.72 to 0.99). Folic acid-iron-zinc had no effect on birth size compared with controls. Multiple micronutrient supplementation increased birth weight by 64 g (12 g to 115 g) and reduced the percentage of low birthweight babies by 14% (0.86, 0.74 to 0.99). None of the supplement combinations reduced the incidence of preterm births. Folic acid-iron and multiple micronutrients increased head and chest circumference of babies, but not length. CONCLUSIONS: Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight. Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk.

Birth Weight↗
PubMed2003

Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal.

BACKGROUND: We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15%. OBJECTIVE: We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality. DESIGN: The study was a double-blind, cluster-randomized, controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal. In addition to vitamin A (1000 microg retinol equivalents), the intervention groups received either folic acid (FA; 400 microg), FA + iron (60 mg), FA + iron + zinc (30 mg), or multiple micronutrients (MNs; the foregoing plus 10 microg vitamin D, 10 mg vitamin E, 1.6 mg thiamine, 1.8 mg riboflavin, 2.2 mg vitamin B-6, 2.6 microg vitamin B-12, 100 mg vitamin C, 64 microg vitamin K, 20 mg niacin, 2 mg Cu, and 100 mg Mg). The control group received vitamin A only. RESULTS: None of the supplements reduced fetal loss. Compared with control infants, infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15-20% lower 3-mo mortality; this pattern was not observed with MNs. The effect on mortality was restricted to preterm infants, among whom the relative risks (RRs) were 0.36 (95% CI: 0.18, 0.75) for FA, 0.53 (0.30, 0.92) for FA + iron, 0.77 (0.45, 1.32) for FA + iron + zinc, and 0.70 (0.41, 1.17) for MNs. Among term infants, the RR for mortality was close to 1 for all supplements except MNs (RR: 1.74; 95% CI: 1.00, 3.04). CONCLUSIONS: Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality. Among preterm infants, FA alone or with iron reduced mortality in the first 3 mo of life. MNs may increase mortality risk among term infants, but this effect needs further evaluation.

Adult↗
PubMed2002

The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells.

Cancer cells frequently show high constitutive activity of the antiapoptotic transcription factor nuclear factor kappaB (NF-kappaB), which results in their enhanced survival. Activation of NF-kappaB classically depends on degradation of its inhibitor IkappaBalpha by the 26s proteasome. Specific proteasome inhibitors induce apoptosis in cancer cells and, at nonlethal concentrations, sensitize cells to the cytotoxic effects of ionizing radiation and chemotherapeutic drugs. Recently, the protease coded by the HIV-I virus has been shown to share cleavage activities with the proteasome. For this reason, we investigated whether the HIV-I protease inhibitor saquinavir can inhibit NF-kappaB activation, block 26s proteasome activity in prostate cancer cells, and promote their apoptosis. The effect of saquinavir on LPS/IFN-gamma-induced activation of NF-kappaB was assessed by gel-shift assays and by Western analysis of corresponding IkappaBalpha-levels. Its effect on 20s and 26s proteasome activity was analyzed with a fluorogenic peptide assay using whole cell lysates from LnCaP, DU-145, and PC-3 prostate cancer cells pretreated with saquinavir for 9 h. Proteasome inhibition in living cells was assessed using ECV 304 cells stably transfected with an expression plasmid for an ubiquitin/green fluorescence protein fusion protein (ECV 304/10). Apoptosis was monitored morphologically and by flow cytometry. Saquinavir treatment prevented LPS/IFN-gamma-induced activation of NF-kappaB in RAW cells and stabilized expression of IkappaBalpha. It inhibited 20s and 26s proteasome activity in lysates from LnCaP, DU-145, and PC-3 prostate cancer cells with an IC(50) of 10 micro M and caused the accumulation of an ubiquitin/green fluorescence protein fusion protein in living ECV 304/10 cells. Incubation of PC-3 and DU-145 prostate cancer, U373 glioblastoma, and K562 and Jurkat leukemia cells with saquinavir caused a concentration-dependent induction of apoptosis. In the case of PC-3 and DU-145, saquinavir sensitized the surviving cells to ionizing radiation. We conclude that saquinavir inhibits proteasome activity in mammalian cells as well as acting on the HIV-I protease. Because saquinavir induced apoptosis in human cancer cells, HIV-I protease inhibitors might become a new class of cytotoxic drugs, alone or in combination with radiation or chemotherapy.

Animals↗
PubMed2002

N-acetyl-L-cysteine inhibits 26S proteasome function: implications for effects on NF-kappaB activation.

Ionizing radiation shares with cytokines, such as TNF-alpha, an ability to generate free radicals in cells and activate downstream proinflammatory responses through NF-kappaB-dependent signal transduction pathways. Support for the role of free radicals in triggering such responses comes from the use of free radical scavengers like N-acetyl-L-cysteine (NAC). The nature of the link between free radical generation and NF-kappaB activation is, however, unclear. In this study, we explore the possibility that scavenging of free radicals by NAC might not be the mechanism by which it inhibits NF-kappaB activation, but rather that NAC acts through inhibition of proteasome function. The effect of NAC on the chymotryptic function of the 26s and 20s proteasome complex was measured in extracts from EVC 304 bladder carcinoma cells by assessing degradation of fluorogenic substrates. NAC inhibited 26s but not 20s proteasome activity, suggesting that it interferes with 19s regulatory subunit function. NAC blocked radiation-induced NF-kappaB activity in ECV 304 cells and RAW 264.7 macrophages, as measured by a gel shift assay, at doses that inhibited proteasome activity. This provides a possible mechanism whereby NAC could block NF-kappaB activation and affect the expression of other molecules that are dependent on the ubiquitin/proteasome system for their degradation, other than by scavenging free radicals.

Acetylcysteine↗
PubMed2002

OAG in Barbados.

Explore the source record for details and available documents.

Barbados↗
PubMed2002

Assessment and control of vitamin A deficiency: the Annecy Accords.

Comprehensive recommendations for the assessment and control of vitamin A deficiency (VAD) were rigorously reviewed and revised by a working group and presented for discussion at the XX International Vitamin A Consultative Group meeting in Hanoi, Vietnam. These recommendations include standardized definitions of VAD and VAD disorders. VAD is defined as liver stores below 20 micro g (0.07 micro mol) of retinol per gram. VAD disorders are defined as any health and physiologic consequences attributable to VAD, whether clinically evident (xerophthalmia, anemia, growth retardation, increased infectious morbidity and mortality) or not (impaired iron mobilization, disturbed cellular differentiation and depressed immune response). An estimated 140 million preschool-aged children and at least 7.2 million pregnant women are vitamin A deficient, of whom >10 million suffer clinical complications, principally xerophthalmia but also increased mortality, each year. A maternal history of night blindness during a recent pregnancy was added to the clinical criteria for assessing vitamin A status of a population, and the serum retinol criterion for a "public health problem" was revised to 15% or more of children sampled having levels of <20 micro g/dL (0.7 micro mol/L). Clinical trials and kinetic models indicate that young children in developing countries cannot achieve normal vitamin A status from plant diets alone. Fortification, supplementation, or other means of increasing vitamin A intake are needed to correct widespread deficiency. To improve the status of young infants, the vitamin A supplements provided to mothers during their first 6 wk postpartum and to young infants during their first 6 mo of life should be doubled.

Child, Preschool↗