Eva M. McGhee

Genomic instability induced by ionizing radiation

Genomic instability is characterized by the increased rate of acquisition of alterations in the mammalian genome. These changes encompass a diverse set of biological end points including karyotypic abnormalities, gene mutation and amplification, cellular transformation, clonal heterogeneity and delayed reproductive cell death. The loss of stability of the genome is becoming accepted as one of the most important aspects of carcinogenesis, and the numerous genetic changes associated with the cancer cell implicate genomic stability as contributing to the neoplastic phenotype. Multiple metabolic pathways govern the accurate duplication and distribution of DNA to progeny cells; other pathways maintain the integrity of the information encoded by DNA and regulate the expression of genes during growth and development. For each of these functions, there is a normal baseline frequency at which errors occur, leading to spontaneous mutations and other genomic anomalies. This review summarizes the current status of knowledge about radiation-induced genomic instability. Those events and processes likely to be involved in the initiation and perpetuation of the unstable phenotype, the potential role of epigenetic factors in influencing the onset of genomic instability, and the delayed effects of cellular exposure to ionizing radiation are discussed.

Natural antimutagenic agents

Following a brief review of recent discoveries in the field of natural antimutagenic and tumor chemopreventive agents, contemporary findings in the authors laboratories employing the direct acting mutagen, ethyl methanesulfonate, in modified Ames tests and eukaryotic murine FM3A mammary tumor cells modified to be subject to thymidine-less death are described to illustrate the underlying principles. The EMS studies are illustrated with the isolation of the novel antimutagen, plicatin B, from the medicinal plants, Psoralea juncaea and P. plicata. The FM3A studies are carried out with extracts of Styrax asiatica, a plant previously studied extensively with the EMS system. The FM3A findings closely parallel the earlier work with EMS showing that the responsible agents, cinnamic acid, cinnamoyl ricinoleate and cinnamoyl cinnamate are effective both in prokaryotic and eukaryotic tests and that the new FM3A assay system has useful properties for screening and assay of novel antimutagenic agents.

Candidate region for Coffin-Siris syndrome at 7q32-->34.

Coffin-Siris syndrome is characterized by intrauterine growth retardation, mental deficiency, coarse face, hypoplastic fifth fingers and nails, hirsutism, and initial difficulties with feeding. The etiology of this syndrome is unknown. We report on an 11-year-old girl with Coffin-Siris syndrome and a de novo, apparently balanced reciprocal translocation between chromosomes 7 and 22 [t(7;22)(q32;q11.2)]. The 7q breakpoint in our patient is very similar to the breakpoint reported in a previous case [McPherson et al., 1997: Am J Med Genet 71:430-433] with a balanced t(1;7)(q21.3;q34). Together, these patients provide evidence that the region 7q32-->34 is a candidate region for the gene responsible for Coffin-Siris syndrome.

Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing

AbstractTargeting glycolysis for cancer treatment has been investigated as a therapeutic method but has not offered a feasible chemotherapeutic strategy. Our aim was to examine whether AMP-activated protein kinase (AMPK), a conditional oncogene, rescues the energetic stress and cytotoxicity induced by 2-deoxyglucose (2-DG), a glycolytic inhibitor, and the related mechanisms. Luciferin/luciferase adenosine triphosphate (ATP) determination, Western analysis, qRT-PCR analyses, MTT growth assay, clonogenic assay, and statistical analysis were performed in this study. 2-DG decreased ATP levels and subsequently activated AMPK, which contribute to intracellular ATP recovery in MCF-7 cells thus exhibiting no apparent cytotoxicity. Compound C, an AMPK inhibitor, further potentiates 2-DG-induced decrease in ATP levels and inhibits their recovery. 2-DG, via AMPK activation, stimulated cAMP response element-binding protein (CREB) phosphorylation and activity and promoted nuclear peroxisome proliferator-activated receptor gamma coactivator-1-beta (PGC-1β) and estrogen-related receptor α (ERRα) protein expression, leading to augmented mitochondrial biogenesis and expression of fatty acid oxidation (FAO) genes including PPARα, MCAD, CPT1C, and ACO. This metabolic adaptation elicited by AMPK counteracts the ATP-depleting and cancer cell-killing effect of 2-DG. However, 2-DG in combination with AMPK antagonists or small interfering RNA caused a dramatic increase in cytotoxicity in MCF-7 but not in MCF-10A cells. Similarly, when combined with inhibition of CREB/PGC-1β/ERRα pathway, 2-DG saliently suppressed mitochondrial biogenesis and the expression of FAO genes, depleted ATP production, and enhanced cytotoxicity in cancer cells. Collectively, the combination of 2-DG and AMPK inhibition synergistically enhanced the cytotoxic potential in breast cancer cells with a relative nontoxicity to normal cells and may offer a promising, safe, and effective breast cancer therapeutic strategy.

Prenatal diagnosis and characterization of an unbalanced whole arm translocation resulting in monosomy for 18p.

Monosomy for the short arm of chromosome 18 is one of the most frequent autosomal deletions observed. While most cases result from terminal deletion of 18p, 16% of cases reported were as a result of an unbalanced whole arm translocation resulting in monosomy 18p. The origin and structure of these derivative chromosomes were reported in only a few cases. We report the prenatal diagnosis and characterization of a new case of monosomy 18p as a result of an unbalanced whole arm translocation. Amniocentesis was performed at 15 weeks of gestation on a 34‐year‐old woman initially referred for advanced maternal age. Holoprosencephaly was identified by ultrasound at the time of amniocentesis. Karyotype analysis showed an unbalanced whole arm translocation between the long arm of one chromosome 18 and the long arm of one chromosome 22, 45,XX,der(18;22)(q10;q10), in all metaphases. In effect, the fetus had monosomy for 18p. Parental karyotypes were normal, suggesting a de novo origin for the der(18;22). Fluorescence in situ hybridization (FISH) analysis was performed with α‐satellite probes D18Z1 and D14Z1/D22Z1 to identify the origin of the centromere on the der(18;22). Signal was observed with both probes, indicating that the centromere was composed of α‐satellite DNA from both constituent chromosomes. Genotyping of the fetus and her parents with chromosome 18p STS marker D18S391 showed only the paternal 187 bp allele was present in the fetus, indicating that it was the maternal chromosome 18 involved in the der(18;22). This case and previous reports show that de novo unbalanced whole arm translocations are more likely to retain α‐satellite sequences from the two chromosomes involved.

Additive Effects of Numbness and Muscle Aches on Fatigue Occurrence in Individuals with HIV/AIDS Who Are Taking Antiretroviral Therapy

CONTEXT Muscle aches, numbness in the feet/toes (neuropathy), and fatigue are often reported concurrently and are among the symptoms most frequently reported by individuals with HIV/AIDS, whether or not they are taking antiretroviral therapy (ART). OBJECTIVES This study used a longitudinal analytical methodology to analyze these symptoms together to determine whether symptom clusters are maintained over time and to determine whether there is a temporal relationship between fatigue and reports of neuropathic pain and muscle aches. METHODS This was a secondary analysis of a subset of data from a six-month, longitudinal, randomized, controlled trial of 243 HIV-positive individuals taking ART. Self-reported symptom frequency and intensity were recorded using the Revised Sign and Symptom Checklist for Persons with HIV disease at baseline (Month 0), one, three, and six months. Multilevel, logistic regression models were used to analyze time-lagged effects of muscle aches, numbness of the feet/toes, and fatigue to estimate any predictive and interactive effects that the symptoms have upon one another. RESULTS A significant relationship between muscle aches and fatigue intercepts was noted (odds ratio [OR]=1.80, P≤0.05). Significant relationships between numbness and fatigue also were noted for the entire measurement period (OR=2.70, P≤0.05). Time-lagged models showed persons reporting neuropathic-related numbness in one period were nearly twice as likely to report fatigue in subsequent periods (OR=1.89, P≤0.05). The final model revealed that the addition of muscle aches and numbness explained 28% of the random variance in the occurrence of fatigue. Between-person descriptive variables including years living with HIV, age, having an AIDS diagnosis, ethnicity, and nucleoside reverse transcriptase inhibitor treatment regimens with stavudine, zalactabine, or didanosine did not significantly explain any additional model variation. CONCLUSION These findings are consistent with physiological research and provide evidence that analyzing multiple symptom change over time can provide a more accurate representation of an individuals symptom experience. When evaluating patients with muscle aches or numbness, particularly when both symptoms are present, an evaluation of fatigue should be considered. Similarly, if fatigue is reported, underlying physiological assessments for neuropathic symptoms and muscle aches may be considered.

Increasing Community Capacity to Reduce Tobacco‐Related Health Disparities in African American Communities

OBJECTIVE The purpose of this study was to understand the processes and interactions that African American tobacco control organizations use to engage African American communities in tobacco control efforts. DESIGN AND SAMPLE The study used grounded theory methods to interpret participants perspectives on tobacco control. The study sample consisted of African American tobacco control program directors from African American tobacco control organizations throughout the United States. MEASURES Data collection involved 1 interview per participant using a semistructured interview at a location selected by the participant. Each interview lasted approximately 30-90 min. RESULTS The results showed that organizations used specific strategies to involve African Americans in tobacco control. The tobacco control organizations built community capacity using 3 processes: developing relationships and partnerships, raising awareness, and creating collective power. CONCLUSION Contextual, cultural processes, and historical references used by African American tobacco control organizations provide insight into how to engage African American communities in tobacco control efforts and achieve tobacco-related health parity. Public health professionals and nurses should be aware of these and other strategies that may increase the involvement of African American communities in tobacco control.

Monosomy 16 as the Sole Abnormality in Myeloid Malignancies

The majority of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients reported with chromosome 16 abnormalities had the inv(16)(p13q22) or t(16;16)(p13;q22) rearrangements, which were associated with a favorable prognosis. In contrast, del(16)(q22) was reported less commonly but was associated with a less favorable prognosis. We describe an 80-year-old woman who presented with MDS (refractory anemia). Chromosome analysis from bone marrow aspirate cultures showed monosomy 16 as the sole cytogenetic abnormality. Comparison of this patient with previously reported cases of monosomy 16 showed that this uncommon abnormality was associated with myeloid disorders. Monosomy 16 patients, similar to del(16)(q22) patients, tended to be elderly, presented with MDS or AML, and had a poor prognosis. The similarity in clinical course for del(16)(q22) and monosomy 16 patients suggests that the phenotype in both groups resulted from loss of important gene(s) on 16q, as distinct from the fusion gene product identified in the inv(16) and t(16;16) rearrangements.