ABSTRACT
OBJECTIVE: Despite national guidelines recommending early concurrent palliative care for individuals newly diagnosed with metastatic cancer, few community cancer centers, especially those in underserved rural areas do so. We are implementing an early concurrent palliative care model, ENABLE (Educate, Nurture, Advise, Before Life Ends) in four, rural-serving community cancer centers. Our objective was to develop a "toolkit" to assist community cancer centers that wish to integrate early palliative care for patients with newly diagnosed advanced cancer and their family caregivers. METHOD: Guided by the RE-AIM (Reach, Effectiveness-Adoption, Implementation, Maintenance) framework, we undertook an instrument-development process based on the literature, expert and site stakeholder review and feedback, and pilot testing during site visits. RESULTS: We developed four instruments to measure ENABLE implementation: (1) the ENABLE RE-AIM Self-Assessment Tool to assess reach, adoption, implementation, and maintenance; (2) the ENABLE General Organizational Index to assess institutional implementation; (3) an Implementation Costs Tool; and (4) an Oncology Clinicians' Perceptions of Early Concurrent Oncology Palliative Care survey. SIGNIFICANCE OF RESULTS: We developed four measures to determine early palliative care implementation. These measures have been pilot-tested, and will be integrated into a comprehensive "toolkit" to assist community cancer centers to measure implementation outcomes. We describe the lessons learned and recommend strategies for promoting long-term program sustainability.
Subject(s)
Community Health Centers/trends , Neoplasms/therapy , Palliative Care/methods , Rural Population , Alabama , Humans , Medical Oncology , Palliative Care/psychology , Perception , Physicians/psychology , Pilot Projects , Program Evaluation/methods , Self-Assessment , South Carolina , Surveys and Questionnaires , WorkforceABSTRACT
BACKGROUND: Early palliative care (EPC) is recommended but rarely integrated with advanced heart failure (HF) care. We engaged patients and family caregivers to study the feasibility and site differences in a two-site EPC trial, ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers). METHODS: We conducted an EPC feasibility study (4/1/14-8/31/15) for patients with NYHA Class III/IV HF and their caregivers in academic medical centers in the northeast and southeast U.S. The EPC intervention comprised: 1) an in-person outpatient palliative care consultation; and 2) telephonic nurse coach sessions and monthly calls. We collected patient- and caregiver-reported outcomes of quality of life (QOL), symptom, health, anxiety, and depression at baseline, 12- and 24-weeks. We used linear mixed-models to assess baseline to week 24 longitudinal changes. RESULTS: We enrolled 61 patients and 48 caregivers; between-site demographic differences included age, race, religion, marital, and work status. Most patients (69%) and caregivers (79%) completed all intervention sessions; however, we noted large between-site differences in measurement completion (38% southeast vs. 72% northeast). Patients experienced moderate effect size improvements in QOL, symptoms, physical, and mental health; caregivers experienced moderate effect size improvements in QOL, depression, mental health, and burden. Small-to-moderate effect size improvements were noted in patients' hospital and ICU days and emergency visits. CONCLUSIONS: Between-site demographic, attrition, and participant-reported outcomes highlight the importance of intervention pilot-testing in culturally diverse populations. Observations from this pilot feasibility trial allowed us to refine the methodology of an in-progress, full-scale randomized clinical efficacy trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT03177447 (retrospectively registered, June 2017).
Subject(s)
Heart Failure/therapy , Palliative Care/methods , Patient Participation , Aged , Aged, 80 and over , Alabama , Caregivers/psychology , Feasibility Studies , Female , Heart Failure/psychology , Humans , Male , Middle Aged , New Hampshire , Palliative Care/standards , Pilot ProjectsABSTRACT
The foundation of firearm and tool mark identification is that no two tools should produce the same microscopic marks on two separate objects that they would be inaccurately or wrongly identified. Studies addressing the validity of identification infrequently employ tests that mirror realistic casework scenarios. This study attempted to do so using a double-blind process, reducing test-taking bias. Test kits including bullets and cartridge cases but not the associated firearms were completed by 31 analysts from 22 agencies. Analysis of the results demonstrated an overall error rate of 0.303%, sensitivity of 85.2%, and specificity of 86.8%. Variability in performance across examiners is addressed, and the effect of examiners' years of experience on identification accuracy is explored. Finally, the article discusses the importance of studies using realistic case work scenarios when validating the field's performance and in providing courts with usable indicators of the accuracy of firearm and tool mark identification.
ABSTRACT
Tuberculosis (TB) has become a curable disease, thanks to the discovery of antibiotics. However, it has remained one of the most difficult infections to treat. Most current TB regimens consist of 6-9 months of daily doses of four drugs that are highly toxic to patients. The purpose of these lengthy treatments is to completely eradicate Mycobacterium tuberculosis, notorious for its ability to resist most antibacterial agents, thereby preventing the formation of drug resistant mutants. On the contrary, the prolonged therapies have led to poor patient adherence. This, together with a severe limit of drug choices, has resulted in the emergence of strains that are increasingly resistant to the few available antibiotics. Here, we review our current understanding of molecular mechanisms underlying the profound drug resistance of M. tuberculosis. This knowledge is essential for the development of more effective antibiotics, which are not only potent against drug resistant M. tuberculosis strains but also help shorten the current treatment courses required for drug susceptible TB.
Subject(s)
Antitubercular Agents/therapeutic use , Drug Resistance, Multiple, Bacterial/genetics , Mutation , Mycobacterium tuberculosis/genetics , Pyrazinamide/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Biological Transport , Biotransformation , Drug Resistance, Multiple, Bacterial/drug effects , Gene Expression , Genes, MDR , Genetic Fitness , Humans , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/metabolism , Patient Compliance , Time Factors , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiologyABSTRACT
Copines are calcium-dependent membrane-binding proteins found in many eukaryotic organisms. We are studying the function of copines using the model organism, Dictyostelium discoideum. When under starvation conditions, Dictyostelium cells aggregate into mounds that become migrating slugs, which can move toward light and heat before culminating into a fruiting body. Previously, we showed that Dictyostelium cells lacking the copine A (cpnA) gene are not able to form fruiting bodies and instead arrest at the slug stage. In this study, we compared the slug behavior of cells lacking the cpnA gene to the slug behavior of wild-type cells. The slugs formed by cpnA- cells were much larger than wild-type slugs and exhibited no phototaxis and negative thermotaxis in the same conditions that wild-type slugs exhibited positive phototaxis and thermotaxis. Mixing as little as 5% wild-type cells with cpnA- cells rescued the phototaxis and thermotaxis defects, suggesting that CpnA plays a specific role in the regulation of the production and/or release of a signaling molecule. Reducing extracellular levels of ammonia also partially rescued the phototaxis and thermotaxis defects of cpnA- slugs, suggesting that CpnA may have a specific role in regulating ammonia signaling. Expressing the lacZ gene under the cpnA promoter in wild-type cells indicated cpnA is preferentially expressed in the prestalk cells found in the anterior part of the slug, which include the cells at the tip of the slug that regulate phototaxis, thermotaxis, and the initiation of culmination into fruiting bodies. Our results suggest that CpnA plays a role in the regulation of the signaling pathways, including ammonia signaling, necessary for sensing and/or orienting toward light and heat in the prestalk cells of the Dictyostelium slug.
Subject(s)
Carrier Proteins/genetics , Carrier Proteins/physiology , Dictyostelium/growth & development , Life Cycle Stages/genetics , Movement , Animals , Carrier Proteins/metabolism , Cells, Cultured , Dictyostelium/cytology , Dictyostelium/genetics , Dictyostelium/physiology , Gene Expression Regulation, Developmental , Lac Operon , Light , Movement/physiology , Movement/radiation effects , Organisms, Genetically Modified , Promoter Regions, Genetic , Temperature , Tissue DistributionABSTRACT
Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as TP53 in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways: (i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) double-strand break repair: NBS1 E185Q and XRCC3 T241M; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q. Younger age at diagnosis (<50) was associated with ERCC2 312 DN/NN genotypes [odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.10, 2.81] and NBS1 185 QQ genotype (OR = 3.09; 95% CI = 1.47, 6.49). The XPC 939 QQ genotype was associated with TP53 mutations (OR = 5.80; 95% CI = 2.23, 15.09). There was a significant trend associating younger age at diagnosis (<50) with increasing numbers of risk genotypes for ERCC2 312 DN/NN, MSH6 39 EE and NBS1 185 QQ (P(trend) < 0.001). A similar significant trend was also observed associating TP53 mutations with increasing numbers of risk genotypes for XRCC1 399 QQ, XPC 939 QQ, ERCC4 415 QQ and XPC 499 AA (P(trend) < 0.001). Our pilot data suggest that nsSNPs of multiple DNA repair pathways are associated with younger age at diagnosis and TP53 mutations in breast cancer and larger studies are warranted to further evaluate these associations.
Subject(s)
Breast Neoplasms/genetics , DNA Repair , Genes, p53 , Mutation , Polymorphism, Genetic , Adult , Age Factors , Aged , Body Mass Index , Breast Neoplasms/pathology , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Female , Humans , Middle Aged , Neoplasm Staging , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide , X-ray Repair Cross Complementing Protein 1ABSTRACT
BACKGROUND: Copines are calcium-dependent phospholipid-binding proteins found in diverse eukaryotic organisms. We are studying the function of copines in Dictyostelium discoideum, a single-celled amoeba that undergoes cell differentiation and morphogenesis to form multicellular fruiting bodies when placed in starvation conditions. Previously, we showed that Dictyostelium cells lacking the copine A (cpnA) gene are not able to complete the developmental cycle, arresting at the slug stage. The aim of this study is to further characterize the developmental defect of the cpnA- cells. RESULTS: Time-lapse imaging revealed that cpnA- cells exhibited delayed aggregation and made large mounds that formed one large slug as compared to the smaller slugs of the wild-type cells. While the prespore cell patterning appeared to be normal within the cpnA- slugs, the prestalk cell patterning was different from wild-type. When cpnA- cells were mixed with a small percentage of wild-type cells, chimeric fruiting bodies with short stalks formed. When a small percentage of cpnA- cells was mixed with wild-type cells, the cpnA- cells labeled with GFP were found located throughout the chimeric slug and in both the stalk and sporehead of the fruiting bodies. However, there appeared to be a small bias towards cpnA- cells becoming spore cells. When cpnA- cells were developed in buffer containing EGTA, they were also able to differentiate into either stalk or spore cells to form fruiting bodies with short stalks. CONCLUSIONS: Our results indicate that CpnA is involved in the regulation of aggregation, slug size, and culmination during Dictyostelium development. More specifically, CpnA appears to be involved in the function and differentiation of prestalk cells and plays a role in a calcium-regulated signaling pathway critical to triggering the initiation of culmination.
Subject(s)
Carrier Proteins/metabolism , Dictyostelium/cytology , Dictyostelium/growth & development , Protozoan Proteins/metabolism , Carrier Proteins/genetics , Dictyostelium/metabolism , Morphogenesis , Protozoan Proteins/genetics , Signal TransductionABSTRACT
Critical care patients present with or develop conditions that require imaging with a variety of radiographic methods. Technological advances such as the introduction of digital imaging instead of screen-film radiography have improved image resolution, readability, management, and portability of results while maintaining confidentiality of patient information. Radiographic imaging in the critical care unit is an integral part of patient management. It is imperative that the critical care nurse be cognizant of radiographic studies and thus be able to collaborate with all health care providers in the administration of quality patient care.
Subject(s)
Critical Care/methods , Radiography/methods , Radiography/nursing , Algorithms , Cone-Beam Computed Tomography , Decision Trees , Health Facility Environment , Humans , Image Processing, Computer-Assisted , Intensive Care Units , Magnetic Resonance Imaging , Nurse's Role , Nursing Assessment , Patient Selection , Point-of-Care Systems , Tomography, X-Ray ComputedABSTRACT
The field of nuclear cardiology has grown significantly over the past decade. This is a reflection of the value seen by providers in these safe and effective procedures. Nuclear scan studies are noninvasive and versatile in their usefulness. These studies assist in determining the likelihood of future cardiac events, guide approaches to revascularization, and assist in evaluation of the adequacy of revascularization procedures. Critical thinking and decision-making abilities are two key requirements for nurses in the critical care environment. Knowledge and understanding of the nuclear scan studies indicated for patients help nurses advocate for those in their care.
Subject(s)
Critical Care/methods , Nurse's Role , Radionuclide Imaging/methods , Radionuclide Imaging/nursing , Clinical Competence , Fluorodeoxyglucose F18 , Gated Blood-Pool Imaging , Humans , Patient Education as Topic , Positron-Emission Tomography , Radionuclide Imaging/adverse effects , Radiopharmaceuticals , Thallium Radioisotopes , Tomography, Emission-Computed, Single-PhotonABSTRACT
Genetic variations in DNA repair may impact repair functions, DNA damage and breast cancer risk. Using data/samples collected from the first 752 Caucasians and 141 African-Americans in an ongoing case-control study, we examined the association between breast cancer risk and 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways-(i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) double-strand break repair: NBS1 E185Q and XRCC3 T241M. In Caucasians, breast cancer risk was significantly associated with ADPRT 762VV [odds ratio (OR) = 1.45; 95% confidence interval (CI) = 1.03, 2.03], APE1 148DD (OR = 1.44; 95% CI = 1.03, 2.00), MLH1 219II/IV (OR = 1.87; 95% CI = 1.11, 3.16) and ERCC4 415QQ (OR = 8.64; 95% CI = 1.04, 72.02) genotypes. With a limited sample size, we did not observe any significant association in African-Americans. However, there were significant trends in breast cancer risk with increasing numbers of risk genotypes for ADPRT 762VV, APE1 148DD, ERCC4 415RQ/QQ and MLH1 219II/IV (P(trend) < 0.001) in Caucasians and ADPRT 762VA, ERCC2 751KQ/QQ and NBS1 185EQ/QQ in African-Americans (P(trend) = 0.006), respectively. Our results suggest that combined nsSNPs in multiple DNA repair pathways may contribute to breast cancer risk and larger studies are warranted to further evaluate polygenic models of DNA repair in breast cancer risk.
Subject(s)
Breast Neoplasms/genetics , DNA Repair/genetics , Models, Genetic , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Aged , Case-Control Studies , Female , Humans , Middle AgedABSTRACT
OBJECTIVE: To prospectively validate the Montreal Cognitive Assessment (MoCA) in a UK memory clinic. METHOD: We administered the MoCA and Mini-Mental State Examination (MMSE) to 32 subjects fulfilling diagnostic criteria for dementia, to 23 subjects fulfilling diagnostic criteria for mild cognitive impairment (MCI), and to 12 memory clinic comparison subjects, at baseline and then at 6-month follow-up. Clinical diagnoses for dementia and MCI were made according to ICD-10 and Petersen criteria. The sensitivity and specificity of both measures were assessed for detection of MCI and dementia. RESULTS: With a cut-off score of 26, the MMSE had a sensitivity of 17% to detect subjects with MCI, whereas the MoCA detected 83%. The MMSE had a sensitivity of 25% to detect subjects with dementia, whereas the MoCA detected 94%. Specificity for the MMSE was 100%, and specificity for the MoCA was 50%. Of subjects with MCI, 35% developed dementia within 6 months, and all scored less than 26 points on the MoCA at baseline. CONCLUSIONS: The MoCA is a useful brief screening tool for the detection of mild dementia or MCI in subjects scoring over 25 points on the MMSE. In patients already diagnosed with MCI, the MoCA helps identify those at risk of developing dementia at 6-month follow-up.
Subject(s)
Alzheimer Disease/diagnosis , Cognition Disorders/diagnosis , Dementia, Vascular/diagnosis , Memory Disorders/diagnosis , Memory Disorders/psychology , Neuropsychological Tests/statistics & numerical data , Aged , Aged, 80 and over , Alzheimer Disease/psychology , Cognition Disorders/psychology , Dementia, Vascular/psychology , England , Female , Follow-Up Studies , Humans , Male , Mass Screening , Mental Status Schedule/statistics & numerical data , Prospective Studies , Psychometrics/statistics & numerical data , Reproducibility of Results , Risk AssessmentABSTRACT
Most infective processes are straightforward and can be diagnosed from bacterial findings in a single test. IE does not always follow this tenet, so establishing the diagnosis can be difficult. The salient features of IE may present atypically or be obscured by the presence of preexisting and coexisting diseases. Flulike symptoms may mask the beginning of this devastating disease. Early diagnosis of IE is important because of its high risk of morbidity and mortality. Management of the patient who has IE is complex and requires interventions by infectious disease specialists, cardiologists, respiratory therapists, and critical care nurses to address the many multifaceted complications. Early evaluation, diagnostic validation, multidisciplinary management, prompt pharmaceutical initiation, and intense critical care nursing intervention are necessary to reduce the probability of long-standing complications and to improve patient outcomes.
Subject(s)
Endocarditis, Bacterial/therapy , Critical Care , Echocardiography, Transesophageal , Embolism/etiology , Endocarditis, Bacterial/complications , Endocarditis, Bacterial/diagnosis , Endocarditis, Bacterial/microbiology , Endocarditis, Bacterial/nursing , Heart Failure/etiology , Humans , Nurse's Role , Splenic Infarction/etiologyABSTRACT
Mammalian cells are constantly exposed to genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair contributes to deficient repair and breast cancer risk. Using samples collected in an ongoing, clinic-based, case-control study (253 cases and 268 controls), we tested whether breast cancer risk is associated with four amino acid substitution variants in three DNA repair genes, including XRCC1 Arg194Trp and XRCC1 Arg399Gln in base excision repair, XRCC3 Thr241Met in homologous recombination repair, and ERCC4/XPF Arg415Gln in nucleotide excision repair. Carriers of at least one variant allele of XRCC1 Arg194Trp [Arg/Trp and Trp/Trp versus Arg/Arg, odds ratio (OR) = 1.60, 95% confidence interval (CI) = 0.89-2.87] or two variant alleles of XRCC3 241Met/Metmay have an increased risk of breast cancer (Met/Met versus Thr/Thr and Thr/Met, OR = 1.54, 95% CI = 0.94-2.52). No association between XRCC1 Arg399Gln Dgenotype and breast cancer risk was observed. The genotype distribution of ERCC4/XPF Arg415Gln differed significantly between cases and controls (P = 0.02), and the ERCC4/XPF 415Gln/Gln genotype was found in only seven cases (3%) but not in controls. In addition, breast cancer risk was significantly associated with an increasing number of combined variant alleles of XRCC1 Arg194Trp, XRCC3 Thr241Met, and ERCC4/XPF Arg415Gln in a four-level model (P(trend) = 0.04): OR = 1.0 for those without a variant allele (referent group); OR = 1.04 (95% CI = 0.67-1.61) for those with one variant allele; OR = 1.38 (95% CI = 0.83-2.29) for those with two variant alleles; and age-adjusted OR = 2.60 (95% CI = 1.03-6.59) for those with three or more variant alleles after adjustment for age, family history, age at menarche, age at first live birth, and body mass index. We provide evidence that variants of XRCC1, XRCC3, and ERCC4/XPF genes, particularly in combination, contribute to breast cancer susceptibility.
Subject(s)
Breast Neoplasms/etiology , Breast Neoplasms/genetics , DNA Repair/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Adult , Aged , Case-Control Studies , DNA-Binding Proteins/genetics , Female , Humans , Middle Aged , Odds Ratio , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , X-ray Repair Cross Complementing Protein 1ABSTRACT
To evaluate whether deficient DNA repair contributes to elevated DNA damage and breast carcinogenesis, we used the comet assay (single-cell alkaline gel electrophoresis) to measure the levels of DNA damage in peripheral lymphocytes from 70 breast cancer cases and 70 controls. DNA damage, measured as the comet tail moment, was not influenced by age, family history (FH), age at menarche, age at first birth or parity. The results showed that cancer cases had significantly higher DNA damage compared with controls; the comet tail moments (mean +/- SD) for cases and controls were: 10.78 +/- 3.63 and 6.86 +/- 2.76 (P < 0.001) for DNA damage at baseline (DB), 21.24 +/- 4.88 and 14.97 +/- 4.18 (P < 0.001) for DNA damage after exposure to 6 Gy of ionizing radiation (DIR), and 14.76 +/- 5.35 and 9.75 +/- 3.35 (P < 0.001) for DNA damage remaining after 10 min repair following exposure to 6 Gy of IR (DRP), respectively. Body mass index (BMI) affected DNA damage differently for cases and controls. Damage decreased with increasing BMI for controls, while damage increased with increasing BMI for cases. Above-median DNA damage was significantly associated with breast cancer risk; the age-adjusted odds ratio (OR) = 13.44 [95% confidence interval (CI) = 5.97-30.24] for DB, 13.65 (6.07-30.71) for DIR and 6.54 (3.11-13.79) for DRP, respectively. This association was stronger in women with above-median BMI. Our results, although based on a relatively small group of subjects, indicate that elevated DNA damage is significantly associated with breast cancer risk and warrant larger studies to further define the molecular mechanisms of DNA damage/repair in breast cancer susceptibility.
Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , DNA Damage , Age Distribution , Aged , Body Mass Index , Case-Control Studies , Comet Assay , DNA Repair , DNA, Neoplasm/radiation effects , Disease Susceptibility , Female , Humans , Lymphocytes/radiation effects , Middle Aged , Odds Ratio , Radiation, Ionizing , Risk FactorsABSTRACT
Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. We used a case-control study design (162 cases and 302 controls) to test the association between three amino acid substitution variants of DNA repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) and breast cancer susceptibility. We found a weak association between the XRCC1 194Trp allele and breast cancer risk (adjusted odds ratio (OR)=1.98; 95% confidence interval (CI)=0.85-4.63). We also found a potential gene-gene interaction between the XRCC1 194Trp allele and XRCC3 241Met allele and breast cancer risk (adjusted OR=8.74; 95% CI=1.13-67.53). Although larger studies are needed to validate the study results, our data suggest that amino acid substitution variants of XRCC1 and XRCC3 genes may contribute to breast cancer susceptibility.
Subject(s)
Breast Neoplasms/genetics , DNA-Binding Proteins/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Genetic/genetics , Adult , Aged , Aged, 80 and over , Female , Gene Frequency , Humans , Middle Aged , Polymerase Chain Reaction , X-ray Repair Cross Complementing Protein 1ABSTRACT
Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes of three DNA repair genes: XRCC1, 194 Arg/Trp and 399 Arg/Gln; XRCC3, 241 Thr/Met; and APE1, 148 Asp/Glu. The data showed that breast cancer patients had a significantly higher delay index than that of controls (P < 0.001); the means +/- SD for cases and controls were 36.0 +/- 13.1 (n = 118) and 31.4 +/- 11.5 (n = 225), respectively. There was a significant dose-response relationship between delay index, categorized into quartiles, and an increasing risk of breast cancer (crude odds ratios: 1.00, 1.00, 1.27, and 2.46, respectively; P(trend) = 0.002). In controls, prolonged cell-cycle delay was significantly associated with the number of variant alleles in APE1 Asp148Glu and XRCC1 Arg399Gln genotypes (P(trend) = 0.001). Although larger studies are needed to validate the results, our data suggest that an inherited hypersensitivity to IR may contribute to human breast carcinogenesis.