Methods to Study Z-DNA-Induced Genetic Instability.

Alternative DNA structures that differ from the canonical B-DNA double helix, including Z-DNA, have received much attention recently due to their impact on DNA metabolic processes, including replication, transcription, and genome maintenance. Non-B-DNA-forming sequences can also stimulate genetic instability associated with disease development and evolution. Z-DNA can stimulate different types of genetic instability events in different species, and several different assays have been established to detect Z-DNA-induced DNA strand breaks and mutagenesis in prokaryotic and eukaryotic systems.

Distinct DNA repair pathways cause genomic instability at alternative DNA structures.

Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology. However, the mechanisms involved are not well characterized. Here, we discover that Z-DNA is mutagenic in yeast as well as human cells, and that the nucleotide excision repair complex, Rad10-Rad1(ERCC1-XPF), and the mismatch repair complex, Msh2-Msh3, are required for Z-DNA-induced genetic instability in yeast and human cells.

Lexical access in semantic variant PPA: Evidence for a post-semantic contribution to naming deficits.

The most salient clinical symptom of semantic variant primary progressive aphasia (PPA) is a profound and pervasive anomia. These patients' naming impairments have been shown to reflect in large part a domain-general deterioration of conceptual knowledge that impacts both linguistic and non-linguistic processing. However, it is possible that post-semantic stages of lexical access may also contribute to naming deficits.

Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.

Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352).

Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer.

Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region.

FOXM1 is an oncogenic mediator in Ewing Sarcoma.

Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor) are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors.

Treatment outcomes with methylphenidate formulations among patients with ADHD: retrospective claims analysis of a managed care population.

Objective: Describe treatment patterns, resource use, and predictors of methylphenidate (MPH) switch among children (6-12 years), adolescents (13-17 years), and adults (≥ 18 years) with attention-deficit/hyperactivity disorder (ADHD).

Methods: This retrospective U.S.

Direct costs of chronic obstructive pulmonary disease among managed care patients.

Purpose: To estimate patient- and episode-level direct costs of chronic obstructive pulmonary disease (COPD) among commercially insured patients in the US.

Methods: In this retrospective claims-based analysis, commercial enrollees with evidence of COPD were grouped into five mutually exclusive cohorts based on the most intensive level of COPD-related care they received in 2006, ie, outpatient, urgent outpatient (outpatient care in addition to a claim for an oral corticosteroid or antibiotic within seven days), emergency department (ED), standard inpatient admission, and intensive care unit (ICU) cohorts. Patient- level COPD-related annual health care costs, including patient- and payer-paid costs, were compared among the cohorts.

Pharmacological treatment patterns among patients with attention-deficit/hyperactivity disorder: retrospective claims-based analysis of a managed care population.

Objective: To develop a descriptive profile of attention-deficit/hyperactivity disorder (ADHD) pharmacological treatment patterns in terms of persistence, adherence, augmentation, switching, and dosing changes; and to assess differences in treatment patterns with regard to ADHD medication type, class, and duration of action.

Methods: This retrospective claims database analysis used medical data, pharmacy data, and enrollment information to examine treatment patterns among patients with at least one claim with a diagnosis code for ADHD and a filled prescription for ADHD medication (index therapy) during the period 01 January 2004 through 30 September 2006. Treatment persistence and adherence (days supplied/days persistent) were calculated.

GLI1 is a central mediator of EWS/FLI1 signaling in Ewing tumors.

The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class.

Efficient processing of TFO-directed psoralen DNA interstrand crosslinks by the UvrABC nuclease.

Photoreactive psoralens can form interstrand crosslinks (ICLs) in double-stranded DNA. In eubacteria, the endonuclease UvrABC plays a key role in processing psoralen ICLs. Psoralen-modified triplex-forming oligonucleotides (TFOs) can be used to direct ICLs to specific genomic sites.

Pre-transplant risk factors for chronic renal dysfunction after pediatric heart transplantation: a 10-year national cohort study.

Background: Chronic renal dysfunction may develop after pediatric heart transplantation (PHTx). We examined the incidence of end-stage renal disease (ESRD) and chronic renal insufficiency (CRI) after PHTx, the associated pre-transplant patient characteristics, and impact of renal disease on survival.

Methods: Data sources included the Scientific Registry of Transplant Recipients, Centers for Medicare and Medicaid Services and the Social Security Death Master File.

Development and current status of ECD kidney transplantation.

The worsening shortage of donor kidneys for transplant and the aging of both the donor and candidate populations have contributed to the increasing importance of ECD kidney transplantation. While ECD transplants have an increased risk of graft failure, for most candidates patient survival is still improved over remaining on dialysis. Because of this risk, however, ECD kidneys have a high likelihood of discard; significant geographic variation in discard and transplant rates impedes maximum utilization of these kidneys.

Review of transplantation in HIV patients during the HAART era.

Human immunodeficiency virus (HIV) infection was once thought to be a relative or even absolute contraindication to transplantation. With the recent advent of highly active antiretroviral therapy (HAART), those infected with HIV are now living longer and dying from illnesses other than acquired immunodeficiency syndrome (AIDS). Although studies prior to the HAART era suggested poor outcomes might occur with transplantation in those infected with HIV, more recent studies have demonstrated results comparable to those of recipients without HIV infection.

Targeting oncogenes to improve breast cancer chemotherapy.

Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations.

Z-DNA-forming sequences generate large-scale deletions in mammalian cells.

Spontaneous chromosomal breakages frequently occur at genomic hot spots in the absence of DNA damage and can result in translocation-related human disease. Chromosomal breakpoints are often mapped near purine-pyrimidine Z-DNA-forming sequences in human tumors. However, it is not known whether Z-DNA plays a role in the generation of these chromosomal breakages.

Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells.

DNA interstrand crosslinks (ICLs) present formidable blocks to DNA metabolic processes and must be repaired for cell survival. ICLs are induced in DNA by intercalating compounds such as the widely used therapeutic agent psoralen. In bacteria, both nucleotide excision repair (NER) and homologous recombination are required for the repair of ICLs.

Current status of kidney and pancreas transplantation in the United States, 1994-2003.

This article reviews the OPTN/SRTR data collected on kidney and pancreas transplantation during 2003 in the context of trends over the past decade. Overall, the transplant community continued to struggle to meet the increasing demand for kidney and pancreas transplantation. The number of new wait-listed kidney registrants under the age of 50 has remained relatively stable since 1994, but the number of new registrants aged 50 to 64 has doubled.

Mutation frequencies in murine keratinocytes as a function of carcinogenic status.

A link between genetic abnormalities and carcinogenesis is well established. It follows that a correlation exists between mutation frequency and malignant progression. We have determined the spontaneous and DNA damage-induced mutation frequencies for a series of cell lines derived from SENCAR mouse keratinocytes at various stages of malignant progression.

The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.

Background: Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence.

Trends in cadaveric organ donation in the United States: 1990-1999.

Despite declining in-hospital deaths, deceased donor organ donation increased in all demographic segments of the US population from 1990 to 1999. Although the rate of growth in older donors was more dramatic, there was substantial growth in the most physiologically suitable donor age groups, which contribute most to the donor pool. Nationwide, the average annual growth in donation rate for in-hospital deaths ages 1-70 was 5.

Chronic renal failure after transplantation of a nonrenal organ.

Background: Transplantation of nonrenal organs is often complicated by chronic renal disease with multifactorial causes. We conducted a population-based cohort analysis to evaluate the incidence of chronic renal failure, risk factors for it, and the associated hazard of death in recipients of nonrenal transplants.

Methods: Pretransplantation and post-transplantation clinical variables and data from a registry of patients with end-stage renal disease (ESRD) were linked in order to estimate the cumulative incidence of chronic renal failure (defined as a glomerular filtration rate of 29 ml per minute per 1.

Liver transplant-associated graft-versus-host disease.

Background: Graft-versus-host disease (GVHD) is an important, underdiagnosed cause of mortality associated with liver transplantation. We identified 12 cases of GVHD among 1,082 liver transplantations performed in patients at our institution between 1991 and 1998. Patients typically developed fever, skin rash, diarrhea, or pancytopenia within 2 to 6 weeks after their transplant.