Role for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic Response of Targeting Both KDM4B and KDM4A.

Histone demethylases are epigenetic modulators that play key roles in regulating gene expression related to many critical cellular functions and are emerging as promising therapeutic targets in a number of tumor types. We previously identified histone demethylase family members as overexpressed in the pediatric sarcoma, rhabdomyosarcoma. Here we show high sensitivity of rhabdomyosarcoma cells to a pan-histone demethylase inhibitor, JIB-04 and identify a key role for the histone demethylase KDM4B in rhabdomyosarcoma cell growth through an RNAi-screening approach. Decreasing KDM4B levels affected cell cycle progression and transcription of G1/S and G2/M checkpoint genes including CDK6 and CCNA2, which are bound by KDM4B in their promoter regions. However, after sustained knockdown of KDM4B, rhabdomyosarcoma cell growth recovered. We show that this can be attributed to acquired molecular compensation via recruitment of KDM4A to the promoter regions of CDK6 and CCNA2 that are otherwise bound by KDM4B. Furthermore, upfront silencing of both KDM4B and KDM4A led to RMS cell apoptosis, not seen by reducing either alone. To circumvent compensation and elicit stronger therapeutic responses, our study supports targeting histone demethylase sub-family proteins through selective poly-pharmacology as a therapeutic approach.

Discovery and SAR of 2-arylbenzotriazoles and 2-arylindazoles as potential treatments for Duchenne muscular dystrophy.

Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.

Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy.

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

Value for taxpayers' dollars: what VA care would cost at medicare prices.

Critics charge that Veterans Health Administration (VA) medical centers are inefficient and the cost of veteran health care would be reduced if VA purchased care for its patients directly from private-sector providers. This analysis compares VA medical care expenditures with estimates of total payments under a hypothetical Medicare fee-for-service payment system reimbursing providers for the same counts of each service VA medical centers provided in fiscal 1999. At six study sites, hypothetical payments were more than 20 percent greater than actual budgets. Nationally, this represented more than 3 billion US dollars in 1999 and more than 5 billion US dollars in 2003. Data limitations suggest the estimate is conservative. Less than half of the difference is due to VA's low pharmacy costs. The study demonstrates the potential savings to patients and taxpayers of the VA health care system.

Estimating private sector values for VA health care: an overview.

OBJECTIVES: To provide an overview of methods used to establish what taxpayer costs would be if all Veterans Health Administration (VA) patient care were paid for by the federal government but provided in the private sector. METHODS: Study assumptions included (1) that there would be a hypothetical policy change to pay for VA care through a Medicare-based fee-for-service program, (2) that the VA coverage benefit would not change, (3) that practice styles would remain the same, and (4) that there would be no impact on market values. To achieve the objective, project staff adapted Medicare payment schedules and guidelines, where available, with oversight of an advisory committee with VA and non-VA expertise in costs and data. For six sites, detailed payments were estimated using VA utilization databases and software and Medicare rate schedules available in the private sector. Overhead, interest on capital, and malpractice costs were added to VA-reported operating costs. Patient severity was examined, and patient-level costs were explored. FINDINGS: Detailed methods for pricing seven types of health services are presented. Three methods articles focus on process issues. DISCUSSION: Because VA care is not directly comparable with private sector health care as a result in part of differences in benefits covered and the scope of services provided, estimating costs for this care based on a private sector model requires careful consideration of market valuation approaches. The articles in this supplement describe the methods used to estimate market values for VA care so that other researchers can use them in future studies.

Estimating private sector professional fees for VA providers.

OBJECTIVES: To describe new methods used to estimate inpatient and outpatient Medicare-based professional fees for Veterans Health Administration (VA) services. METHODS: National VA utilization files provided estimates of inpatient physician services, whereas local provider and utilization files gave counts of outpatient services by physicians, nurse practitioners, physician assistant, clinical psychologists, and clinical social workers. Services from ambulatory surgery, emergency room, and clinics (eg, dermatology and gastroenterology) were coded by study health information management staff (coders). VA-based billing information was edited against Medicare guidelines. Estimates for VA services without comparable Medicare fees were obtained from other commercial sources. RESULTS: Hypothetical professional fees for VA services were 17% more ($109 million vs. $93 million) than the VA budget for physicians over 1 fiscal year at six sites. Total payments of nearly $21 million were generated for VA inpatient care. In fiscal year 1999, there were 30,209 admissions (of which 4549 were psychiatric) to the study sites; 30,518 discharges; 229,783 inpatient days, including 27,235 in critical care units; and 38,348 surgical days of care. DISCUSSION: Differences between the VA and the private sector maybe overstated because VA salaries of nonphysicians were not included in the VA budgets. Conversely, the extent to which VA professional services were undercounted in VA information systems used in this study may understate the difference. Future research may consider additional data collection approaches or information systems enhancements to enumerate more accurately all provider services that are reimbursable in the private sector.

Methods to determine private sector payment for VA outpatient services: institutional payments to providers.

OBJECTIVES: To describe methods used to estimate hospital institutional (facility) payments for providing Veterans Health Administration (VA) outpatient services. METHODS: A series of audits compared the accuracy of outpatient coding at six VA medical centers in federal fiscal year 1999 with private sector standards. Outpatient records were processed through industry standard software to determine validity and remove inappropriate services. Private sector payments were estimated by applying average payment data from Medicare cost reports and Medicare outpatient prospective payment schedules to counts of VA services. RESULTS: Coding audits found little difference in accuracy between VA and the community. Physician visits generated the most estimated payments and deviated most from Medicare payment experience. Radiology and laboratory services were the next highest expenditure categories for both the VA and Medicare. The proportion of radiology payments in VA data was notably lower and ambulatory surgery notably higher than Medicare's experience. Within major categories, the relative rankings of VA and Medicare services were consistent. DISCUSSION: Differences in payment criteria make exact cost comparisons of hospital-based and office-based settings difficult, particularly physician visits. Two VA clinical software applications, radiology and laboratory, provide information not readily convertible to a claims format; these applications need significant changes to be used for these purposes. They understate radiology services and overstate laboratory services compared with private sector standards. In addition, the laboratory application contains inappropriate or unspecified codes that cannot be accurately valued for many reasons.

What would VA nursing home care cost? Methods for estimating private sector payments.

OBJECTIVES: To describe the methods used to validate Veterans Health Administration (VA) nursing home acuity data and estimate hypothetical payments for nursing home patients in VA-based and community-based units. METHODS: For a sample of VA-based and community-based nursing home patients at six sites, auditors validated the resource utilization classifications from the most recent complete full or quarterly assessments. Scores were averaged to obtain an acuity index for each nursing home population. Per diem rates were calculated for a fully phased-in Medicare prospective payment system, a transitional prospective payment system for free-standing and hospital-based nursing homes, and average national Medicaid benefits based on VA patients in community nursing facilities. Days of care came from each site's end of year gains and losses financial statement. Nursing home estimates were calculated by multiplying together the number of days of care, the per diem, and the acuity index. RESULTS: The VA acuity information was valid. Generally, veterans' dependencies and depression were underscored (similar to the practice for non-VA patients). The cost of patients' nursing home care absent VA facilities would depend on the types of nursing homes in which they were placed. The most costly option (hospital-based facilities with cost exemptions) would cost 3.5 times the least costly. Only the Medicaid-only estimate was lower than actual VA expenditures. DISCUSSION: Future research on nursing homes must relate quality to the cost of care to help policy makers assess the value of different options for providing that care.

Methods to estimate and compare VA expenditures for assistive devices to Medicare payments.

OBJECTIVE: To describe the methods used to estimate and compare Veterans Health Administration (VA) annual expenditures for assistive devices and their repair at six VA hospitals with payments for those same devices in the private sector. METHODS: Information about dispensed assistive devices and their costs was extracted from (1) the VA's National Prosthetic Patient Database, (2) each site's listing of the VA's Denver Distribution Center cost center in the Cost Distribution Jurisdictional Report, and (3) review of invoices for implanted prosthetics at each study site. We estimated private sector payments by applying Medicare geographically adjusted rates for purchases or rentals, where rates existed, or by inflating VA costs by 30%. RESULTS: The VA spent a total of $30.6 million for prosthetics at the six sites in fiscal year 1999, of which $14.2 million was for items captured in the National Prosthetic Patient Database, $3.4 million for the Denver Distribution Center, and more than $8.1 million for implants. Indirect VA costs were estimated at $4.8 million. Hypothetical private sector payments were estimated at $49.8 million. CONCLUSIONS: Unlike Medicare, VA both contracts to provide assistive devices (through a competitive bidding process) and dispenses devices it has purchased. This approach results in significantly lower expenditures, consistent with other reports. Generalizing these cost savings to other private or federal programs covering assistive devices requires further study.

Using the cost distribution report in estimating private sector payments: what adjustments should researchers make?

OBJECTIVES: To reapportion Veterans Health Administration (VA) annual expenditures into benefit categories for comparison with estimated payments by private sector providers. METHODS: Total expenditures for six VA medical centers for federal fiscal year 1999 were reapportioned by benefit category using the cost distribution report (CDR). Health benefit categories were based on those of health care insurers. Cost reapportionment was based on CDR data and reviews of source accounting and payroll documents. RESULTS: Actual expenditures for many benefits can be accurately identified and reapportioned using CDR data, but other expenditures were not identifiable in the CDR and required inspection of source documents. Inpatient expenditures amounting to $75,110,094 US dollars and outpatient expenditures amounting to $73,594,284 US dollars were reapportioned into other benefit categories, primarily professional fees. Expenditures for some VA benefits could not be identified because of differences in accounting and clinical practice between the VA and the community. DISCUSSION: Revisions to bring the CDR more in line with private sector payment categories would improve effectiveness for internal VA analyses and external expenditure comparisons. CDR revisions would require changes in recording some clinical workload (eg, rehabilitation and extended care) and classifying residential and domiciliary programs separate from inpatient care. Benefits that were not assigned expenditures for comparison with payments represent a potential liability if the VA were to purchase health care services in the marketplace. Variation among hospitals on expenditures not clearly identified in the CDR was significant and raises questions about the effectiveness of capitated budget methodologies using either the CDR or the decision support system.