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In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy., (©2013 AACR.)

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations., ((c) 2007 Wiley-Liss, Inc.)

Background: The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country's 61 Poison Control Centers (PCCs). Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). U.S. Poison Centers make possible the compilation and reporting of this report through their staffs' meticulous documentation of each case using standardized definitions and compatible computer systems. The 61 participating poison centers in 2005 are: Regional Poison Control Center, Birmingham, AL; Alabama Poison Center, Tuscaloosa, AL; Arizona Poison and Drug Information Center, Tucson, AZ; Banner Poison Control Center, Phoenix, AZ; Arkansas Poison and Drug Information Center, Little Rock, AK; California Poison Control System-Fresno/Madera Division, CA; California Poison Control System-Sacramento Division, CA; California Poison Control System-San Diego Division, CA; California Poison Control System-San Francisco Division, CA; Rocky Mountain Poison and Drug Center, Denver, CO; Connecticut Poison Control Center, Farmington, CT; National Capital Poison Center, Washington, DC; Florida Poison Information Center, Tampa, FL; Florida Poison Information Center, Jacksonville, FL; Florida Poison Information Center, Miami, FL; Georgia Poison Center, Atlanta, GA; Illinois Poison Center, Chicago, IL; Indiana Poison Center, Indianapolis, IN; Iowa Statewide Poison Control Center, Sioux City, IA; Mid-America Poison Control Center, Kansas City, KA; Kentucky Regional Poison Center, Louisville, KY; Louisiana Drug and Poison Information Center, Monroe, LA; Northern New England Poison Center, Portland, ME; Maryland Poison Center, Baltimore, MD; Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island, Boston, MA; Children's Hospital of Michigan Regional Poison Control Center, Detroit, MI; DeVos Children's Hospital Regional Poison Center, Grand Rapids, MI; Hennepin Regional Poison Center, Minneapolis, MN; Mississippi Regional Poison Control Center, Jackson, MS; Missouri Regional Poison Center, St Louis, MO; Nebraska Regional Poison Center, Omaha, NE; New Jersey Poison Information and Education System, Newark, NJ; New Mexico Poison and Drug Information Center, Albuquerque, NM; New York City Poison Control Center, New York, NY; Long Island Regional Poison and Drug Information Center, Mineola, NY; Ruth A. Lawrence Poison and Drug Information Center, Rochester, NY; Upstate (formerly Central) New York Poison Center, Syracuse, NY; Western New York Poison Center, Buffalo, NY; Carolinas Poison Center, Charlotte, NC; Cincinnati Drug and Poison Information Center, Cincinnati, OH; Central Ohio Poison Center, Columbus, OH; Greater Cleveland Poison Control Center, Cleveland, OH; Oklahoma Poison Control Center, Oklahoma City, OK; Oregon Poison Center, Portland, OR; Pittsburgh Poison Center, Pittsburgh, PA; The Poison Control Center, Philadelphia, PA; Puerto Rico Poison Center, San Juan, PR; Palmetto Poison Center, Columbia, SC; Tennessee Poison Center, Nashville, TN; Central Texas Poison Center, Temple, TX; North Texas Poison Center, Dallas, TX; Southeast Texas Poison Center, Galveston, TX; Texas Panhandle Poison Center, Amarillo, TX; West Texas Regional Poison Center, El Paso, TX; South Texas Poison Center, San Antonio, TX; Utah Poison Control Center, Salt Lake City, UT; Virginia Poison Center, Richmond, VA; Blue Ridge Poison Center, Charlottesville, VA; Washington Poison Center, Seattle, WA; West Virginia Poison Center, Charleston, WV; Wisconsin Poison Center, Milwaukee, WI.

Several models of disability proposed in recent years share many common elements and are helping to direct research and inform practice. One new development is that disablement, a concept that emphasizes the impairments--handicap continuum, is now being implemented by concepts related to enablement. Enablement focuses attention on the capacity for rehabilitation. Coincidentally, a new generation of functional assessment measures has evolved that allow greater sensitivity not only to levels of disability but also to levels of ability. Together, the new models and tools hold promise of providing a more sensitive evaluation of rehabilitation efforts and a more accurate forecasting of future needs.

Ataxia telangiectasia (AT) is a recessive syndrome, including cerebellar degeneration, immunologic defects and cancer predisposition, attributed to mutations in the recently isolated ATM (ataxia telangiectasia, mutated) gene. AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise approximately 1% of the population. Studies of AT families have suggested that female relatives presumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer, raising the possibility that germline ATM mutations may account for approximately 5% of all breast cancer cases. The increased risk for breast cancer reported for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40-59 years. To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5%) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer.