Citations

Objective The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. Background A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. Methods The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. Recommendations The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration–regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Nodular fasciitis (NF) is a clonal self‐limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well‐documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6‐USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

A peptide-universal nucleotide conjugate that mimics the topoisomerase I-DNA covalent complex was synthesized and then utilized to raise monoclonal antibodies.

Africa is a continent characterized by marked ethnic, sociodemographic, and economic diversity, with profound changes in many regions over the past 2 decades. This diversity has an impact on cardiovascular disease presentation and outcomes. Within Africa and within the individual countries, one can find regions having predominantly communicable diseases such as rheumatic heart disease, tuberculous pericarditis, or cardiomyopathy and others having a marked increase in noncommunicable disease such as hypertension and hypertensive heart disease. Ischemic heart disease remains rare in most countries. Difficulties in the planning and implementation of effective health care in most African countries are compounded by a paucity of studies and a low rate of investment in research and data acquisition. The fiduciary responsibilities of companies working in Africa should include the effective and efficient use of natural resources to promote the overall health of populations.

Significant functional impairment and psychological distress have been observed in adolescent patients with postural orthostatic tachycardia syndrome (POTS). Interdisciplinary rehabilitation programs have been shown to be beneficial in the treatment of chronic pain in adults and adolescents. Only preliminary data have examined interdisciplinary rehabilitation efforts in patients with POTS. This study evaluated the impact of an interdisciplinary rehabilitation program on the functional impairment and psychological distress in 33 adolescents diagnosed with POTS. Patients included in the study were adolescents ages 11 to 18 diagnosed with POTS. Measures completed at admission and discharge from the program included the Functional Disability Index, Center for Epidemiological Studies–Depression–Child scale, and the Pain Catastrophizing Scale for Children. After participation in the 3-week program, adolescents with POTS demonstrated a significant increase in overall functional ability and significant reductions in depression and catastrophizing.

Abstract Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.

Key Points Agents that inhibit both complexes containing the mammalian target of rapamycin are particularly toxic to acute lymphocytic leukemia cells. This killing reflects engagement of a 4EBP1/c-MYC/PUMA axis downstream of mTORC1 and an NF-κB/EGR1/BIM axis downstream of mTORC2.