clinicaltrials.gov Identifier: NCT02139930.

Matched-pair design is often used in clinical trials to increase the efficiency of treatment comparison. We consider the problem of equivalence test with a relative risk endpoint in matched-pair studies with binary outcomes, and develop several score and Wald-type statistics for testing a hypothesis of non-unity relative risk. Examples from an assessment of HIV screening test and a cross-over clinical trial of soft contact lenses are used to illustrate the proposed methods. Through simulations we compare the empirical performance of these tests with the test proposed by Lachenbruch and Lynch. We show that a score test based on a reparameterized multinomial model by Tango performs best in the sense that the test satisfactorily controls the type I error rate and its empirical type I error rates are generally much closer to the prespecified nominal significance level than those of the other tests.

SUMMARY During pancreatic development, proliferating pancreatic progenitors activate the proendocrine transcription factor neurogenin 3 (NEUROG3), exit the cell cycle, and differentiate into islet cells. The mechanisms that direct robust NEUROG3 expression within a subset of progenitor cells control the size of the endocrine population. Here we demonstrate that NEUROG3 is phosphorylated within the nucleus on serine 183, which catalyzes its hyperphosphorylation and proteosomal degradation. During progression through the progenitor cell cycle, NEUROG3 phosphorylation is driven by the actions of cyclin-dependent kinases 2 and 4/6 at G1/S cell-cycle checkpoint. Using models of mouse and human pancreas development, we show that lengthening of the G1 phase of the pancreatic progenitor cell cycle is essential for proper induction of NEUROG3 and initiation of endocrine cell differentiation. In sum, these studies demonstrate that progenitor cell-cycle G1 lengthening, through its actions on stabilization of NEUROG3, is an essential variable in normal endocrine cell genesis.

Tumors are believed to emerge only when immune surveillance fails. We wished to ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer. We molecularly typed HLA DPB1, DQB1, DRB1, and DRB3 alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB*03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P ‫؍‬ 0.0001). HLA DRB1*11 alleles were also significantly overrepresented (P < 0.0001) in controls (16.3%) as compared with patients with early-onset breast cancer (3.5%). HLA DQB*03032 and HLA DRB1*11 alleles may have a protective role in human breast cancer.A lthough it is likely that genetic susceptibility plays a role in the development of most human cancers, evidence supporting this view hitherto has been obtained in only a small fraction of patients who typically carry germ-line mutations in tumor suppressor genes. In addition to the widely recognized role of acquired alterations in oncogenes and tumor suppressor genes, considerable evidence exists to suggest that the immune system might play a protective role in tumorigenesis. Although immune surveillance is believed to be involved in the elimination of tumors (1, 2), immunotherapeutic approaches to human cancer by and large have proved unsuccessful.T cell responses are dependent on the inheritance of specific alleles of the highly polymorphic HLA class I and class II genes. Although weak associations of specific HLA alleles with tumors of viral origin have been described (3-10), the relevance of MHC polymorphisms to the broader category of spontaneous nonviral human tumors remains to be established. Somatic alterations in many tumors can contribute to the down-regulation of HLA class I gene expression in tumor cells (11). These alterations potentially could contribute to immune evasion and might represent a discrete event in the multistep paradigm of tumorigenesis. Although HLA class I genes are expressed in all cells, immune responses also require the presentation of antigenic peptides to T cells by HLA class II molecules. These heterodimers primarily are expressed by professional antigen-presenting cells such as macrophages, dendritic cells, and B lymphocytes. Somatic alterations in tumor cells cannot inf luence the expression of HLA class II genes in dendritic cells and other professional antigen-presenting cells. If, indeed, immune surveillance is important during tumorigenesis, certain individuals who inherit specific alleles of the highly polymorphic HLA class II DPB, DQB, or DRB genes might be resistant to specific types of cancers.We reasoned that a detailed molecular analysis of HLA DPB, DQB, and DRB alleles in patients with breast cancer and ethnically matched controls might provide information on the potential existence of alleles that could confer susceptibility or resistance to this human cancer. Women with early-onset breast cancer (diagnosed at or before the age of 40...