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Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains. A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

The existence of a healthy immigrant effect—where immigrants are on average healthier than the native born—is a widely cited phenomenon across a multitude of literatures including epidemiology and the social sciences. There are many competing explanations. The goals of this paper are twofold: first, to provide further evidence on the presence of the healthy immigrant effect across source and destination country using a set of consistently defined measures of health; and second, to evaluate the role of selectivity as a potential explanation for the existence of the phenomenon. Utilizing data from four major immigrant recipient countries, USA, Canada, UK, and Australia allows us to compare the health of migrants from each with the respective native born who choose not to migrate. This represents a much more appropriate counterfactual than the native born of the immigrant recipient country and yields new insights into the importance of observable selection effects. The analysis finds strong support for the healthy immigrant effect across all four destination countries and that selectivity plays an important role in the observed better health of migrants vis a vis those who stay behind in their country of origin.

Cervical cancer is one of the most preventable forms of cancer and the Pap smear test is one of the most widely accessible forms of cancer screening. An important public health issue is the extent to which Canadian women are engaging in regular screening for cervical cancer, particularly potentially at-risk groups such as recent immigrants and women from minority ethnic backgrounds. We use recent population health surveys to analyze immigrant and native-born women's use of Pap smear testing, with a focus on how screening rates differ by ethnic background and characteristics of immigration. We find that almost all recent immigrant women have markedly lower use of Pap smear testing than comparable Canadian-born women, but these rates slowly increase with years in Canada. However, we find wide variation in rates of screening by ethnic background. Screening rates for White immigrant women from countries where the official language is neither English nor French approach Canadian-born women's utilization rates after 15-20 years in Canada, as do the screening rates of Black and Hispanic women. Screening rates for those from Asian backgrounds remain significantly below native-born Canadian levels even after many years in Canada. As well, immigrant women of Asian background who arrived as children and second-generation Asian Canadians both exhibit significantly lower rates of Pap smear testing than Canadian-born White women.