During vesicular transport between the endoplasmic reticulum and the Golgi, members of the TMED/p24 protein family form hetero-oligomeric complexes that facilitate protein cargo recognition as well as vesicle budding. In addition, they regulate each other's level of expression. Despite analyses of TMED/p24 protein distribution in mammalian cells, yeast, and C. elegans, little is known about the role of this family in vertebrate embryogenesis. We report the presence of a single point mutation in Tmed2/p24β1 in a mutant mouse line, 99J, identified in an ENU mutagenesis screen for recessive developmental abnormalities. This mutation does not affect Tmed2/ p24β1 mRNA levels but results in loss of TMED2/p24β1 protein. Prior to death at midgestation, 99J homozygous mutant embryos exhibit developmental delay, abnormal rostral-caudal elongation, randomized heart looping, and absence of the labyrinth layer of the placenta. We find that Tmed2/ p24β1 is normally expressed in tissues showing morphological defects in 99J mutant embryos and that these affected tissues lack the TMED2/p24β1 oligomerization partners, TMED7/p24γ3 and TMED10/p24δ1. Our data reveal a requirement for TMED2/p24β1 protein in the morphogenesis of the mouse embryo and placenta.

Patients with advanced melanoma have a compromised anti-tumor immune response leading to tumor immune tolerance and a tumor microenvironment conducive to disease progression. Immunotherapy that successfully overcomes this tumor-mediated immune suppression has made the greatest impact in the management of this disease over the past few years. This progress through immunotherapy builds upon earlier successes that interferon-α had in the treatment of melanoma in the adjuvant setting, as well as that of high-dose interleukin-2 in advanced melanoma. The development of immune checkpoint inhibitors has led to dramatic clinical activity in advanced melanoma. In particular, anti-CTLA4 and anti-PD1 monoclonal antibodies have taken us forward into the realm of longer survival and durable responses with the possibility of cure in a continuously increasing proportion of patients. Combination immunotherapeutic strategies and novel immunotherapeutic agents are being tested at an accelerated pace where the outlook for long-term survival benefits for the majority of patients appears brighter than ever.

Background Cessation of chemotherapy in the last few weeks of life could be an important quality of care benchmark. Proportion of metastatic breast cancer patients who receive end of life chemotherapy is not well described. We aimed to determine the prevalence and determinants of end of life chemotherapy use in patients with metastatic breast cancer. Methods A retrospective cohort study using a prospectively collated database of patients with metastatic breast cancer who died between January 1, 2010 and September 30, 2014 was conducted. End of life chemotherapy (EOLC) use was defined as receipt of chemotherapy within 2 weeks of death (EOLC2), and receipt of chemotherapy within 4 weeks of death (EOLC4). Patients who did not receive any chemotherapy in the last 4 weeks before death were categorized as non-EOLC. Results We identified 274 patients with metastatic breast cancer, of whom 28 received EOLC2 (10.2%) and 62 received EOLC4 (22.6%). In comparison to non-EOLC, patients receiving EOLC4 were younger and had greater disease burden. Patients in EOLC4 group received more number of lines of chemotherapy. In a multivariable analysis, younger age at metastatic disease and greater number of metastatic organ systems involved were predictors of end of life chemotherapy use. Conclusions Prevalence of the use of end of life chemotherapy in our cohort was higher than previously described. More end of life chemotherapy was used in younger women, and those with greater disease burden. Earlier initiation of end of life discussions may be targeted to such patients.