Uncovering Minimal Pathways in Melanoma Initiation.

Cutaneous melanomas are clinically and histologically heterogeneous. Most display activating mutations in Braf or Nras and complete loss of function of one or more tumor suppressor genes. Mouse models that replicate such mutations produce fast-growing, pigmented tumors. However, mice that combine Braf activation with only heterozygous loss of Pten also produce tumors and, as we show here, in an Albino background this occurs even with Braf activation alone. Such tumors arise rarely, grow slowly, and express low levels of pigmentation genes. The timing of their appearance was consistent with a single step stochastic event, but no evidence could be found that it required de novo mutation, suggesting instead the involvement of an epigenetic transition. Single-cell transcriptomic analysis revealed such tumors to be heterogeneous, including a minor cell type we term LNM ( L ow-pigment, N eural- and extracellular M atrix-signature) that displays gene expression resembling "neural crest"-like cell subsets detected in the fast-growing tumors of more heavily-mutated mice, as well as in human biopsy and xenograft samples. We provide evidence that LNM cells pre-exist in normal skin, are expanded by Braf activation, can transition into malignant cells, and persist with malignant cells through multiple rounds of transplantation. We discuss the possibility that LNM cells not only serve as a pre-malignant state in the production of some melanomas, but also as an important intermediate in the development of drug resistance.

The Literature that Commercial Insurance Payers Use to Substantiate Knee Osteochondral Allograft Policies Are of a Low Level of Evidence.

OBJECTIVE: The purpose of this study is to analyze how the largest insurance companies support their medical necessity policies regarding osteochondral allograft transplantation (OCA) and to determine whether the literature they cite in their policies is of a high level of evidence (LOE). DESIGN: The 10 largest national health insurance companies were identified. Each payer was contacted via phone or email to obtain their coverage policy regarding OCA. For each policy, the medical necessity criteria were recorded, and all cited references were screened. For all references applicable to OCA, the LOE was recorded, and each reference was screened to determine whether they mentioned the specific criteria reported in the policies. RESULTS: The medical policies for 6 of the 10 national health insurance companies were identified. These 6 policies cited a collective total of 102 applicable references. Most of these studies were an LOE of IV (n = 58, 56.9%) and an LOE of V (n = 18, 17.6%). There were similarities amongst the medical necessity criteria between different commercial payers; however, most criteria were poorly supported by the cited literature. CONCLUSIONS: Our results demonstrate that commercial insurance companies utilize studies that are of a low LOE when justifying their medical necessity criteria. Moreover, these cited studies infrequently support or mention the commercial payers' criteria. Future studies should continue to explore how well-supported insurance policies are with the goal of potentially increasing access and authorization for well-supported treatment modalities.

The maternal microbiome promotes placental development in mice.

The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored. Here, we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate cultured endothelial cell tube formation and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

The maternal microbiome promotes placental development in mice.

The maternal microbiome is an important regulator of gestational health, but how it impacts the placenta as the interface between mother and fetus remains unexplored. Here we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate angiogenesis-related tube formation by endothelial cells and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.