The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus.

In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.

Quantitative Estimation of the Equivalent Radiation Dose Escalation using Radiofrequency Hyperthermia in Mouse Xenograft Models of Human Lung Cancer.

Hyperthermia is a potent radiosensitizer, and its effect varies according to the different types of cancer cells. In the present study, the radiosensitizing effect of hyperthermia on lung cancer cell lines A549 and NCI-H1299 was determined based on the equivalent radiation dose escalation. In vitro cell experiments were conducted using lung cancer cell lines A549 and NCI-H1299 to determine thermal radiosensitivity. In vivo experiments were conducted using mouse heterotopic xenograft models to determine the treatment response and increase in the temperature of tumors using a 13.56 MHz radiofrequency (RF) hyperthermia device. Using the α and ß values of the linear-quadratic equations of cell survival curves, numerical simulations were performed to calculate the equivalent radiation dose escalations. The dielectric properties of tumors were measured, and their effect on the calculated equivalent radiation dose was analyzed. Hyperthermia increased the equivalent radiation dose of lung cancer xenografts and a higher escalation was found in NCI-H1299 cells compared with that observed in A549 cells. An underestimation of the calculated equivalent radiation dose was observed when the dielectric property of the tumor was varied. This study may contribute to the effective planning of thermoradiotherapy in clinics.

Prognostic Influence of BCL2 on Molecular Subtypes of Breast Cancer.

PURPOSE: We aimed to reveal the prognostic influence of B-cell CLL/lymphoma 2 (BCL2) on molecular subtypes of breast cancer. METHODS: We analyzed 9,468 patients with primary breast cancer. We classified molecular subtypes according to the National Comprehensive Cancer Network (NCCN) and St. Gallen guidelines, mainly on the basis of the expression of hormonal receptor (HR), human epidermal growth factor receptor 2 (HER2), and Ki-67. RESULTS: Regarding NCCN classification, BCL2 was a strong favorable prognostic factor in the HR(+)/HER2(-) subtype (p<0.001) and a marginally significant favorable prognosticator in the HR(+)/HER2(+) subtype (p=0.046). BCL2 had no prognostic impact on HR(-)/HER2(+) and HR(-)/HER2(-) subtypes. In relation to St. Gallen classification, BCL2 was a strong favorable prognosticator in luminal A and luminal B/HER2(-) subtypes (both p<0.001). BCL2 was a marginally significant prognosticator in the luminal B/HER2(+) subtype (p=0.046), and it was not a significant prognosticator in HER2 or triple negative (TN) subtypes. The prognostic effect of BCL2 was proportional to the stage of breast cancer in HR(+)/HER2(-), HR(+)/HER2(+), and HR(-)/HER2(-) subtypes, but not in HR(-)/HER2(+) subtype. BCL2 was not a prognostic factor in TN breast cancer regardless of epidermal growth factor receptor expression. CONCLUSION: The prognostic influence of BCL2 was different across molecular subtypes of breast cancer, and it was largely dependent on HR, HER2, Ki-67, and the stage of cancer. BCL2 had a strong favorable prognostic impact only in HR(+)/HER2(-) or luminal A and luminal B/HER2(-) subtypes, particularly in advanced stages. Further investigations are needed to verify the prognostic influence of BCL2 on molecular subtypes of breast cancer and to develop clinical applications for prognostication using BCL2.