Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KO^SF-1) using steroidogenic factor 1–Cre (SF-1–Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KO^SF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.

Jung IY, et al. Yonsei Med J. 2019 Jun;60(6):592-596. https://doi.org/10.3349/ymj.2019.60.6.592

Anti-epidermal growth factor receptor (EGFR) therapy has been tried in triple negative breast cancer (TNBC) patients without evaluation of molecular and clinical predictors in several randomized clinical studies. Only fewer than 20% of metastatic TNBCs showed response to anti-EGFR therapy. In order to increase the overall response rate, first step would be to classify TNBC into good or poor responders according to oncogenic mutation profiles. This study provides the molecular characteristics of TNBCs including EGFR gene copy number changes and mutation status of EGFR and KRAS gene in Korean TNBC patients. Mutation analysis for EGFR, KRAS, BRAF and TP53 from a total of 105 TNBC tissue samples was performed by direct sequencing, peptide nucleic acid-mediated PCR clamping method and real-time PCR. Copy number changes of EGFR gene were evaluated using multiplex ligation-dependent probe amplification. Out of all 105 TNBCs, 15.2% (16/105) showed EGFR copy number changes. Among them, increased or decreased EGFR copy number was detected in 13 (5 single copy gain, 2 amplification and 4 high-copy number amplification) and 3 cases (3 hemizygous deletion), respectively. The mutation frequencies of KRAS, EGFR and TP53 gene were 1.9% (G12V and G12D), 1.0% (exon 19 del) and 31.4%, respectively. There was no BRAF V600E mutation found. Future studies are needed to evaluate the clinical outcomes of TNBC patients who undergo anti-EGFR therapy according to the genetic status of EGFR.

Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients

Sepsis is a life-threatening disorder with high incidence and mortality rate. However, the early detection of sepsis is challenging due to lack of specific marker and various etiology. This study aimed to identify robust risk factors for sepsis via cluster analysis. The integrative task of the automatic platform (i.e., electronic medical record) and the expert domain was performed to compile clinical and medical information for 2,490 sepsis patients and 16,916 health check-up participants. The subjects were categorized into 3 and 4 groups based on seven clinical and laboratory markers (Age, WBC, NLR, Hb, PLT, DNI, and MPXI) by K-means clustering. Logistic regression model was performed for all subjects including healthy control and sepsis patients, and cluster-specific cases, separately, to identify sepsis-related features. White blood cell (WBC), well-known parameter for sepsis, exhibited the insignificant association with the sepsis status in old age clusters (K3C3 and K4C3). Besides, NLR and DNI were the robust predictors in all subjects as well as three or four cluster-specific subjects including K3C3 or K4C3. We implemented the cluster-analysis for real-world hospital data to identify the robust predictors for sepsis, which could contribute to screen likely overlooked and potential sepsis patients (e.g., sepsis patients without WBC count elevation).