microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity

褐色脂肪細胞の燃焼を促す新たなメカニズムを解明 --体の熱産生にマイクロRNA-33が関与--. 京都大学プレスリリース. 2021-02-17.Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress

Pain-Related Abnormal Neuronal Synchronization of the Nucleus Accumbens in Parkinson’s Disease

Patients with Parkinson’s disease (PD) often experience pain, which fluctuates in “on” and “off” states, but the underlying mechanism is unclear. The nucleus accumbens (NAc) is a central component of the mesolimbic dopaminergic pathway involved in pain processing. We conducted resting-state functional magnetic resonance imaging (rsfMRI) analysis to explore the relationship between the neuronal synchronization of NAc with pain-related brain regions and pain intensity in “on” and “off” states. We assessed 23 patients with sporadic PD based on rsfMRI and pain intensity using the revised Short-Form McGill Pain Questionnaire. Patients with PD displayed higher pain intensity scores in the “off” state than in the “on” state. The pain intensity in the “off” state was substantially correlated with the functional connectivity (FC) between the NAc and primary motor/sensory cortices and contralateral NAc. Changes in pain intensity from the “on” to “off” state displayed correlations with those between the right (rNA) and left NAc (lNAc) and the right precentral gyrus (rPreCG) /right insular cortex (rIC) from the “off” to “on” state. Aberrant bilateral NAc and rNAc–rPreCG/rIC FC in the “off” state were closely related to pain symptoms developed from the “on” to “off” states. These results suggest that the NAc in the mesolimbic pathway is related to pain in PD and may help understand the mechanism of pain development in patients with PD

Evaluating the Toxicity Reduction With Computed Tomographic Ventilation Functional Avoidance Radiation Therapy

PurposeComputed tomographic (CT) ventilation imaging is a new modality that uses 4-dimensional (4D) CT information to calculate lung ventilation. Although retrospective studies have reported on the reduction in dose to functional lung, no work to our knowledge has been published in which the dosimetric improvements have been translated to a reduction in the probability of pulmonary toxicity. Our work estimates the reduction in toxicity for CT ventilation-based functional avoidance planning.Methods and materialsSeventy previously treated lung cancer patients who underwent 4DCT imaging were used for the study. CT ventilation maps were calculated with 4DCT deformable image registration and a density change-based algorithm. Pneumonitis was graded on the basis of imaging and clinical presentation. Maximum likelihood methods were used to generate normal tissue complication probability (NTCP) models predicting grade 2 or higher (2+) and grade 3+ pneumonitis as a function of dose (V5 Gy, V10 Gy, V20 Gy, V30 Gy, and mean dose) to functional lung. For 30 patients a functional plan was generated with the goal of reducing dose to the functional lung while meeting Radiation Therapy Oncology Group 0617 constraints. The NTCP models were applied to the functional plans and the clinically used plans to calculate toxicity reduction.ResultsBy the use of functional avoidance planning, absolute reductions in grade 2+ NTCP of 6.3%, 7.8%, and 4.8% were achieved based on the mean fV20 Gy, fV30 Gy, and mean dose to functional lung metrics, respectively. Absolute grade 3+ NTCP reductions of 3.6%, 4.8%, and 2.4% were achieved with fV20 Gy, fV30 Gy, and mean dose to functional lung. Maximum absolute reductions of 52.3% and 16.4% were seen for grade 2+ and grade 3+ pneumonitis for individual patients.ConclusionOur study quantifies the possible toxicity reduction from CT ventilation-based functional avoidance planning. Reductions in grades 2+ and 3+ pneumonitis were 7.1% and 4.7% based on mean dose-function metrics, with reductions as high as 52.3% for individual patients. Our work provides seminal data for determining the potential toxicity benefit from incorporating CT ventilation into thoracic treatment planning

Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity

The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes‐associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD‐mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD‐mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD‐induced phenotypic switching. We generated Hoxa4‐deficient mice and confirmed the downregulation of smooth muscle‐specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD‐mediated transcription

Treatment outcomes of patients with adenocarcinoma of the uterine cervix after definitive radiotherapy and the prognostic impact of tumor-infiltrating CD8+ lymphocytes in pre-treatment biopsy specimens: a multi-institutional retrospective study.

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III-IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT

Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy

ObjectiveTo elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy.MethodsNinety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome.ResultsRecurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1–4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables.ConclusionsFGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies