Glutamine deficiency drives transforming growth factor-ß signaling activation that gives rise to myofibroblastic carcinoma-associated fibroblasts.

Tumor-promoting carcinoma-associated fibroblasts (CAFs), abundant in the mammary tumor microenvironment (TME), maintain transforming growth factor-ß (TGF-ß)-Smad2/3 signaling activation and the myofibroblastic state, the hallmark of activated fibroblasts. How myofibroblastic CAFs (myCAFs) arise in the TME and which epigenetic and metabolic alterations underlie activated fibroblastic phenotypes remain, however, poorly understood. We herein show global histone deacetylation in myCAFs present in tumors to be significantly associated with poorer outcomes in breast cancer patients. As the TME is subject to glutamine (Gln) deficiency, human mammary fibroblasts (HMFs) were cultured in Gln-starved medium. Global histone deacetylation and TGF-ß-Smad2/3 signaling activation are induced in these cells, largely mediated by class I histone deacetylase (HDAC) activity. Additionally, mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling is attenuated in Gln-starved HMFs, and mTORC1 inhibition in Gln-supplemented HMFs with rapamycin treatment boosts TGF-ß-Smad2/3 signaling activation. These data indicate that mTORC1 suppression mediates TGF-ß-Smad2/3 signaling activation in Gln-starved HMFs. Global histone deacetylation, class I HDAC activation, and mTORC1 suppression are also observed in cultured human breast CAFs. Class I HDAC inhibition or mTORC1 activation by high-dose Gln supplementation significantly attenuates TGF-ß-Smad2/3 signaling and the myofibroblastic state in these cells. These data indicate class I HDAC activation and mTORC1 suppression to be required for maintenance of myCAF traits. Taken together, these findings indicate that Gln starvation triggers TGF-ß signaling activation in HMFs through class I HDAC activity and mTORC1 suppression, presumably inducing myCAF conversion.

Liuzijue Qigong: A Voice Training Method For Unilateral Vocal Fold Paralysis Patients.

OBJECTIVES: Liuzijue Qigong (LQG), a kind of traditional Chinese health exercise (TCHE), is not only widely used to strengthen physical fitness and maintain psychological well-being in the elderly but has also been utilized to help improve respiratory function. As respiratory support is an important driving force for speech production, it is logical to postulate that the LQG training method with 6 monosyllabic speech sounds, xu, he, hu, si, chui, and xi, can help individuals (1) experience a relaxing and natural state of speech production, (2) eliminate voice symptoms, and (3) improve their overall body function and mood. In the current study, we hypothesized that the LQG method with these 6 sounds can be effective in improving vocal function in subjects with unilateral vocal fold paralysis (UVFP) in comparison with a conventional voice therapy method. METHODS: A total of 48 patients with UVFP who met the inclusion criteria were randomly divided into 2 groups. Twenty-four subjects in the experimental group were trained with LQG, and those in the control group received conventional voice training (abdominal breathing and yawn-sign exercises) for a total of 4 sessions, twice a week. Patients in both groups were assessed with acoustic tests, the GRBAS scale, the Voice Handicap Index (VHI-10), and the Hospital Anxiety and Depression Scale (HADS) pre- and posttreatment. Statistical analysis was conducted using nonparametric tests and t tests. RESULTS: There existed significant changes in maximum phonation time (MPT), jitter, shimmer, normalized noise energy (NNE), GRBAS scores, VHI-10 scores, and grade of A in HADS scores pre- and posttreatment in both the experimental group and the control group ( P < .004). However, no significant changes were seen posttreatment between the 2 groups ( P > .05). CONCLUSIONS: LQG could help improve vocal function in UVFP patients as our preliminary data showed no significant differences between LQG and conventional voice therapy methods.