TGFß-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.

Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFß in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFß and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.

[Developing and Verifying the Validity and Reliability of the Electronic Menopausal Health Screen System].

BACKGROUND: Menopausal women are in a transitional phase between health and sickness. Although the highest standards of menopausal care include clinical assessment and patient education on menopausal symptoms, current practices lack integrated care that aim to prevent chronic diseases for which menopause is a predisposing factor. PURPOSE: To integrate menopausal disturbances; to evaluate the risk factors for osteoporosis, cardiovascular disease, and diabetes; and to create a reliable and effective electronic menopausal health screen system (EMHSS). METHODS: The research was conducted in the four stages of assessment and analysis, design, development, and pretest stage in order to explore the effectiveness of the developed EMHSS. RESULTS: The EMHSS has a high degree of reliability and validity. Analysis found an expert validity of .97~.99, content validity of .99, and test-retest reliabilities of .80~.96 (Pearson's correlation) and .79~.96 (intra-class correlation). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The EPMHSS was developed using cross-disciplinary collaboration among nursing staff, medical practitioners, and information engineers in order to screen menopausal women. The EPMHSS provides tailored health education content for patients in a timely manner and compiles historical assessment data that may be referenced by nursing staff when providing health consultations and by physicians when delivering diagnoses and treatment.

Empowering self-care ability - a follow-up study of clinical-based perimenopausal women personal health counselling.

AIMS AND OBJECTIVES: This study aimed to evaluate the longitudinal effects of a personal counselling intervention for perimenopausal women in northern Taiwan. BACKGROUND: Women face a variety of physical changes during menopause. Counselling intervention could enrich individual health education for menopausal women. DESIGN: Quasi-experimental design. METHODS: The study used one-on-one personal health counselling with a 'menopausal health passport' for perimenopausal women. The Perceived Perimenopausal Disturbances scale, the Practice of Health Behavior scale and the Perceived Uncertainty scale were used to measure the intervention effects. Results were estimated by a Generalized Estimating Equation procedure at one and a half months, three months and six months post intervention. In addition, data regarding perceived health changes were collected qualitatively through interviews in the experimental group at the sixth month. RESULTS: A total of 34 women were included in the experimental group, while 33 were in the control group. Interaction effect results showed that personal health counselling significantly increased the practice of health behaviours at one and a half months and extended to three months post intervention. Additionally, content categories, including 'relief of symptoms', 'establishment of health behaviors', 'interaction with others' and 'consideration from others' were identified in quantitative analysis. CONCLUSIONS: The results suggest that perimenopausal personal health counselling can effectively improve healthy behaviours. This study can also serve as a future reference for effective perimenopausal counselling. RELEVANCE TO CLINICAL PRACTICE: It is crucial to set up personal health counselling for perimenopausal women in clinics and develop information technology systems to support menopausal women in the technological era.

Defective autophagy and mTORC1 signaling in myotubularin null mice.

Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis.