Bronchial thermoplasty for severe asthma

Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series

Autonomic function measurements for evaluating fatigue and quality of life in patients with breast cancer undergoing radiation therapy: a prospective longitudinal study

Background: Fatigue during radiation therapy in women with breast cancer can decrease quality of life (QOL), yet it is often underestimated and needs to be evaluated objectively. This longitudinal study aimed to evaluate fatigue and QOL of women with breast cancer undergoing radiotherapy with a simple autonomic function measurement. Methods: Women with breast cancer who underwent postoperative radiotherapy in eight cancer care hospitals in Chubu and Kinki regions in Japan were recruited between October 2021 and June 2022. The women underwent a self-administered questionnaire that included the Cancer Fatigue Scale (CFS) and the Short Form-8 Health Survey (SF-8) and an autonomic nervous function measurement using a simple, non-invasive device before (T0, baseline), mid (T1), and at the end (T2) of treatment. Results: The 57 women showed similar trends, with CFS scores and log LF/HF ratio being the highest at T0 and significantly decreasing at T1 (both p < 0.05). The log LF/HF trends differed between those with high and low baseline log LF/HF values. Women with mental component summary (MCS) score improvement (T0 to T2) had the highest log LF/HF ratio at T0 and had significantly lower log LF/HF values at T1 and T2 than at T0 (p < 0.01 and p < 0.05, respectively). The change of (⊿) MCS from T0 to T1 was negatively correlated with ⊿log LF/HF from T0 to T1 (r = − 0.36, p < 0.01). Conclusions: Measurement of autonomic nerve function with a simple device is useful for objective fatigue assessment during radiotherapy. Psychological support is important as improvement in mental health helps improve autonomic nerve function and, in turn, fatigue.Aoki M., Kuratsune H., Yamamoto S., et al. Autonomic function measurements for evaluating fatigue and quality of life in patients with breast cancer undergoing radiation therapy: a prospective longitudinal study. Radiation Oncology 18, 171 (2023); https://doi.org/10.1186/S13014-023-02362-W

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory-related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory-related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy

Functional TFIIH Is Required for UV-Induced Translocation of CSA to the Nuclear Matrix▿

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. Mutations in Cockayne syndrome group A and B genes (CSA and CSB) result in defective TCR, but the molecular mechanism of TCR in mammalian cells is not clear. We have found that CSA protein is translocated to the nuclear matrix after UV irradiation and colocalized with the hyperphosphorylated form of RNA polymerase II and that the translocation is dependent on CSB. We developed a cell-free system for the UV-induced translocation of CSA. A cytoskeleton (CSK) buffer-soluble fraction containing CSA and a CSK buffer-insoluble fraction prepared from UV-irradiated CS-A cells were mixed. After incubation, the insoluble fraction was treated with DNase I. CSA protein was detected in the DNase I-insoluble fraction, indicating that it was translocated to the nuclear matrix. In this cell-free system, the translocation was dependent on UV irradiation, CSB function, and TCR-competent CSA. Moreover, the translocation was dependent on functional TFIIH, as well as chromatin structure and transcription elongation. These results suggest that alterations of chromatin at the RNA polymerase II stall site, which depend on CSB and TFIIH at least, are necessary for the UV-induced translocation of CSA to the nuclear matrix

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cell line for their usefulness as syngeneic models for canine HSA. Our results showed that the ISOS-1 cell line developed tumors with similar morphology to canine HSA. ISOS-1 cells highly expressed KDM2B and had similar KDM2B target expression patterns with canine HSA. Moreover, we determined that in both ISOS-1 and canine HSA tumors, macrophages were present as a major constituent of the tumor microenvironment. These macrophages were positive for CD204, an M2 macrophage marker, and express PD-L1, an immune checkpoint molecule. Canine HSA with macrophages expressing PD-L1 had a smaller number of T-cells in tumor tissues than tumors with PD-L1 negative macrophages. ISOS-1-conditioned medium could induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line and mouse peritoneal macrophages. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA