Sema6D forward signaling impairs T cell activation and proliferation in head and neck cancer.

Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.

Semaphorin 6D-expressing mesenchymal cells regulate IL-10 production by ILC2s in the lung.

Group 2 innate lymphoid cells (ILC2s) have been implicated in both physiologic tissue remodeling and allergic pathology, yet the niche signaling required for ILC2 properties is poorly understood. Here, we show that an axonal guidance cue semaphorin 6D (Sema6D) plays critical roles in the maintenance of IL-10-producing ILC2s. Sema6d -/- mice exhibit a severe steady-state reduction in ILC2s in peripheral sites such as the lung, visceral adipose tissue, and mesentery. Interestingly, loss of Sema6D results in suppressed alarmin-driven type 2 cytokine production but increased IL-10 production by lung ILC2s both in vitro and in vivo. Consequently, Sema6d -/- mice are resistant to the development of allergic lung inflammation. We further found that lung mesenchymal cells highly express Sema6D, and that niche-derived Sema6D is responsible for these phenotypes through plexin A1. Collectively, these findings suggest that niche-derived Sema6D is implicated in physiological and pathological characteristics of ILC2s.

Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component.

OBJECTIVES: Autoimmune and allergic diseases are outcomes of the dysregulation of the immune system. Our study aimed to elucidate differences or shared components in genetic backgrounds between autoimmune and allergic diseases. METHODS: We estimated genetic correlation and performed multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of six immune-related diseases: rheumatoid arthritis, Graves' disease, type 1 diabetes for autoimmune diseases and asthma, atopic dermatitis and pollinosis for allergic diseases. By integrating large-scale biobank resources (Biobank Japan and UK biobank), our study included 105 721 cases and 433 663 controls. Newly identified variants were evaluated in 21 778 cases and 712 767 controls for two additional autoimmune diseases: psoriasis and systemic lupus erythematosus. We performed enrichment analyses of cell types and biological pathways to highlight shared and distinct perspectives. RESULTS: Autoimmune and allergic diseases were not only mutually classified based on genetic backgrounds but also they had multiple positive genetic correlations beyond the classifications. Multi-trait GWAS meta-analysis newly identified six allergic disease-associated loci. We identified four loci shared between the six autoimmune and allergic diseases (rs10803431 at PRDM2, OR=1.07, p=2.3×10-8, rs2053062 at G3BP1, OR=0.90, p=2.9×10-8, rs2210366 at HBS1L, OR=1.07, p=2.5×10-8 in Japanese and rs4529910 at POU2AF1, OR=0.96, p=1.9×10-10 across ancestries). Associations of rs10803431 and rs4529910 were confirmed at the two additional autoimmune diseases. Enrichment analysis demonstrated link to T cells, natural killer cells and various cytokine signals, including innate immune pathways. CONCLUSION: Our multi-trait and cross-population study should elucidate complex pathogenesis shared components across autoimmune and allergic diseases.

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.

Acute Myeloid Leukemia Complicated by Giant Cell Arteritis.

Giant cell arteritis (GCA), a type of systemic arteritis, is rare in Japan. We herein report a case of acute myeloid leukemia (AML) complicated by GCA that manifested during chemotherapy for AML. A 77-year-old woman with severe back pain was diagnosed with AML. She achieved complete remission with the resolution of her back pain following induction chemotherapy. However, she developed a headache and fever after consolidation chemotherapy. A diagnosis of GCA was made based on a biopsy of the temporal artery and arterial imaging. GCA should therefore be included in the differential diagnosis in AML patients complicated with a headache and fever of unknown origin.

Successful treatment of refractory cold hemagglutinemia in MYD88 L265P mutation-negative Waldenström's macroglobulinemia with bortezomib.

We report here the successful treatment of cold agglutinin-associated refractory hemolysis with bortezomib in a patient with Waldenström's macroglobulinemia (WM). A 78-year-old man was referred to our hospital with cold hemagglutinemia of unknown cause. Laboratory examination revealed a hemoglobin concentration of 6.9 g/dL, serum IgM concentration of 1904 mg/dL, and a titer of cold hemagglutinin of over ×8192. Serum immunoelectrophoresis demonstrated monoclonal protein of the IgM-κ type. A bone marrow aspirate showed many lymphoplasmacytic cells, which were positive for CD19, CD20, CD38, and cytoplasmic µ and κ light chains. A diagnosis of WM-associated cold hemagglutinemia was made. Because of red blood cell transfusion-dependency, we treated him with intravenous fludarabine, oral melphalan-prednisolone, cyclophosphamide, and melphalan, and two courses of R-CHOP in sequence with a marked decrease of serum IgM (928 mg). We then started weekly bortezomib plus dexamethasone (BD) therapy, as he was still transfusion-dependent. Soon after the initiation of BD, he achieved transfusion independence, with a further decrease in serum levels of IgM and marked improvement of anemia. Interestingly, his marrow abnormal lymphocytes were later found not to carry the MYD88 L265P mutation. The successful treatment with bortezomib for WM lacking this mutation is discussed.

[Familial Annulo-aortic Ectasia without Marfan Syndrome].

Marfan syndrome is a hereditary disease that presents ocular, skeletal, and cardiovascular abnormalities. In recent years, there have been several reports of patients with familial cardiovascular disease but no physical features of Marfan syndrome. We encountered 3 cases of familial annulo-aortic ectasia (AAE). Their father had also had aortic regurgitation, and died during surgery 10 years before. No case demonstrated any physical characteristics of Marfan syndrome or any other connective tissue disease. All cases were operated successfully. One case showed cystic medial necrosis, and 2 cases showed degenerative change. The present report suggests that familial AAE may be caused by weakness of the aortic wall related to heredity. If AAE is left untreated, it can lead to aortic dissection. Thus, we recommend that patients with familial AAE should undergo screening and follow-up similar to patients with Marfan syndrome.

Testing a cascade model of linkage between child abuse and negative mental health among battered women in Japan.

This study examined the following hypotheses: (1) a child abuse history (CAH), domestic violence (DV), and child abuse by an intimate partner might have a crucial and specific influence but act differently on women's negative mental health; (2) CAH, DV, child abuse by an intimate partner, and negative mental health might be predictors of maternal child abuse, with complex interactions. A self-administered questionnaire survey was conducted among a sample of mothers (N=304) and their children (N=498) staying in 83 Mother-Child Homes in Japan to assess the women's CAH and DV experiences, along with their current mental health problems, including dissociated, depressed, and traumatic symptoms. A structural equation modeling (SEM) was adapted to test whether a complex theoretical model fits the actual relationship among a set of observed measures. Our model confirmed the linkage with broader aspects of violence within the family such as CAH and DV, focusing on women's mental health problems reported by them. In addition, CAH, DV, child abuse by intimate partner, and maternal mental health might have a crucial and specific but act influence on maternal child abuse.

Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis.

BACKGROUND: Itch impairs the quality of life for many patients with dermatoses, especially atopic dermatitis (AD), and is frequently induced by a warm environment. OBJECTIVE: To determine the mechanism underlying itch induction by warmth, we focused on artemin, a member of glial cell line-derived neurotrophic factors (GDNFs). METHODS: A gene array assay revealed that artemin was expressed in substance P-treated dermal fibroblasts. The expression of artemin in healthy and AD-lesional skin was evaluated with immunohistochemistry and in situ hybridization. The impact of fibroblast-derived artemin on the proliferation and morphology of neural cell was investigated in vitro. To confirm the involvement of artemin in skin sensibility, wild-type and GDNF family receptor α3 knockout mice were employed for sensory examination. RESULTS: Artemin-expressing fibroblasts accumulated in skin lesions of patients with AD. Artemin induced cell proliferation of a neuroblastoma cell line in vitro, and intradermal injection of artemin in mice resulted in peripheral nerve sprouting and thermal hyperalgesia. Artemin-treated mice demonstrated scratching behavior in a warm environment, but mice deficient for GDNF family receptor α3, a potent artemin receptor, did not show this behavior. Furthermore, the escaping response to heat stimulus was attenuated in GDNF family receptor α3 knockout mice, suggesting that artemin may contribute to sensitivity to heat. CONCLUSION: These data suggest that dermal fibroblasts secrete artemin in response to substance P, leading to abnormal peripheral innvervation and thermal hyperalgesia. We hypothesize that artemin lowers the threshold of temperature-dependent itch sensation and might therefore be a novel therapeutic target for treating pruritic skin disorders, including AD.

Factors that contribute to the improvement in maternal parenting after separation from a violent husband or partner.

The authors test the hypothesis that separation from a violent husband or partner improves maternal parenting in Japan and examine how childhood abuse history (CAH), experience of domestic violence (DV), mental health problems, husband or partner's child maltreatment, and other demographic factors affect maternal parenting after such separation. A self-administered questionnaire survey is conducted for mothers (n = 304) and their children (n = 498) staying in 83 mother-child homes in Japan to assess the mothers' CAH, DV experiences, current mental health problems, and exposure to a husband or partner's child maltreatment. The authors also assess maternal poor parenting (physical and psychological abuse, neglect, no playing, and no praise) before and after admission into the mother-child homes. The total poor parenting score (specifically for neglect, no playing, and no praise) significantly reduces after separation from a violent husband or partner (p = .001, paired t test). However, scores for psychological abuse significantly increase after admission (p < .001, paired t test). CAH, DV, and mental health problems are not associated with a reduced total poor parenting score after admission. Husband or partner's child maltreatment is independently significantly associated with a reduced maternal poor parenting score: A 10% increase in such maltreatment is associated with a 5% reduction in the poor parenting score after separation. Marital status also contributes to the score reduction: The reduction is less in married or divorced mothers than in those who did not marry the partner. Mother-child homes might be useful for improving maternal parenting. Further study is needed to elucidate the mechanism of the impact of separation from a violent husband or partner on maternal parenting.

The impact of childhood abuse history and domestic violence on the mental health of women in Japan.

OBJECTIVE: To understand the independent and interactive effects of childhood abuse history (CAH) and domestic violence (DV) on the mental health status of women in Japan. METHODS: A self-administered questionnaire survey was conducted among a sample of 340 women staying in 83 Mother-Child Homes in Japan to assess the women's CAH and DV experiences, along with their current mental health problems, including dissociated, depressed, and traumatic symptoms. RESULTS: Independent from DV, CAH, especially psychological abuse, had a significant impact on all of the women's mental health symptoms. DV was found to have an independent effect on traumatic symptoms. Weak interactive effects of CAH and DV were found on dissociated and traumatic symptoms. Among those women without CAH, DV was significantly associated with dissociated and traumatic symptoms; however, DV had no impact on dissociated and traumatic symptoms if CAH was present. CONCLUSIONS: The findings suggest the significant impact of CAH on women's mental health problems, independent from DV. CAH and DV weakly interact on women's mental health. PRACTICE IMPLICATIONS: In psychological therapy for battered women with mental health problems, if the cases were abused during childhood, it is recommended that therapy be focused on childhood abuse, especially if the client was psychologically abused. In addition, mental health care and welfare providers should be aware that the mental health problems of mothers without CAH might be exacerbated by DV; thus, appropriate resource allocation should be considered.

Asymmetric intramolecular michael addition of alpha-sulfinyl vinylic carbanion to enoates.

The first example of an asymmetric intramolecular Michael addition reaction with use of alpha-lithiated vinylic sulfoxide as a Michael donor is reported. Michael addition of the alpha-lithiated vinylic sulfoxide to (Z)-enoates proceeds with high diastereoselectivity to give the adducts with (R)-configuration at the beta-position of the ester in the five-membered-ring formation. The selectivity was reversed in the six-membered-ring formation. The resulting ester enolates were reacted with alkyl halides or benzaldehyde with high diastereoselectivity.