Deciphering OPDA Signaling Components in the Momilactone-Producing Moss Calohypnum plumiforme.

Jasmonic acid (JA) and its biologically active form jasmonoyl-L-isoleucine (JA-Ile) regulate defense responses to various environmental stresses and developmental processes in plants. JA and JA-Ile are synthesized from α-linolenic acids derived from membrane lipids via 12-oxo-phytodienoic acid (OPDA). In the presence of JA-Ile, the COI1 receptor physically interacts with JAZ repressors, leading to their degradation, resulting in the transcription of JA-responsive genes by MYC transcription factors. Although the biosynthesis of JA-Ile is conserved in vascular plants, it is not recognized by COI1 in bryophytes and is not biologically active. In the liverwort Marchantia polymorpha, dinor-OPDA (dn-OPDA), a homolog of OPDA with two fewer carbons, and its isomer dn-iso-OPDA accumulate after wounding and are recognized by COI1 to activate downstream signaling. The moss Calohypnum plumiforme produces the antimicrobial-specialized metabolites, momilactones. It has been reported that JA and JA-Ile are not detected in C. plumiforme and that OPDA, but not JA, can induce momilactone accumulation and the expression of these biosynthetic genes, suggesting that OPDA or its derivative is a biologically active molecule in C. plumiforme that induces chemical defense. In the present study, we investigated the biological functions of OPDA and its derivatives in C. plumiforme. Searching for the components potentially involving oxylipin signaling from transcriptomic and genomic data revealed that two COI1, three JAZ, and two MYC genes were present. Quantification analyses revealed that OPDA and its isomer iso-OPDA accumulated in larger amounts than dn-OPDA and dn-iso-OPDA after wounding. Moreover, exogenously applied OPDA, dn-OPDA, or dn-iso-OPDA induced the transcription of JAZ genes. These results imply that OPDA, dn-OPDA, and/or their isomers potentially act as biologically active molecules to induce the signaling downstream of COI1-JAZ. Furthermore, co-immunoprecipitation analysis showed the physical interaction between JAZs and MYCs, indicating the functional conservation of JAZs in C. plumiforme with other plants. These results suggest that COI1-JAZ-MYC mediated signaling is conserved and functional in C. plumiforme.

Proton beam therapy for recurrent ovarian carcinoma: A case report.

The efficacy and feasibility of proton beam therapy (PBT) for recurrent ovarian carcinoma had not been determined. Here we presented a case of recurrent ovarian carcinoma that was successfully treated with PBT. A 48-year-old woman who was diagnosed as left ovarian clear cell carcinoma underwent surgery without removal of two tumors. After achieving complete remission with postoperative chemotherapy, a recurrent tumor was found in the sigmoid colon, for which a colostomy was performed. Because second-line chemotherapy was not effective, PBT was selected; there were no complications, except for a transient low-grade fever. After 1 year of PBT, the tumor completely disappeared and the patient had been disease-free for over 8 years. PBT may be an effective and less invasive treatment modality for recurrent ovarian carcinoma.

A case of uterine carcinosarcoma which was strongly suspected to have metastases to the psoas and gluteus muscles.

Metastasis to the skeletal muscles is uncommon. We report a case which was strongly suspected to have psoas and gluteus muscle metastases from uterine carcinosarcoma. A 68-year-old woman (gravida, 2; para, 0) underwent retroperitoneal endoscopic paraaortic lymphadenectomy, laparoscopic modified radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy for uterine carcinosarcoma, suspected to be stage IB. Metastasis to one right pelvic lymph node was observed. Ascites fluid cytology was negative. Postoperative pathological examination revealed stage IIIC1 (pT1bN1M0) disease. Five cycles of chemotherapy with paclitaxel + carboplatin were performed. 10 months after chemotherapy, serum cancer antigen-125 level was elevated. Computed tomography (CT) revealed a 3-cm tumor of the left psoas muscle and magnetic resonance imaging revealed a tumor of the left gluteus maximus muscle. These lesions showed fluorodeoxyglucose uptake in positron emission tomography-CT. Because we considered the tumors were metastases of uterine carcinosarcoma, we recommended her chemotherapy. However, after one cycle of chemotherapy, the patient underwent immunotherapy elsewhere with immune checkpoint inhibitors. 5 months after the recurrence, she was alive.

Hyperthyroidism due to struma ovarii: Diagnostic pitfalls and preventing thyroid storm.

We report struma ovarii in a case that had hyperthyroidism and was treated with laparoscopic tumor resection. A 40-year-old Japanese woman presented with tachycardia, finger tremor, and weight loss. Although blood examination showed hyperthyroidism, test results for thyroid stimulating hormone receptor antibody and thyroid stimulating antibody were negative, and thyroid scintigraphy showed no abnormal findings. Because she was diagnosed with an ovarian tumor, and whole-body scintigraphy showed that iodine uptake was detected in the pelvic space, we diagnosed her with an ovarian tumor, which caused excessive thyroid hormone secretion. After controlling the thyroid hormone level, we resected the ovarian tumor laparoscopically. The thyroid hormone level was within the normal range postoperatively without any medications. Based on our experience, physicians need to remember that ovarian tumors can cause hyperthyroidism. Controlling the thyroid hormone level preoperatively by using antithyroid drugs and performing minimally invasive laparoscopic surgery is considered useful for preventing thyroid storm.

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock.

BACKGROUND: The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions. OBJECTIVE: We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions. METHODS: We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. RESULTS: PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis. CONCLUSION: Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice.

There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, "the circadian clock," remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ+ T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ+ T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ+ T cells, establishing a mechanistic link between psoriasis and the circadian clock.

Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells.

We report a case of an 88-year-old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death-1 (PD-1), Bcl-6 and CXCL13. Flow cytometry analysis showed that CD4(+) PD-1(hi) T cells also expressed CD10, inducible T-cell co-stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T-cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)-cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH-cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. METHODS: Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. RESULTS: Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb-IV). CONCLUSIONS: While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Concerns about inherited risk of breast cancer prior to diagnosis in Japanese patients with breast complaints.

The purpose of this study was to reveal characteristics that underlie patients' expressions of concern about their genetic risk of breast cancer at an initial outpatient clinic visit prior to a definitive diagnosis of cancer. A total of 233 women, at their initial outpatient clinic visits, participated in semi-structured and open-ended interviews that surveyed their anxieties, worries, thoughts, and feelings. Each patient completed a self-administered survey comprising questions about her family history of breast cancer and responded to a questionnaire that assessed psychological distress. Patients were divided into those who expressed concerns about inherited risk of breast cancer during the interview (expression group, n = 39) and those who did not (non-expression group, n = 194). Although patients in the expression group tended to have higher rates of breast cancer in their families, patients without a family history of breast cancer also expressed concerns. We used qualitative content analysis to identify the emotions and thoughts of patients expressing these concerns. Patients with a family history of breast cancer experienced anxiety/worry, risk-reducing behavior, acceptance, objective fact, and denial, whereas patients without a family history of breast cancer experienced anxiety/worry, risk-reducing behavior, surprise/shock, acceptance, objective fact, denial, optimistic thought, regret, and realistic thought. Some patients in the breast clinic had concerns about their inherited risk of cancer, despite lacking a family history of breast cancer. Health care professionals should inquire about family histories and provide appropriate support and counseling to patients as needed, regardless of the patient's genetic risk for the disease.

Predictors of psychological distress after diagnosis in breast cancer patients and patients with benign breast problems.

OBJECTIVE: The objective of this study was to determine how age and psychological characteristics assessed prior to diagnosis could predict psychological distress in outpatients immediately after disclosure of their diagnosis. METHODS: This is a longitudinal and prospective study, and participants were breast cancer patients and patients with benign breast problems (BBP). Patients were asked to complete questionnaires to determine levels of the following: trait anxiety (State-Trait Anxiety Inventory), negative emotional suppression (Courtauld Emotional Control Scale), life stress events (Life Experiences Survey), and psychological distress (Profile of Mood Status) prior to diagnosis. They were asked to complete a questionnaire measuring psychological distress after being told their diagnosis. We analyzed a total of 38 women diagnosed with breast cancer and 95 women diagnosed with a BBP. RESULTS: A two-way analysis of variance (prior to, after diagnosis × cancer, benign) showed that psychological distress after diagnosis among breast cancer patients was significantly higher than in patients with a BBP. The multiple regression model accounted for a significant amount of variance in the breast cancer group (model adjusted R(2) = 0.545, p < 0.001), and only trait anxiety was statistically significant (ß = 0.778, p < 0.001). In the BBP group, the multiple regression analysis yielded a significant result (model adjusted R(2) = 0.462, p < 0.001), with trait anxiety and negative life changes as statistically significant factors (ß = 0.449 and 0.324 respectively; p < 0.01). CONCLUSIONS: In both groups, trait anxiety assessed prior to diagnosis was the significant predictor of psychological distress after diagnosis, and might have prospects as a screening method for psychologically vulnerable women.

Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure.

Premature ovarian failure (POF) is a disorder characterized by amenorrhea and elevated serum gonadotropins before 40 years of age. As X chromosomal abnormalities are often recognized in POF patients, defects of X-linked gene may contribute to POF. Four cases of POF with t(X;autosome) were genetically analyzed. All the translocation breakpoints were determined at the nucleotide level. Interestingly, COL4A6 at Xq22.3 encoding collagen type IV alpha 6 was disrupted by the translocation in one case, but in the remaining three cases, breakpoints did not involve any X-linked genes. According to the breakpoint sequences, two translocations had microhomology of a few nucleotides and the other two showed insertion of 3-8 nucleotides with unknown origin, suggesting that non-homologous end-joining is related to the formation of all the translocations.

Perceptions of the concept of mutation among family members of patients receiving outpatient genetic services and university students.

Our objectives were to investigate: (1) relationships between perceptions of various terms regarding mutation and the depth of knowledge regarding mutation among family members of patients receiving genetic outpatient services, and (2) differences in perceptions of the term "gene mutation" for family members versus university students. Fifty-eight family members and 178 university students responded to two questionnaires: Impressions regarding the term, and Knowledge about the concept of mutation. Factor analyses were conducted to determine the factor structure of ratings of the terms, and two-way analyses of variance [(1)Term, (2)Group x Knowledge] were conducted to examine differences in perceptions of the terms as measured by scores for each extracted factor. Family members had a significantly more negative perception of the term "gene mutation" than "gene change" and a less negative perception of the term "gene mutation" than "gene lesion"; they had significantly more negative perceptions of the term "gene mutation" than did university students.

Psychological characteristics and subjective symptoms as determinants of psychological distress in patients prior to breast cancer diagnosis.

GOALS OF WORK: The objective of this study was to determine how psychological characteristics, subjective symptoms, a family history of breast cancer, and age impact psychological distress in outpatients at the first hospital visit prior to breast cancer diagnosis. MATERIALS AND METHODS: Participants were prediagnosed women with complaints of breast symptoms who either came to our hospital directly, or with a referral from another clinic. Patients were asked to complete questionnaires to determine the following: trait anxiety (State-Trait Anxiety Inventory), negative emotional suppression (Courtauld Emotional Control Scale), life stress events (Life Experiences Survey), and psychological distress (Profile of Mood States). We examined subjective symptoms (lumps, pain, abnormal nipple discharge, or deformed nipple) and family history of breast cancer based on answers to the interview sheet filled out by patients on their first visit. We analyzed a total of 154 patients who completed the questionnaires out of 237 eligible patients. MAIN RESULTS: A significant model was obtained by multiple regression analysis (adjusted R (2) = 0.574, p < 0.01) in which the standard partial regression coefficients for trait anxiety, suppression of anxiety, negative life change events, positive life change events, and subjective symptoms were statistically significant (beta = 0.623, 0.133, 0.155, 0.108, and 0.124, respectively; p < 0.05). CONCLUSIONS: Psychological distress prior to diagnosis was higher in patients who had high trait anxiety, suppression of anxiety, many life stress events, and subjective symptoms. In particular, trait anxiety had a large impact on psychological distress, underscoring the need for and importance of adequate psychological care.

A Streptomyces griseus gene (sgaA) suppresses the growth disturbance caused by high osmolality and a high concentration of A-factor during early growth.

A-factor (2-isocapryloyl-3R-hydroxymethyl-gamma-butyrolactone), produced in a growth-dependent manner, switches on secondary metabolite formation and morphological differentiation in Streptomyces griseus, presumably by binding to the A-factor receptor protein (ArpA)-DNA complex and releasing the repression caused by ArpA. In the A-factor-deficient mutant strain S. griseus HH1 a large deletion includes afsA which is required for A-factor production. Growth and aerial mycelium formation of strain HH1 on media containing high concentrations of sucrose, sorbitol, mannitol, KCl or NaCl was disturbed by the presence of a large amount of A-factor supplied either exogenously or by a high-copy-number plasmid carrying afsA. This disturbance did not occur on media of normal osmolality and was observed only when A-factor was supplied during the very early stage of growth, about 8 h after inoculation. In addition, neither the wild-type strain nor S. griseus KM7 defective in ArpA exhibited the disturbance. These observations suggest that the presence of a large amount of A-factor during the very early stage of growth, probably during the A-factor-sensitive stage, triggered abrupt and disordered expression of some genes. The effect was apparently mediated through ArpA in the A-factor regulatory cascade and disturbed the physiology of strain HH1 under high osmolality. A gene that suppressed the disturbance was identified 5.5 kb upstream of the afsA locus in the wild-type strain. The gene, named sgaA, encoded a protein of 264 aa with a calculated molecular mass of 28 kDa.