Interleukin-3-dependent potentiation of IgE responsiveness in mouse basophils

Basophils produce interleukins (IL)-4 in response to various stimuli and may contribute to type 2 immune responses to various infections and allergens. We found that resting basophils freshly isolated from mice produce IL-4 in response to IL-3 but not to high-affinity Fc receptor (FcεRI) cross-linking (CL), yet both required the immunoreceptor tyrosine-based activation motif (ITAM) containing adaptor Fc receptor γ-chain (FcRγ), while basophils activated in vitro by IL-3 become responsive to FcεRI CL. Acquisition of responsiveness to FcεRI CL occurred upon infection with Trichinella spiralis or administration of superantigen. Because cultured basophils return to a quiescent state upon starvation with IL-3 with surface FcεRI levels unchanged, this acquisition is reversible and probably reflects intracellular events requiring protein synthesis. Interestingly, similar activation-associated acquisition was observed for responsiveness to other stimuli, including CD200R3 CL, which is known to signal via DAP-12, and the allergen protease papain. This acquisition of responsiveness to FcεRI CL was inhibited by Jak inhibitor. Thus, the IL-3 signal bifurcates downstream of Jak, into two distinct pathway, one leading to IL-4 production and the other to render basophils competent to respond to stimuli dependent on ITAM-containing adaptors DAP12 and FcRγ for IL-4 production.     

A new mutation in the POU3F4 gene in a japanese family with x-linked mixed deafness (DFN3)

Objective: The molecular defect in patients with X-linked mixed deafness showing a perilymphatic gusher at stapedectomy (DFN3) has been attributed to mutations in the POU3F4 gene. This study aimed to clarify an allelic variant of this gene. Study Design: This was a genetic study of a single Japanese family with DFN3. Methods: Products of a polymerase chain reaction (PCR) were subjected to single-strand conformation polymorphism (SSCP) analysis. Direct sequencing of PCR products from patients and carriers showing SSCP variants was performed using the fluorescent dideoxy termination method and a sequencer. Results: Sequencing of the PCR product revealed a 6-base deletion (TTCAAA) at nucleotides 601 to 606, resulting in a two-amino-acid deletion in the POU3F4 protein, (phenylalanine and lysine at amino acid residues 201 and 202). The deletion was adjacent to the site of a nonsense mutation previously described. Conclusion: Microdeletions at a previously undescribed location account for some clinically important POU3F4 mutations. Laryngoscope, 108:1544–1547, 1998     

Frequent expression of CD30 in extranodal NK/T‐cell lymphoma: Potential therapeutic target for anti‐CD30 antibody‐based therapy

Extranodal NK/T‐cell lymphoma, nasal type (ENKTL) is a subtype of non‐Hodgkin lymphoma with a poor prognosis. Although first‐line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti‐CD30 antibody‐based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T‐cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut‐off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non‐nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30‐positive cases and CD30‐negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression‐free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti‐CD30 antibody‐based therapy may be an effective treatment.     

Synovitis-acne-pustulosis-hyperostosis-osteitis Syndrome with Bilateral Pleural Effusion

Pleural effusion is a rare manifestation in synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, which is characterized by the presence of osteoarticular lesions and dermatological involvement. We herein report a 71-year-old man with pleural effusion resulting from SAPHO syndrome. He was successfully treated using corticosteroids and has experienced no recurrence for one year. We should consider SAPHO syndrome when encountering cases of anterior chest pain and pleural fluid.     

Cellular senescence and the tumour microenvironment

The senescence‐associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP‐mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour‐suppressive and tumour‐promoting effects, as observed in senescence surveillance effects (tumour‐suppressive) and suppression of anti‐tumour immunity in most senescent cancer‐associated fibroblasts and senescent T cells (tumour‐promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context‐dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.     

Preimplantation genetic diagnosis/screening by comprehensive molecular testing

Although embryo screening by preimplantation genetic diagnosis (PGD) has become the standard technique for the treatment of recurrent pregnancy loss in couples with a balanced gross chromosomal rearrangement, the implantation and pregnancy rates of PGD using conventional fluorescence in situ hybridization (FISH) remain suboptimal. Comprehensive molecular testing, such as array comparative genomic hybridization and next‐generation sequencing, can improve these rates, but amplification bias in the whole genome amplification method remains an obstacle to accurate diagnosis. Recent advances in amplification procedures combined with improvements in the microarray platform and analytical method have overcome the amplification bias, and the data accuracy of the comprehensive PGD method has reached the level of clinical laboratory testing. Currently, comprehensive PGD is also applied to recurrent pregnancy loss due to recurrent fetal aneuploidy or infertility with recurrent implantation failure, known as preimplantation genetic screening. However, there are still numerous problems to be solved, including misdiagnosis due to somatic mosaicism, cell cycle‐related background noise, and difficulty in diagnosis of polyploidy. The technology for comprehensive PGD also requires further improvement.     

Clinical evaluations of pituitary apoplexy in incidental nonfunctional pituitary adenomas

Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each P < .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (P < .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each P < .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (P = .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each P < .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.     

Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR‐expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C‐terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ‐EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ‐targeting therapy for liver cancer.     

Contrast Enhancement of the Normal Infundibular Recess Using Heavily T2-weighted 3D FLAIR

Purpose: The purpose of the present study was to evaluate contrast enhancement of the infundibular recess in the normal state using heavily T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) (HT2-FLAIR).Methods: Twenty-six patients were retrospectively recruited. We subjectively assessed overall contrast enhancement of the infundibular recess between postcontrast, 4-hour (4-h) delayed postcontrast, and precontrast HT2-FLAIR images. We also objectively conducted chronological and spatial comparisons by measuring the signal intensity (SI) ratio (SIR). Chronological comparisons were performed by comparing SI of the infundibular recess/SI of the midbrain (SIR_IR-MB). Spatial comparisons were conducted by comparing SI on postcontrast HT2-FLAIR/SI on precontrast HT2-FLAIR (SIR_Post-Pre) of the infundibular recess with that of other cerebrospinal fluid (CSF) spaces, including the superior part of the third ventricle, lateral ventricles, fourth ventricle, and interpeduncular cistern.Results: In the subjective analysis, all cases showed contrast enhancement of the infundibular recess on both postcontrast and 4-h delayed postcontrast HT2-FLAIR, and showed weaker contrast enhancement of the infundibular recess on 4-h delayed postcontrast HT2-FLAIR than on postcontrast HT2-FLAIR. In the objective analysis, SIR_IR-MB was the highest on postcontrast images, followed by 4-h delayed postcontrast images. SIR_Post-Pre was significantly higher in the infundibular recess than in the other CSF spaces.Conclusion: The present results demonstrated that the infundibular recess was enhanced on HT2-FLAIR after an intravenous gadolinium injection. The infundibular recess may be a potential source of the leakage of intravenously administered gadolinium into the CSF.