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Marek’s disease virus (MDV) causes malignant lymphoma (Marek’s disease; MD) in chickens. The Meq protein is essential for tumorigenesis since it regulates the expression of host and viral genes. Previously, we reported that the deletion of the short isoform of Meq (S-Meq) decreases the pathogenicity of MDV. Recently, we identified a further short isoform of Meq (very short isoform of Meq, VS-Meq) in chickens with MD in Japan. A 64-amino-acid deletion was confirmed at the C-terminus of VS-Meq. We measured the transcriptional regulation by VS-Meq in three gene promoters to investigate the effect of VS-Meq on protein function. Wild-type VS-Meq decreased the transrepression of the pp38 promoter but did not alter the transactivation activity of the Meq and Bcl-2 promoters. The deletion in VS-Meq did not affect the activity of the pp38 promoter but enhanced the transactivation activities of the Meq and Bcl-2 promoters. Collectively, the deletion of VS-Meq potentially enhanced the activity of the Meq promoter, while other amino acid sequences in wild-type VS-Meq seemed to affect the weak transrepression of the pp38 promoter. Further investigation is required to clarify the effects of these changes on pathogenicity.

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

Sphingosine 1-phosphate (S1P) is an intercellular signaling molecule present in blood. Erythrocytes have a central role in maintaining the S1P concentration in the blood stream. We previously demonstrated that S1P is exported from erythrocytes by a glyburide-sensitive S1P transporter. However, the gene encoding the S1P transporter in erythrocytes is unknown. In this study, we found that the mouse erythroid cell line, MEDEP-E14, has S1P export activity and exhibits properties that are consistent with those of erythrocytes. Using microarray analysis of MEDEP-E14 cells and its parental cell line, E14TG2a, we identified several candidate genes for S1P export activity. Of those genes, only one gene, Mfsd2b , showed S1P transport activity. The properties of S1P release by MFSD2B were similar to those in erythrocytes. Moreover, knockout of MFSD2B in MEDEP-E14 cells decreased S1P export from the cells. These results strongly suggest that MFSD2B is a novel S1P transporter in erythroid cells.

Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1-5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus.

Sphingosine-1-phosphate (S1P) is a secreted lipid mediator that functions in vascular development; however, it remains unclear how S1P secretion is regulated during embryogenesis. We identified a zebrafish mutant, ko157, that displays cardia bifida (two hearts) resembling that in the S1P receptor-2 mutant. A migration defect of myocardial precursors in the ko157 mutant is due to a mutation in a multipass transmembrane protein, Spns2, and can be rescued by S1P injection. We show that the export of S1P from cells requires Spns2. spns2 is expressed in the extraembryonic tissue yolk syncytial layer (YSL), and the introduction of spns2 mRNA in the YSL restored the cardiac defect in the ko157 mutant. Thus, Spns2 in the YSL functions as a S1P transporter in S1P secretion, thereby regulating myocardial precursor migration.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called “conversion surgery” has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.

•Modified frailty index was reliable predictor of postoperative outcome.•The intracerebral hemorrhage score with modified frailty index predicted outcome.•Modified frailty index showed additive ability to the intracerebral hemorrhage score. Frailty is an indispensable concept among elderly. The purpose of this study was to determine the association between modified frailty index (mFI) and the postoperative outcome of surgery for spontaneous intracerebral hemorrhage (sICH). Outcome measures included an unfavorable outcome (modified Rankin Scale score of 4–6) or mortality at 6–8 months after hemorrhage. The prognostic ability of mFI was assessed by comparing adjusted and nonadjusted effects with the Hemphill’s ICH score. The performance of the ICH score combined with mFI was assessed for discriminative ability. In total, 156 patients satisfied the inclusion criteria. Multivariate analyses revealed that higher mFI was significantly associated with an unfavorable outcome (p-value = 0.004) and mortality (p-value < 0.001). Compared with the ICH score alone, the ICH score combined with mFI revealed significantly higher discriminative ability for predicting postoperative outcome. mFI was a useful and reliable predictor of postoperative unfavorable outcome for sICH. Frailty may be an important essence to be considered before operation for sICS in the aging society.

Several prior reports have investigated worsening renal function around transcatheter aortic valve replacement (TAVR) procedures. However, in clinical practice, it seems more important to evaluate changes associated with TAVR-related procedures, including preoperative enhanced computed tomography (CT), as well as the TAVR procedure itself, as CT assessment is considered essential for safe TAVR. This study evaluated worsening renal function during the TAVR perioperative period, from the preoperative enhanced CT to 1 month after TAVR, and then compared the incidence with that in patients undergoing surgical aortic valve replacement (SAVR). This retrospective single-center study investigated 123 TAVR patients and 130 SAVR patients. We evaluated baseline renal function before enhanced CT in TAVR patients and before operation in SAVR patients, and again at 1 month post-operatively. We defined worsening renal function at 1 month according to three definitions: (1) an increase in serum creatinine ≥ 0.3 mg/dL or ≥ 1.5-fold from baseline or initiation of dialysis, (2) a decline in eGFR at 1 month ≥ 20% from baseline or initiation of dialysis, (3) a decline in eGFR at 1 month ≥ 30% from baseline or initiation of dialysis. TAVR patients were significantly older and had higher surgical risk scores than SAVR patients. In TAVR patients, serum creatinine levels were 1.00 ± 0.32 mg/dL at baseline and 1.01 ± 0.40 mg/dL at 1 month post-operatively ( p  = 0.58), while in SAVR patients, these levels were 0.99 ± 0.51 mg/dL and 0.98 ± 0.49 mg/dL, respectively ( p  = 0.59). In TAVR patients, 7 (5.7%), 14 (11.4%), and 3 (2.4%) patients experienced worsening renal function according to the three definitions, respectively, but there were no significant differences from those in SAVR patients, for any definition. Worsening renal function after TAVR was uncommon, and the incidence rate was comparable to that in SAVR patients, even though TAVR patients had worse baseline characteristics.

Background Prognostic factors for superficial esophageal cancer cannot be limited to such factors as lymph node metastasis (N factor), depth of tumor invasion (T factor), and genetic alterations. The purpose of this study was to examine whether invasive growth patterns of tumors, such as infiltrative growth pattern c (INFc) and budding, represent new useful prognostic factors for superficial esophageal cancer. Methods We investigated 87 cases of superficial esophageal cancer in patients treated with radical surgery. First, the invasive growth pattern of the tumor was pathologically evaluated based on the traditional infiltrative growth pattern (INF) classification. Next, new INF criteria were proposed, and the invasive pattern was re-evaluated. We also investigated budding (Bud) in the stroma of the invasive frontal lesion. Results When the patients were divided into two groups, with and without an INFc component, the group with an INFc component had a poorer outcome than the group without an INFc component. When the group with an INFc component was defined as “new INFc”, new INFc was correlated with the T factor ( p  = 0.006) and the ly factor (lymphatic invasion) ( p  = 0.041). Bud was correlated with the T factor ( p  = 0.001), the N factor ( p  = 0.030), and new INFc ( p  < 0.001). An analysis of survival revealed new INFc ( p  = 0.002) and Bud ( p  = 0.006) to be prognostic factors. The survival of the group with new INFc(+)/Bud(+) was poorer than that with new INFc(−)/Bud(−) ( p  = 0.007). Conclusions New INFc and Bud, which represent new invasive patterns, were prognostic factors for superficial esophageal cancer.

Background/Objectives: Epidemiological and clinical studies have linked both hypothyroidism and hyperthyroidism to adverse cardiac outcomes, including heart failure and myocardial fibrosis. Triiodothyronine (T3), a biologically active thyroid hormone, is important for cardiovascular homeostasis. While the effects of physiological and non-physiological T3 levels on cardiomyocytes have been extensively investigated, the impact of hypothyroidism and hyperthyroidism on cardiac stromal cells (CSCs), which constitute the majority of the cells in the heart, remains understudied. Given CSCs’ essential role in extracellular matrix (ECM) remodeling and paracrine signaling, understanding their response to altered T3 states is necessary to fully elucidate the thyroid hormone-induced cardiac responses. Methods: Cardiac stromal cells were isolated from human atrial appendages and cultured under hypothyroid (0 nM T3), euthyroid (2.5 nM T3), and hyperthyroid (25 nM T3) conditions for 24 (short term) and 120 h (long term). The cells were harvested after 24 h of treatment using trypsin and automatically counted, and their ECM-related gene and growth factor expression levels were assessed using quantitative RT-PCR. Cardiac glucose uptake in hypothyroid, euthyroid, and hyperthyroid mice was monitored using [18F]-FDG PET/CT at acute (7 days) and chronic (42 days) time points. Results: Both hypo- and hyperthyroidism significantly increased the number of CSCs harvested after 24 h. There were acute alterations in the expression of the ECM-related genes COL1A1, COL3A1, TIMP3 (p < 0.05), and TIMP1 (p < 0.01). Similarly, growth factors such as PDGF-A (p < 0.001), TGF-b, and IGF1 (p < 0.05) were transiently upregulated under non-physiological T3 conditions, especially hypothyroidism. Most of these alterations were attenuated or reversed at the 120 h time point. In vivo PET imaging revealed significant increases in cardiac glucose uptake under acute hypothyroidism (p < 0.05) and decreases under acute hyperthyroidism (p < 0.05). However, these metabolic shifts normalized with chronic exposure, paralleling the transient nature of the gene expression changes observed in vitro. Conclusions: Non-physiological T3 concentrations induce proliferation and changes in ECM-related and growth factor gene expression in CSCs. Most of these changes are acute and return to normal levels after chronic exposure. These transient cellular responses correlate closely with the cardiac metabolic response patterns to acute and chronic hypothyroidism and hyperthyroidism.