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The systemic treatment of psoriasis has changed markedly with the introduction of many novel drugs. However, clinicians have had limited opportunities to evaluate these new therapies. One of the new drugs, apremilast (a phosphodiesterase-4 inhibitor), was approved in 2017 in Japan. We previously reported oral treatment for psoriasis before the introduction of apremilast. In this study, we investigated the impact of apremilast on oral medication for psoriasis by comparing data obtained before and after apremilast became available. This retrospective study enrolled patients who visited the Department of Dermatology, Fukuoka University Hospital, who were diagnosed with psoriasis and treated with anti-psoriatic oral medications. Patients were divided into two groups: Group 1, who first visited our clinic between January 2010 and March 2016; and Group 2, who first visited our clinic between April 2016 and March 2022. The information collected included patient demographics, drug use (apremilast, cyclosporine, methotrexate, and etretinate), and treatment duration. In Group 1 (n = 149 patients), cyclosporine, methotrexate, and etretinate were prescribed to 59.1%, 16.6%, and 24.3% of the patients, respectively. In Group 2 (n = 129 patients), apremilast was prescribed to 52.5% of patients, while the number of prescriptions for cyclosporine and etretinate had decreased to 17.1% and 8.3%, respectively. The number of methotrexate prescriptions did not change significantly. Apremilast, methotrexate, and etretinate had longer continuation rates than cyclosporine in Group 2. In conclusion, apremilast replaced cyclosporine and etretinate mainly because of its better safety profile, whereas methotrexate remained in constant demand in both eras. New oral treatments for psoriasis, such as tyrosine kinase-2 inhibitors, are now in the pipeline, and our data will serve as a control for oral anti-psoriatic medicine before the coming era.

PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 12 individuals from 10 unrelated families with biallelic ultra-rare variants inPNPLA8presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders. Complete loss of PNPLA8 was associated with the severe end of the spectrum, showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 reduced the number of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism inPNPLA8knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.

Optogenetic techniques have been intensively applied to the nematode Caenorhabditis elegans to investigate its neural functions. However, as most of these optogenetics are responsive to blue light and the animals exhibits avoidance behavior to blue light, the application of optogenetic tools responsive to longer wavelength light has been eagerly anticipated. In this study, we report the implementation in C. elegans of a phytochrome-based optogenetic tool that responds to red/near-infrared light and manipulates cell signaling. We first introduced the SynPCB system, which enabled us to synthesize phycocyanobilin (PCB), a chromophore for phytochrome, and confirmed the biosynthesis of PCB in neurons, muscles, and intestinal cells. We further confirmed that the amount of PCBs synthesized by the SynPCB system was sufficient for photoswitching of phytochrome B (PhyB)-phytochrome interacting factor 3 (PIF3). In addition, optogenetic elevation of intracellular Ca2+ levels in intestinal cells induced a defecation motor program. These SynPCB system and phytochrome-based optogenetic techniques would be of great value in elucidating the molecular mechanisms underlying C. elegans behaviors.

Angelman syndrome (AS) is caused by the functional absence of the maternal ubiquitin-protein ligase E3A (UBE3A) gene. Approximately 5% of AS is caused by paternal uniparental disomy of chromosome 15 (UPD(15)pat), most of which is considered to result from monosomy rescue. However, little attention has focused on how UPD(15)pat occurs. We suggest the mitotic nondisjunction mechanism as a cause of UPD(15)pat in a six-year-old patient presenting with distinctive characteristics in line with AS. DNA methylation screening of 15q11-q13 showed a paternal band and a faint maternal band, suggestive of mosaic status. By trio-based microsatellite analysis, we confirmed a large proportion of UPD(15)pat cells and a small proportion of cells of biparental origin. Single nucleotide polymorphism (SNP) microarray revealed isodisomy of the entire chromosome 15. These results suggest that the UPD(15)pat of the patient resulted from mitotic nondisjunction, which may also be the cause of other cases of AS with UPD(15)pat.

Herpes simplex virus (HSV) periodically forms characteristic blisters in the perioral and genital areas in a subset of people. Because of the lack of accurate tests for this common virus, various types of perioral/anogenital lesions are often misdiagnosed as herpes. Also, though asymptomatic HSV-positive people shed virus, the precise time course of symptoms and viral shedding is unclear. The loop-mediated isothermal amplification (LAMP) method amplifies target DNA sequences without thermal cycles, simpler and faster than polymerase chain reaction (PCR). To investigate clinico-laboratorial correlation and whether HSV can be detected in the oral cavity during symptom occurrence, we collected 445 specimens from 211 patients who visited our clinic with suspected herpetic lesions or non-symptomatic volunteers. DNA was extracted from swabs simultaneously taken from lesions (n = 219) and seemingly asymptomatic oral mucosa (n = 226). HSV-1 and HSV-2 DNA sequences were amplified by LAMP and validated by quantitative real-time PCR. The LAMP method detected HSV DNA almost as sensitively (97%) as PCR. Positivity for HSV DNA was found in 54% (40/74) of specimens from the perioral/oral area. Review of clinical images of recurrent herpes labialis revealed that HSV DNA was detected only from lesions located on the perioral skin and/or the dry, vermillion part of the lip; no HSV DNA was found in immunocompetent patients with lesions confined to the oral mucosa except primary infection. This observation may be an important principle for clinical diagnosis of recurrent herpes. HSV was detected in the oral mucosa in 2.7% (6/226) of samples; all of these patients had either primary infection or were immunosuppressed. Virus shedding in the mucosa was apparently tightly regulated by the immune system. Patients with suppressed or no immunity (naive cases) did shed virus in the mucosa. LAMP is a simple method to reliably distinguish recurrent/primary herpes from other conditions.

Background Delayed identification of infiltration and dysfunction of peripheral intravenous (PIV) access can lead to serious consequences during general anesthesia in children. This preliminary study aimed to describe the application of precordial Doppler ultrasound during general anesthesia in children to detect and confirm the correct PIV access and to evaluate the accuracy of this method. Methods This was a single-center, preliminary study that was conducted in children ( Results The total incidence of peripheral infiltration and dysfunction of PIV catheter was 7/512 (1.4%). In the S test, the sensitivity, specificity, positive and negative likelihood ratios, and area under the receiver-operating characteristic curves (AUCs) were 5/7 (71.4%; 95% confidence interval [CI], 29.0%–96.3%), 490/505 (97.0%; 95% CI, 95.1%–98.3%), 24.0, 0.29, and 0.84, respectively. The V test showed that the reasonable threshold of blood flow velocity change was 1.0 m/s, with sensitivity, specificity, positive and negative likelihood ratios, and AUC of 4/7 (57.1%; 95% CI, 18.4%–90.1%), 489/505 (96.8%; 95% CI, 94.9%–98.2%), 18.0 and 0.44, and 0.84, respectively. Conclusions This preliminary study demonstrated that precordial Doppler ultrasound is a feasible, easy-to-use, and noninvasive technique with good accuracy to confirm the correct PIV access during general anesthesia in children. However, its accuracy requires further evaluation.

Simple Summary Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. This study suggested that better baseline liver function was predictive of longer treatment duration and better prognosis in patients with advanced HCC treated with lenvatinib. Moreover, an AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer survival. Abstract Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.

A genetically modified (GM) soybean kernel detection system using combination of DNA preparation from individual soybean kernels and event-specific real-time PCR was developed to simultaneously identify GM soybean events authorized for food after safety assessments in Japan. Over 100 kernels in the non-identity-preserved soybean samples imported from the United States of America (two U.S.A. lots) and Brazil (one lot) were randomly selected and examined. In total, 98 and 96% of the two independent U.S.A. lots, and 100% of the Brazilian lot contained GM soybean kernels. Herbicide-tolerant events, MON89788 (trade name Genuity® Roundup Ready 2 Yield™), GTS 40-3-2 (trade name Roundup Ready™ soybean) and A2704-12 (trade name Liberty Link® soybean), were detected similarly in both U.S.A. lots. In the Brazilian lot, in addition to GTS 40-3-2, a stacked GM event, MON87701 × MON89788, having insect-resistance and herbicide-tolerance, was detected. There were no unauthorized GM soybeans comingled, and the ratio of GM soybean events detected was consistent with statistical reports on the cultivated GM soybean events in both countries.

The purpose of this study was to examine cerebral blood flow in the frontal cortex area during personality self-rating tasks. Our two hypotheses were (1) cerebral blood flow varies based on personality rating condition and (2) cerebral blood flow varies based on the personality traits. This experiment measured cerebral blood flow under 3 personal computer rating conditions and 2 questionnaire conditions. Comparing the rating conditions, the results of the t-test indicated that cerebral blood flow was higher in the questionnaire condition than it was in the personal computer condition. With respect to the Big Five, the result of the correlation coefficient, that is, cerebral blood flow during a personality rating task, changed according to the trait for agreeableness. The results of the analysis of the 5-cluster on individual differences indicated that certain personality traits were related to the factors that increased or decreased cerebral blood flow. An analysis of variance indicated that openness to experience and Behavioural Activation System-drive was significant given that participants with high intellectual curiosity were motivated in this experiment, thus, their cerebral blood flow may have increased. The significance of this experiment was that by employing certain performance measures we could examine differences in physical changes based on personality traits.

In an attempt to examine the cross-cultural expression of shyness, the purpose of the present study was to replicate and validate the three-component model of shyness as assessed by the 20-item Cheek-Buss Shyness Scale in a Japanese sample. The principal framework for this investigation is based on the cultural differences in the way Japanese shyness is thought about in everyday life compared with the U.S.A. In the present study, we compared the structural components of shyness in the U.S.A. with the results of a factor analysis of the CBSS-J, the Japanese translation of the CBSS. As further support of this conceptualization of shyness and the construct validity of the CBSS-J, we assumed the three factors of shyness would be related to interpersonal anxiety and other personality traits assessed by Big Five-J scale. The results of the factor analysis indicated the CBSS-J to have a three-factor structure. The results indicated scores on the CBBS-J to be negatively correlated with scores on The Big Five-J and positively correlated with LOC-J scale and BIS-J scale. Further analyses of the results suggest that there are differences in Big Five-J scores and BIS-J scores depending on the degree of shyness and locus of control.

In this study, we report that TIP39, a parathyroid hormone ligand family member that was recently identified to be expressed in the skin, can induce decorin expression and enhance wound repair. Topical treatment of mice with TIP39 accelerated wound repair, whereas TIP39-deficient mice had delayed repair that was associated with formation of abnormal collagen bundles. To study the potential mechanism responsible for the action of TIP39 in the dermis, fibroblasts were cultured in three-dimensional collagen gels, a process that results in enhanced decorin expression unless activated to differentiate to adipocytes, whereupon these cells reduce expression of several proteoglycans, including decorin. Small interfering RNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, suppressed the expression of extracellular matrix-related genes, including decorin, collagens, fibronectin, and matrix metalloproteases. Skin wounds in TIP39 –/– mice had decreased decorin expression, and addition of TIP39 to cultured fibroblasts induced decorin and increased phosphorylation and nuclear translocation of CREB. Fibroblasts differentiated to adipocytes and treated with TIP39 also showed increased decorin and production of chondroitin sulfate. Furthermore, the skin of PTH2R –/– mice showed abnormal extracellular matrix structure, decreased decorin expression, and skin hardness. Thus, the TIP39-PTH2R system appears to be a previously unrecognized mechanism for regulation of extracellular matrix formation and wound repair.

The prognosis of patients with recurrent/persistent endometrial cancer, particularly type II cancer, remains poor, and effective treatment has not yet been established. We herein present the case of a patient with recurrent type II endometrial cancer who received bevacizumab + chemotherapy continued beyond progression, after previously receiving bevacizumab + chemotherapy. This patient experienced recurrence after first- and second-line adjuvant chemotherapy followed by modified radical hysterectomy and she was administered bevacizumab + paclitaxel + carboplatin therapy. After six cycles of treatment, all metastatic lesions shrunk, indicating partial response. The patient next received single-agent bevacizumab as maintenance therapy. After 12 cycles of bevacizumab monotherapy, disease progression was detected; therefore, combination therapy consisting of bevacizumab, doxorubicin and carboplatin was initiated. After six cycles of this combination therapy, the patient exhibited disease stabilization. Finally, 18 months after the initial bevacizumab treatment, the patient remained on combination chemotherapy, without complaints or signs of tumor progression (last follow-up, October 2014).

Background: Contrast-enhanced ultrasound (CEUS) is a modality capable of visualizing the blood vessels through the use of the microbubble agent “Perflubutane”. It can also allow for an improved visualization of breast tumors. Currently, CEUS is being used on a daily practice for breast cancer screening and treatment planning in many medical centers. This technique was approved in Japan following evidence gleaned through Phase-2 and Phase-3 clinical studies and has advanced over the past seven years. Regarding the extent of malignant breast tumor, it has been revealed that contrast-enhanced lesions observed using CEUS might be longer than those same lesions visible on B-mode. However, what contrast-enhanced images on CEUS reflect pathologically remains unclear. To resolve this issue, more complete evidence of the detailed imagery of lesions obtained by CEUS seemed to be needed. In the present study, we investigated the maximum tumor width on B-mode/CEUS images compared with the maximum pathological extent of the cancer. (Evergreen study, UMIN: 000028995). Methods: In this retrospective multi-center study, 153 operable breast cancer patients who had undergone B-mode and CEUS prior to breast surgery between August 2012 and January 2017 were registered. The maximum tumor width was measured on B-mode and CEUS, and the tumor diameter width was determined at a postoperative histopathological examination (P) by investigators. With five blind readers as independent reviewers, the lesion width of 303 images was read (B-mode and CEUS). We analyzed the difference between the lesion width on CEUS or B-mode and the pathological width using paired t-tests and the Pearson product-moment correlation coefficient. Results: The mean tumor widths (±standard deviation) measured by investigators were 15±7 mm (B-mode), 19±8 mm (CEUS) and 17±9 mm (P). The difference calculated by P from B-mode was -3±7 mm (p P from B-mode was -2±8 mm (p=0.0005, r=0.5067), while that from CEUS was 1±8 mm (p=0.1256 r=0.5354). CEUS and B-mode also showed a significantly positive high correlation (p Discussion: Our data suggested that the maximum lesion width might increase, in order, from B-mode to P and CEUS. Furthermore, the difference in the lesion width determined by B-mode and P appeared to be significant, although not that between P and CEUS. Moreover, a positive high correlation was detected between B-mode and CEUS. Therefore, the width on CEUS might tend to be larger than that on B-mode, regardless of the tumor size. Additional information may be determined through an analysis of the design and extent of dissection when partial mastectomy is to be performed. These findings may also provide clues as to what can be anticipated pathologically when a lesion is enhanced with CEUS. Citation Format: Aya Noro, Hiroaki Shima, Toshiko Hirai, Midori Noma, Takashi Nakamura, Emi Sato, Terumi Kaga, Yukio Mitsuzuka, Keitaro Kamei, Yumi Imayoshi, Toshikazu Ito, Shinsaku Kanazawa, Kumiko Kato, Ryuzo Sekiguchi, Goro Kutomi, Mitsuru Mori, Tadashi Hasegawa, Ichiro Takemasa, Toshitaka Okuno. The difference between tumor width on a contrast-enhanced ultrasound and the extent of pathological breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-02-11.

We evaluated the efficacy of gonadotropin-releasing hormone agonist (GnRHa) therapy for improving the myometrial thickness in women with thin (less than 1 cm) uterine walls, a contraindication for microwave endometrial ablation (MEA). The normal myometrium thickness was 0.5 cm, 0.7 cm and 0.9 cm. After the third GnRHa dose, the myometrial thickness increased to over 1 cm in all the three patients, and all were able to undergo MEA. The VAS score for menorrhagia improved in all the cases. The patient satisfaction levels were 10 in 2 of the 3 patients, and 5 in the other. There was no symptom recurrence, and no adjuvant therapy was administered. GnRHa therapy in women with submucous leiomyomata and a myometrial thickness of less than 1 cm could effectively thicken the myometrium, allowing for the use of MEA.

Immunotherapies targeting interleukin (IL)-17 greatly improve plaque psoriasis. Most previous studies on IL-17 focused on the T-helper (Th)17 immune response, but investigation of the effects of IL-17A on psoriatic epidermal structure are limited. Using an in vitro 3-D human epidermis model, we investigated the effects of IL-17A and IL-17C on morphological changes and gene expression. IL-17A directly suppressed the formation of the granular layer, whereas IL-17C did not. IL-17A significantly downregulated the gene expression of profilaggrin (FLG), which is a major component of keratohyalin granules in the granular layer. Global gene expression analysis of this 3-D epidermis model showed that both IL-17A and IL-17C upregulated S100A7A and type 1 interferon-related genes including MX1, IFI44L, XAF1 and IFIT1. However, only IL-17A directly downregulated keratinocyte differentiation-related and cornified envelope-related genes including FLG, LOR, C1ORF68, LCE1E, LCE1B, KRT10, CST6 and RPTN. In conclusion, IL-17A, a systemic inflammatory cytokine, affected keratinization in our 3-D epidermis model. In contrast, IL-17C, a locally produced cytokine, did not have strong effects on keratinization. Targeting IL-17A does not only reduce inflammation but it may also directly affect epidermal differentiation in psoriasis.