SR-16234, a Novel Selective Estrogen Receptor Modulator for Pain Symptoms with Endometriosis: An Open-label Clinical Trial

[Background]SR-16234 is a selective estrogen receptor modulator (SERM) structurally different from approved SERM and has been reported to have estrogen receptor (ER) α antagonistic activity and strong affinity with a weak partial agonistic activity to ERβ receptor. SR-16234 showed strong inhibitory effects on transplanted endometrial cysts in the endometriosis model of rat and mouse. In this clinical trial, efficacy and safety of SR-16234 have been evaluated in endometriosis patients. [Methods]This trial was an open-label single arm clinical trial. Ten patients with dysmenorrhea and pelvic pain associated with endometriosis and adenomyosis were enrolled in this trial, and received 40 mg of SR-16234 once daily for 12 weeks. The primary endpoint was the visual analogue scale (VAS) of pelvic pain. The secondary endpoints included dysmenorrhea score, pelvic pain score, objective observations (stiffness of Douglas’ pouch, limitation of uterine movement, size of ovarian chocolate cysts, thickness of endometrium, and serum CA125 concentration) and safety. [Results]After oral administration of SR-16234 40 mg for 12 weeks, there were statistically significant decreases in pelvic pain VAS, total pelvic pain score, total dysmenorrhea score, stiffness of Douglas’ pouch, limitation of uterine movement compared with the baseline values. [Conclusion]The present trial suggested that a selective estrogen receptor modulator could be used for treatment of pain associated with endometriosis for the first time

DCP Production Mechanism in HCC

Background and Aim: Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. Methods: Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. Results: The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. Conclusions: Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells

Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher

Prostaglandin (PG)

Analysis of Medaka sox9 Orthologue Reveals a Conserved Role in Germ Cell Maintenance

The sex determining gene is divergent among different animal species. However, sox9 is up-regulated in the male gonads in a number of species in which it is the essential regulator of testis determination. It is therefore often discussed that the sex determining gene-sox9 axis functions in several vertebrates. In our current study, we show that sox9b in the medaka (Oryzias latipes) is one of the orthologues of mammalian Sox9 at syntenic and expression levels. Medaka sox9b affects the organization of extracellular matrices, which represents a conserved role of sox9, but does not directly regulate testis determination. We made this determination via gene expression and phenotype analyses of medaka with different copy numbers of sox9b. Sox9b is involved in promoting cellular associations and is indispensible for the proper proliferation and survival of germ cells in both female and male medaka gonads. Medaka mutants that lack sox9b function exhibit a seemingly paradoxical phenotype of sex reversal to male. This is explained by a reduction in the germ cell number associated with aberrant extracellular matrices. Together with its identified roles in other vertebrate gonads, a testis-determining role for Sox9 in mammals is likely to have been neofunctionalized and appended to its conserved role in germ cell maintenance

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

メンタルヘルス不調者へのセルフマネジメントプログラムの効果に関する研究

本研究の目的は、心療内科に通院するメンタルへルス不調者に、セルフマネジメントプログラムを用いた介入を行い、セルフマネジメント力を高める効果があるかを実証的に検証することである。方法は、「治療のみの変化」「介入による変化」「介入後の持続効果」を比較した群間比較研究である。対象は、うつ・不安障害などで心療内科に通院している患者10 名で、1 回2 時間、3 回からなるプログラムに参加し、その前後と1ヶ月後に質問紙調査を実施した。調査内容は、自己効力感、自己抑制型行動特性、問題解決型行動特性、抑うつ度とした。プログラム内容は、メンタルヘルス不調の心理教育、自己理解、イメージセラピー、エンカウンターグループで構成した。調査の結果、介入前後の比較において、自己抑制型行動特性、問題解決型行動特性に有意差は認められなかった。自己効力感（p＜0.5）、抑うつ（p＜0.1〉で有意な改善が認められた。また、自己効力感の下位因子であるネガティブ因子に有意傾向が認められた（p＜1）。これらの効果は介入1ヵ月後まで維持されていた。さらに、治療のみの期間における尺度の変化は認められなかったことから、介入前後の変化は介入による効果の可能性が高い。セルフマネジメントプログラム実施により、抑うつ気分の改善と自己効力認知の改善が認められ、セルフマネジメントに向けた効果が確認された。自己抑制型行動特性と問題解決型行動特性に変化は認められず、行動変容に至る期間を加味した長期的なフォローアップが必要である。一部の参加者の記述から気分と認知にセルフマネジメントに向けた肯定的な変化があり、統計的分析結果が参加者の主観からも裏付けられた。The purpose of this study is to empirically indicate whether intervention of patientswith mental health disorders, who regularly see doctors, with a self-management program is effective in improving their self-management capabilities.The method used was intergroup research comparing “change only by treatment”,“change by intervention”and“continuing effects after intervention”.Subjects were10patients who regularly saw psychosomatic doctors with the symptoms of depression,anxiety disorder, etc. The program was comprised of three2-hour sessions, and a questionnaire survey was taken before and after those sessions plus one month later.Survey contents included a feeling of self-efficacy,self-restraint behavioral characteristics, problem solving behavioral characteristics,and degree of depression.The program was comprised of psychoeducation of mental health disorders,self-understanding,image therapy, and encounter groups.The results did not show any significance in self-restraint behavioral characteristics or problem solving behavioral characteristics when comparing the before and after intervention, but significant improvement was confirmed on self-efficacy（p<0.5）and depression（p<0.1）.Additionally, a negativefactor, which is the hypostatic factor of self-efficacy, showed a tendency of marginal significance（p<1）.These effects remained1month after intervention. Since the scale didn’t change in the period of only receiving doctor’s treatment, it is highly possible that the intervention was responsible for the effective changes.Improvement in depression and recognition of self-efficacy from the intervention was recognized and the researchers confirmed its effect toward patients’self-management. Some of the written answers from participants stated they had positive changes in their mood and cognition,which confirmed the results of the statistical analysis from the participants’subjective viewpoint

Both type I and II germ cells are eliminated by apoptosis in the <i>sox9b</i> mutant medaka.

<p>(A–H) Ventral views of 10 dph medaka gonads immunostained with anti-OLVAS (germ cell marker, purple) and anti-cleaved caspase 3 (blue). Merged images (A, C, E and G) and cleaved caspase 3 signals (B, D, F and H) are shown. Low levels of germ cell apoptosis only were evident in wild-type XY and XX medaka at 10 dph. However, type I and type II germ cells (type I, arrows; type II, a bracket) were eliminated by apoptosis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029982#pone-0029982-t002" target="_blank">Table 2</a>) in the homozygous (E and F) and heterozygous (G and H) mutants. Scale bar, 50 µm.</p

Mutant <i>sox9b</i>-expressing cells demonstrate a reduced cellular association.

<p>(A–F) The morphologies of wild-type (A and B) and mutant (C–F) medaka gonads. Ventral views of XX gonads at 8 dpf (A–D) and 10 dph (E and F) are shown. Green, <i>sox9b</i>-expressing cells were immunostained with anti-GFP; red, germ cells were stained with anti-OLVAS; blue, nuclei were counterstained with DAPI. Medaka germ cells are completely surrounded by <i>sox9b</i>-expressing supporting cells and demonstrate a smooth surface (B), whilst mutant <i>sox9b</i>-expressing cells have cytoplasmic protrusions (D, arrows). Some isolated germ cells were not completely surrounded by <i>sox9b</i>-expressing cells in the mutants (F, asterisks). This was not seen in wild-type animals. (G–K) Representative images of somatic chimera. Green, donor-derived <i>sox9b</i>-EGFP expressing cells; red, host <i>sox9b</i>-DsRed positive cells; blue, germ cells stained with anti-OLVAS. (L) Calculated ratio of donor-derived <i>sox9b</i>-EGFP expressing cells associated with germ cells (black) to those not associated with germ cells (white). Scale bar, 50 µm.</p