Synthesis Optimization of L-Aspartic acid β-hydroxamate by a novel Enzyme, β-Aspartyl-γ-glutamyl transferase

L-Aspartic acid β-hydroxamate or L-β-Aspartyl hydroxamate (BAH), water soluble- chemical compound currently obtains popularity due to its role in several important biochemical processes and to its bioactivities. The information regarding synthesis process of BAH is not available yet. Novel enzyme, β-aspartyl-γ-glutamyl transferase from Pseudomonas syringae can catalyze the transfer reaction of β-aspartyl moieties from β-aspartyl compounds to water or to hydroxylamine. In this study we describe the synthesis optimization of BAH using this novel enzyme. We prepared the L-β-aspartyl hydroxamate using L- asparagine as a donor substrate and hydroxylammonium chloride as an acceptor substrate. The effects of temperature, pH, concentrations of substrate donor and acceptor were investigated. Spectrophotometry and HPLC analyses were performed to determine the reaction products. The optimum synthesis reaction was observed in 60˚C. BAH synthesis was optimum at pH 6. The concentrations of donor and acceptor substrates affected the BAH production and the best concentrations of both substrates were 80 mM and 40 mM, respectively. The BAH production of 0.106 mM has been obtained under the optimized condition and it is approximately two-times higher than 0.047 mM produced under in standard reaction. In conclusion, biosynthesis of L-β-aspartyl hydroxamate using a novel enzyme, β- aspartyl-γ-glutamyl transferase from Pseudomonas syringae was successfully performed for the first time. Under the optimized conditions, two times higher L-β-aspartyl hydroxamate production was obtained

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy

Serum Level of Soluble CD163 May Be a Predictive Marker of the Effectiveness of Nivolumab in Patients With Advanced Cutaneous Melanoma

Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy

The Pattern of Sexual Interest of Female-to-Male Transsexual Persons With Gender Identity Disorder Does Not Resemble That of Biological Men: An Eye-Tracking Study

Introduction: Very little has been elucidated about sexual interest in female-to-male (FtM) transsexual persons. Aims: To investigate the sexual interest of FtM transsexual persons vs that of men using an eye-tracking system. Methods: The study included 15 men and 13 FtM transsexual subjects who viewed three sexual videos (clip 1: sexy clothed young woman kissing the region of the male genitals covered by underwear; clip 2: naked actor and actress kissing and touching each other; and clip 3: heterosexual intercourse between a naked actor and actress) in which several regions were designated for eye-gaze analysis in each frame. The designation of each region was not visible to the participants. Main Outcome Measures: Visual attention was measured across each designated region according to gaze duration. Results: For clip 1, there was a statistically significant sex difference in the viewing pattern between men and FtM transsexual subjects. Longest gaze time was for the eyes of the actress in men, whereas it was for non-human regions in FtM transsexual subjects. For clip 2, there also was a statistically significant sex difference. Longest gaze time was for the face of the actress in men, whereas it was for non-human regions in FtM transsexual subjects, and there was a significant difference between regions with longest gaze time. The most apparent difference was in the gaze time for the body of the actor: the percentage of time spent gazing at the body of the actor was 8.35% in FtM transsexual subjects, whereas it was only 0.03% in men. For clip 3, there were no statistically significant differences in viewing patterns between men and FtM transsexual subjects, although longest gaze time was for the face of the actress in men, whereas it was for non-human regions in FtM transsexual subjects. Conclusion: We suggest that the characteristics of sexual interest of FtM transsexual persons are not the same as those of biological men. Tsujimura A, Kiuchi H, Soda T, et al. The Pattern of Sexual Interest of Female-to-Male Transsexual Persons With Gender Identity Disorder Does Not Resemble That of Biological Men: An Eye-Tracking Study. Sex Med 2017;5:e169–e174

Ovarian Endometrioid and Clear Cell Carcinomas with Low Prevalence of Microsatellite Instability: A Unique Subset of Ovarian Carcinomas Could Benefit from Combination Therapy with Immune Checkpoint Inhibitors and Other Anticancer Agents

Ovarian cancer has the highest mortality rate among all gynecological malignancies; therefore, a novel treatment strategy is needed urgently. Utilizing immune checkpoint inhibitors has been considered for microsatellite instability (MSI)-high (MSI-H) tumors. However, the prevalence of MSI-H tumors in ovarian endometrioid and clear cell carcinomas remains unclear. Here, polymerase chain reaction was used to analyze 91 cases of ovarian endometrioid and clear cell carcinomas for the MSI status and the relationship between MSI-H, immune checkpoint molecules, and clinicopathological factors (including patient survival). Only 5 of 91 (5%) cases were MSI-H endometrioid carcinomas. In these cases, CD-8 expression was significantly higher (p = 0.026), confirming an enhanced immune response. From the survival curve, no statistical correlations were found between the MSI-H group and the microsatellite stable (MSS) group; however, the MSS group trended towards better progression-free survival than the MSI-H group (p = 0.056). Patients with PD-L1 expression had shorter overall survival than those without (p = 0.022). Thus, MSI-H is a rare event and not a favorable prognostic factor in ovarian endometrioid and clear cell carcinomas. Thus, to improve the prognosis of ovarian endometrioid carcinoma and clear cell carcinomas, a combination therapy of immune checkpoint inhibitors and other molecular targeted therapies may be required

Clinical utility of next‐generation sequencing‐based panel testing under the universal health‐care system in japan: A retrospective analysis at a single university hospital

金沢大学医薬保健研究域医学系Next‐generation sequencing (NGS) assay is part of routine care in Japan owing to its reimbursement by Japan’s universal health‐care system; however, reimbursement is limited to patients who finished standard treatment. We retrospectively investigated 221 patients who underwent Foundation One CDX (F1CDx) at our hospital. Every F1CDx result was assessed at the molecular tumor board (MTB) for treatment recommendation. Based on patients’ preferences, presumed germline findings were also assessed at the MTB and disclosed at the clinic. In total, 204 patients underwent F1CDx and 195 patients completed the analysis; however, 13.8% of them could not re-ceive the report due to disease progression. Among 168 patients who received the results, 41.6% had at least one actionable alteration, and 3.6% received genomically matched treatment. Presumed germline findings were nominated in 24 patients, and 16.7% of them contacted a geneticist counse-lor. The NGS assay should be performed earlier in the clinical course to maximize the clinical ben-efit. Broader reimbursement for the NGS assay would enhance the delivery of precision oncology to patients. Access to clinical trials affects the number of patients who benefit from NGS. Addition-ally, the disclosure of presumed germline findings is feasible in clinical practice. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Clinical utility of next‐generation sequencing‐based panel testing under the universal health‐care system in japan: A retrospective analysis at a single university hospital

Next-generation sequencing (NGS) assay is part of routine care in Japan owing to its reimbursement by Japan’s universal health-care system; however, reimbursement is limited to patients who finished standard treatment. We retrospectively investigated 221 patients who underwent Foundation One CDX (F1CDx) at our hospital. Every F1CDx result was assessed at the molecular tumor board (MTB) for treatment recommendation. Based on patients’ preferences, presumed germline findings were also assessed at the MTB and disclosed at the clinic. In total, 204 patients underwent F1CDx and 195 patients completed the analysis; however, 13.8% of them could not receive the report due to disease progression. Among 168 patients who received the results, 41.6% had at least one actionable alteration, and 3.6% received genomically matched treatment. Presumed germline findings were nominated in 24 patients, and 16.7% of them contacted a geneticist counselor. The NGS assay should be performed earlier in the clinical course to maximize the clinical benefit. Broader reimbursement for the NGS assay would enhance the delivery of precision oncology to patients. Access to clinical trials affects the number of patients who benefit from NGS. Additionally, the disclosure of presumed germline findings is feasible in clinical practice