Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine, 8-Oxo-erythraline, and Erythraline.

A general synthetic methodology toward the erythrina alkaloids has been developed. Inspired by a proposed biosynthetic mechanism, the medium-sized chiral biaryl lactam was asymmetrically transformed into the common core A-D rings by a stereospecific singlet oxygen oxidation of the phenol moiety, followed by a transannular aza-Michael reaction to the dienone functionality. The late-stage manipulation of the oxidation and oxygenation states of the functional groups on the peripheral moieties enabled the flexible syntheses of the erythrina alkaloids.

Diffuse neonatal hemangiomatosis in a very low-birthweight infant treated with erythropoietin.

Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemannigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long-term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment.

Burnout and Turnover Intention in Critical Care Professionals During the COVID-19 Pandemic in Japan: A Cross-sectional Survey.

Rationale: The prevalence of burnout among critical care professionals during the coronavirus disease (COVID-19) pandemic varies in different countries. Objectives: To investigate the prevalence of burnout and turnover intention in Japanese critical care professionals in March 2021. Methods: This cross-sectional study used a web-based survey of Japanese critical care professionals working in 15 intensive care units in 15 prefectures. Burnout was measured using the Mini Z 2.0 Survey. Intention to leave (turnover intention) was assessed by survey. Resilience was measured using the Brief Resilience Scale (Japanese version). Demographics and personal and workplace characteristics were also collected. Results: Of 1,205 critical care professionals approached, 936 (77.6%) completed the survey. Among these, 24.3%, 20.6%, and 14.2% reported symptoms of burnout, depression, and anxiety, respectively. A total of 157 respondents (16.8%) reported turnover intention. On multivariate analysis, higher resilience scores (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.84-0.95; and OR, 0.94; 95% CI, 0.91-0.96) and perceived support from the hospital (OR, 0.64; 95% CI, 0.44-0.93; and OR, 0.54; 95% CI, 0.40-0.73) were associated with a lower odds of burnout and turnover intention, respectively. Conclusions: Approximately 24% and 17% of the Japanese critical care professionals surveyed had symptoms of burnout and turnover intention from critical care, respectively, during the COVID-19 pandemic. Such professionals require organizational support to cultivate both individual and organizational resilience to reduce burnout and turnover intention.

Development of a Detection System for ESR1 Mutations in Circulating Tumour DNA Using PNA-LNA-Mediated PCR Clamping.

Although circulating tumour DNA (ctDNA)-based next-generation sequencing (NGS) is a less invasive method for assessing ESR1 mutations that are essential mechanisms of endocrine therapy resistance in patients with oestrogen receptor-positive breast cancer, adequate amounts of DNA are required to assess polyclonal ESR1 mutations. By combining a peptide nucleic acid and locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamping assay, we have developed a novel detection system to screen for polyclonal ESR1 mutations in ctDNA. A validation assay was prospectively performed on clinical samples and compared with the NGS results. The PNA-LNA PCR clamp assay was validated using six and four blood samples in which ESR1 mutations were detected by NGS and no mutations were detected, respectively. The PNA-LNA assay results were comparable with those of NGS. We prospectively assessed the concordance between the PNA-LNA PCR clamp method and NGS. Using the PNA-LNA PCR clamp method, ESR1 mutations were detected in 5 out of 18 samples, including those in which mutations were not detected by NGS due to small amounts of ctDNA. The PNA-LNA PCR clamping method is a highly sensitive and minimally invasive assay for polyclonal ESR1 mutation detection in the ctDNA of patients with breast cancer.

TERT promoter hotspot mutations in breast cancer.

BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations have been discovered in solid and hematological malignancies, where they reflect TERT activation and cell-cycle progression. In melanoma, glioma, and thyroid cancers, TERT promoter mutations are associated with a poor prognosis. However, no studies have evaluated the prevalence and prognostic significance of TERT promoter mutations in breast cancer. METHODS: We analyzed TERT promoter hotspot mutations (C228T and C250T) using direct sequencing of DNA from 319 tumor tissues. We also collected clinical data from cases that were positive for TERT promoter mutations. RESULTS: We detected TERT promoter mutations in three (0.9%) of the 319 cases. Two patients had hormone receptor-positive and human epidermal growth factor receptor 2-negative cancer, while the third patient had triple-negative cancer. All three patients had initially been diagnosed with operable breast cancer and undergone surgical treatment. The relapse-free survivals of these patients were 83, 226, and 270 months, respectively. The mutations were C250T in the triple-negative cancer case and C228T in the remaining two cases. CONCLUSION: Given the rarity of TERT promoter mutations, further studies are needed to confirm their prognostic significance in breast cancer cases.