Construction of BCDEF Core of Andilesin C.

A synthetic study toward the BCDEF core skeleton of andilesin C is presented. Key elements involved iron-promoted intramolecular perezone-type [5 + 2] cycloaddition to install the BCD ring system simultaneously in a one-step, copper-catalyzed intramolecular cyclopropanation followed by BiCl3-promoted retro-aldol reaction to construct ring E and a one-pot manipulation involving reduction, lactonization, and isomerization to introduce the lactone ring F. We finally synthesized the congested BCDEF ring system of andilesin C, featuring four quaternary centers and two tertiary centers, by following a strategy with a 15-pot reaction and 11 purification operations.

Medical student mistreatment by patients in the clinical environment: prevalence and management.

INTRODUCTION: Medical students rely on patients and their families as teachers during the learning journey. However, ill patients and their families may not welcome having students participating in their care, and anecdotal instances of abuse against clinical medical students are not uncommon. We aimed to determine the prevalence of medical student mistreatment by patients and their families and describe students' self-reported responses to such incidents. METHODS: An email link to an anonymised electronic survey form was sent to all clinical students (n = 184) at a Singapore medical school. The first part of the survey sought information on whether the student had previous experiences of mistreatment by patients and their families. If so, the frequency of mistreatment, circumstances when mistreatment happened and students' reactions were collected. In the second part, the students were asked if they knew how to handle such mistreatment incidents. RESULTS: There were a total of 91 respondents, 14.3% of whom had experienced mistreatment by patients and their families in our institution. One-third of the affected students felt fearful or humiliated. However, the majority chose to be passive by saying nothing or moving away. Less than half of the students knew how to handle such incidents or where to seek help. CONCLUSION: Incidents of mistreatment in our school are not uncommon. Our study revealed a need for more clarity and guidance about how students can manage such situations. This is an important topic because such mistreatment is known to inflict emotional disturbance in students. We proposed a workflow to help students deal with mistreatment.

Total synthesis of (±)-epi-stemodan-13α,17-diol.

Stemodan-13α,17-diol is a natural stemodane-type diterpenoid isolated from Stemodia chilensis. Herein we report the total synthesis of its epimer, stemodan-13ß,17-diol, by applying titanium-mediated polyene cyclization and iron-catalyzed [5 + 2] cycloaddition as the key transformations to expeditiously install the molecular scaffold.

Divergent Total Synthesis of Atisane-Type Diterpenoids.

Atisane-type diterpenoids are the principal constituent of tetracyclic C20 -diterpenoids, widely isolated from the plant kingdom with varying degrees of structural complexity and pharmacological activity. The tetracarbocyclic system with the unique bicyclo[2.2.2]octane skeleton of this natural product family has generated interest within the synthetic community. Divergent total synthesis is an effective tactic to synthesize several atisane-type diterpenoids using structural interconversion from a common intermediate. This account summarizes the divergent total synthesis of atisane-type diterpenoids.

The transcriptomic G1-G6 signature of hepatocellular carcinoma in an Asian population: Association of G3 with microvascular invasion.

In this study, a transcriptomic group classification based on a European population is tested on a Singapore cohort. The results highlight the genotype/phenotype correlation in a Southeast Asian population. The G1-G6 transcriptomic classification derived from hepatocellular carcinoma (HCC) resected from European patients, robustly reflected group-specific clinical/pathological features. We investigated the application of this molecular classification in Southeast Asian HCC patients.Gene expression analysis was carried out on HCC surgically resected in Singapore patients who were grouped into G1-G6 transcriptomic categories according to expression of 16 predictor genes (illustrated in Supplementary Table 1, http://links.lww.com/MD/B413 and Supplementary Fig. 1, http://links.lww.com/MD/B413) using quantitative reverse transcription polymerase chain reaction (RT-PCR). Univariate and multivariate polytomous logistic regression was used to investigate association between clinical variables and pooled transcriptomic classes G12, G3, and G456.HCC from Singapore (n = 82) were distributed (%) into G1 (13.4), G2 (24.4), G3 (15.9), G4 (24.4), G5 (14.6), and G6 (7.3) subgroups. Compared to the European data, the Singapore samples were relatively enriched in G1-G3 versus G4-G6 tumors (53.7% vs 46.3%) reflecting the higher proportion of hepatitis B virus (HBV) patients in Singapore versus Europe samples (43% vs 30%). Pooled classes were defined as G12, G3, and G456. G12 was associated with higher alpha-fetoprotein (AFP) concentrations (OR = 1.69, 95% CI: 1.30-2.20; P < 0.0001) and G3 with microvascular invasion (OR = 4.91, 95% CI: 1.06-24.8; P = 0.047).The European and Singapore cohorts were generally similar relative to associations between transcriptomic groups and clinical features. This lends credence to the G1-G6 transcriptomic classifications being applicable regardless of the ethnic origin of HCC patients. The G3 group was associated with microvascular invasion and holds potential for investigation into the underlying mechanisms and selection for therapeutic clinical trials.

Total Synthesis of Atisane-Type Diterpenoids: Application of Diels-Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones.

Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (±)-crotobarin, crotogoudin, atisane-3ß,16α-diol, and 16S,17-dihydroxy-atisan-3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl3-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone-opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different skeleton-rearranged natural product-like compounds.

A quantitative chemical proteomics approach to profile the specific cellular targets of andrographolide, a promising anticancer agent that suppresses tumor metastasis.

Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drug-binding sites of two protein targets, NF-κB and actin.

Survival and pattern of tumor progression with yttrium-90 microsphere radioembolization in predominantly hepatitis B Asian patients with hepatocellular carcinoma.

PURPOSE: Intra-arterial yttrium-90 ((90)Y) microsphere radioembolization (RE) is an emerging treatment option with good outcomes reported predominantly in hepatitis C Western populations with hepatocellular carcinoma (HCC). We report outcomes in predominantly hepatitis B Asian patients treated with (90)Y-RE focusing on overall survival (OS), time to progression (TTP), tumor response, pattern of tumor recurrence and adverse events. Prognostic factors for survival were also identified. METHODS: A retrospective cohort study was conducted in a single tertiary institution. All non-trial patients treated with (90)Y-RE at our institution from 1 January 2008 to 30 June 2012 were included. RESULTS: Data from 103 consecutive patients were analyzed. The majority of patients were Child-Pugh class A (59.2 %) and Barcelona Clinic Liver Cancer (BCLC) stage C (68.9 %). Median OS was 14.4 months (95 % CI 11.0-22.2), which varied by disease stage: Child-Pugh A, 21.7 months; Child-Pugh B, 7.1 months; BCLC B, 23.8 months; BCLC C, 11.8 months. Response and disease control rates by RECIST 1.1 were 21.2 and 59.6 %, respectively, while disease control for index lesions treated with (90)Y-RE was 100 %. Development of new intrahepatic lesions was the main reason for eventual disease progression. Median overall TTP was 5.3 months (95 % CI 4.1-10.0). Pretreatment vascular invasion, low serum albumin and elevated total bilirubin levels predicted poorer survival. CONCLUSIONS: Survival outcomes in hepatitis B Asian patients treated with (90)Y-RE for HCC are comparable to hepatitis C Western populations. While disease control for lesions treated with (90)Y-RE is excellent, the development of new lesions suggests a role for concomitant systemic therapy.

A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects.

The segmental premature aging disease Hutchinson-Gilford Progeria syndrome (HGPS) is caused by a truncated and farnesylated form of Lamin A called progerin. HGPS affects mesenchymal lineages, including the skeletal system, dermis, and vascular smooth muscle (VSMC). To understand the underlying molecular pathology of HGPS, we derived induced pluripotent stem cells (iPSCs) from HGPS dermal fibroblasts. The iPSCs were differentiated into neural progenitors, endothelial cells, fibroblasts, VSMCs, and mesenchymal stem cells (MSCs). Progerin levels were highest in MSCs, VSMCs, and fibroblasts, in that order, with these lineages displaying increased DNA damage, nuclear abnormalities, and HGPS-VSMC accumulating numerous calponin-staining inclusion bodies. Both HGPS-MSC and -VSMC viability was compromised by stress and hypoxia in vitro and in vivo (MSC). Because MSCs reside in low oxygen niches in vivo, we propose that, in HGPS, this causes additional depletion of the MSC pool responsible for replacing differentiated cells lost to progerin toxicity.