Citations

Abstract Bile duct injury ( BDI ) during laparoscopic cholecystectomy remains a serious iatrogenic surgical complication. BDI most often occurs as a result of misidentification of the anatomy; however, clinical evidence on its precise mechanism and surgeons’ perceptions is scarce. Surgeons from Japan, Korea, Taiwan, and the USA, etc. ( n = 614) participated in a questionnaire regarding their BDI experience and near‐misses; and perceptions on landmarks, intraoperative findings, and surgical techniques. Respondents voted for a Delphi process and graded each item on a five‐point scale. The consensus was built when ≥80% of overall responses were 4 or 5. Response rates for the first‐ and second‐round Delphi were 60.6% and 74.9%, respectively. Misidentification of local anatomy accounted for 76.2% of BDI . Final consensus was reached on: (1) Effective retraction of the gallbladder, (2) Always obtaining critical view of safety, and (3) Avoiding excessive use of electrocautery/clipping as vital procedures; and (4) Calot's triangle area and (5) Critical view of safety as important landmarks. For (6) Impacted gallstone and (7) Severe fibrosis/scarring in Calot's triangle, bail‐out procedures may be indicated. A consensus was reached among expert surgeons on relevant landmarks and intraoperative findings and appropriate surgical techniques to avoid BDI .

Abstract Oncogenic role of p21-activated protein 4 (PAK4) in relation to cell growth and migration through various signalling cascades has been well studied in multiple cancer types. Such role might be contributed largely by cytoplasmic PAK4 as most of the known PAK4 signalling events occur in the cytoplasm. However, recent studies have demonstrated that PAK4 is capable of shuttling between nucleus and cytoplasm. The precise function of nuclear PAK4 (nPAK4) remains substantially unexplored. We have previously shown that PAK4 can act as a transcription factor. Herein, we aim to identify nPAK4-regulated genes by delineating the PAK4-binding landscape in ovarian cancer genome and mapping the PAK4 transcriptome in ovarian cancer cells. PAK4-enriched genomic regions were identified by chromatin immunoprecipitation with a PAK4 antibody followed by next-generation sequencing (ChIP-seq) in OVCAR3 cells. PAK4 transcriptome data was generated using RNA extracted from SKOV3 cells stably expressing PAK4 in the Affymetrix GeneChIP® Human Transcriptome Array 2.0 system. Gene lists generated from both ChIP-seq and microarray dataset were subjected to pathway enrichment analysis by Partek® PathwayTM. Among the 20 most significantly enriched pathways from microarray studies, several pathways in which PAK4 has no known reported function by far have been identified. Notably, DNA repair pathways that are known to influence drug chemosensitivity in ovarian cancer, such as the nucleotide excision repair (p=0.008), homologous recombination (p=0.012), mismatch repair (p=0.018) and DNA replication (p=0.018) pathways were significantly enriched. In concordance with the findings, the nucleotide excision repair pathway was also significantly enriched (p<0.006) in the gene list derived from promoter-restricted PAK4 binding sites in the ovarian cancer genome. Among the many candidates that were deregulated by PAK4, cyclin-dependent kinase 7 (CDK7), a core component in the CAK subcomplex crucial to nucleotide excision repair pathway, was further validated. The transcription start site (TSS) of cyclin-dependent kinase 7 (CDK7) was bound by PAK4. CDK7 mRNA expression was upregulated upon PAK4 overexpression. Quantitative-PCR showed downregulated CDK7 mRNA expression upon siRNA-mediated knockdown of PAK4 in OVCAR3 and TUOS3. This study points to the possible role of PAK4 in regulating gene transcription as PAK4 is mapped to several core promoter/TSS regions in the ovarian cancer genome. Our findings also shed light into the potential role of PAK4 in regulating drug chemosensitivity via its transcriptional control on genes implicated in DNA repair pathways. We postulate CDK7 as a direct transcriptional target of PAK4 and thereby contributes to chemoresistance in ovarian cancer cells. Citation Format: Ivy Tsz-Lo Wong, Oscar Gee-Wan Wong, Yiming Qin, Junwen Wang, Annie Nga-Yin Cheung. Genome-wide profiling of PAK4 DNA-binding sites and transcriptome reveals its potential transcriptional control on DNA repair-related genes in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2017-2419

AbstractBackgroundThis study compared prucalopride, a selective, prokinetic, 5‐HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high‐amplitude propagating contractions (HAPCs) in patients with chronic constipation.MethodsThis randomized, cross‐over, reader‐blinded study was conducted at a single site in the USA. The study was open to men and women aged 18–75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co‐primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.Key ResultsThirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12‐h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate.Conclusions & InferencesPrucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation.ClinicalTrials.gov number NCT01707667.

Summary Background and Purpose Sprawling ( Swl ) is a radiation‐induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1 ). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. Methods and Results To display the phenotype of Swl mutant mice, we examined the embryos of homozygous ( Swl/Swl ) and heterozygous ( Swl /+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl /+ mice. The Swl /+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/ + DRG neurons was revealed during E11.5–E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein‐driven nerve growth factor (NGF). Mitochondria, another dynein‐driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild‐type (WT) neurons. Nevertheless, the Swl , Loa, and Cra mutations did not affect homodimerization of DYNC1H1. Conclusion The Swl/Swl mutation of Dync1h1 gene led to embryonic mal‐development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein‐driven cargos and excessive apoptosis during mid‐ to late‐developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1.