Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK

Background Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy. Method We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer. Result We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo. Conclusion Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer

Phosphorylation of nucleophosmin at threonine 234/237 is associated with HCC metastasis

Hepatocellular carcinoma (HCC) is frequently complicated by the occurrence of intrahepatic and extrahepatic metastases, leading to poor prognosis. To improve the prognosis for HCC patients, there is an urgent need to understand the molecular mechanisms of metastasis in HCC. Since protein Serine/Threonine phosphorylation emerges to be an important posttranslational modification critical in signaling process associated with cell proliferation, survival and metastasis, we employed a pair of primary tumor-derived and corresponding lung-metastatic counterparts (PLC/PRF/5-PT and PLC/PRF/5-LM) and aimed to identify these changes using CelluSpotTM Serine/Threonine kinase peptide array. Upon analysis, we found phosphorylated level of nucleophosmin (NPM) at Threonine 234/237 (p-NPM-Thr234/237) had remarkably high level in metastatic HCC cells (PLC-LM) than the corresponding primary HCC cell line (PLC-PT). Similar observation was observed in another match primary and their metastatic counterparts (MHCC-97L and MHCC-97H). By immunohistochemical staining, p-NPM-Thr234/237 was consistently found to be preferentially expressed in metastatic HCCs when compared with primary HCC in 28 HCC cases (p 234/237 expressing cells (Hep3B and Huh7) using a lentiviral based approach, we demonstrated that p-NPM-Thr234/237 is critical in invasion and migration of HCC cells, and this effect was mediated by cyclin-dependent kinase 1 (CDK1). Wild-type NPM was found to physically interact with a metastatic gene, ROCK2, and defective in Thr234/237 phosphorylation decreased its binding affinity, resulting in decrease in ROCK2 mediated signaling pathway. Identification of CDK1/p-NPM/ROCK2 signaling pathway provides a novel target for molecular therapy against HCC metastasis

Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling

SummaryLike normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC

Application of Prenatal Whole Exome Sequencing for Structural Congenital Anomalies—Experience from a Local Prenatal Diagnostic Laboratory

Fetal structural congenital abnormalities (SCAs) complicate 2–3% of all pregnancies. Whole-exome sequencing (WES) has been increasingly adopted prenatally when karyotyping and chromosomal microarray do not yield a diagnosis. This is a retrospective cohort study of 104 fetuses with SCAs identified on antenatal ultrasound in Hong Kong, where whole exome sequencing is performed. Molecular diagnosis was obtained in 25 of the 104 fetuses (24%). The highest diagnostic rate was found in fetuses with multiple SCAs (29.2%), particularly those with involvement of the cardiac and musculoskeletal systems. Variants of uncertain significance were detected in 8 out of the 104 fetuses (7.7%). Our study shows the utility of WES in the prenatal setting, and the extended use of the technology would be recommended in addition to conventional genetic workup

The use of bubble charts in analyzing the global second-stage cesarean delivery rates: a systematic reviewAJOG Global Reports at a Glance

OBJECTIVE: This study aimed to systematically review the worldwide second-stage cesarean delivery rate concerning pre–second-stage cesarean delivery and assisted vaginal birth rates. DATA SOURCES: PubMed, Medline Ovid, EBSCOhost, Embase, Scopus, and Google Scholar were queried from inception to February 2023, with the following terms: “full dilatation,” “second stage,” and “cesarean,” with their word variations. Furthermore, an additional cohort of 353,434 cases from our recently published study was included. STUDY ELIGIBILITY CRITERIA: Only original studies that provided sufficient information on the number of pre–second-stage cesarean deliveries, second-stage cesarean deliveries, and vaginal births were included for the calculation of different modes of delivery. Systemic reviews, meta-analyses, or case reports were excluded. METHODS: Study identification and data extraction were independently performed by 2 authors. Selected studies were categorized on the basis of parity, study period, and geographic regions for comparison. RESULTS: A total of 25 studies were included. The overall pre–second-stage cesarean delivery rate, the second-stage cesarean delivery rate, and the second-stage cesarean delivery–to–assisted vaginal birth ratio were 17.94%, 2.65%, and 0.19, respectively. Only 5 studies described singleton, term, cephalic presenting pregnancies of nulliparous women, and their second-stage cesarean delivery rates were significantly higher than those studies with cohorts of all parity groups (4.50% vs 0.83%; P<.05). In addition, the second-stage cesarean delivery rate showed a secular increase across 2009 (0.70% vs 1.05%; P<.05). Moreover, it was the highest among African studies (5.14%) but the lowest among studies from East Asia and South Asia (0.94%). The distributions of second-stage cesarean delivery rates of individual studies and subgroups were shown with that of pre–second-stage cesarean delivery and assisted vaginal birth using the bubble chart. CONCLUSION: The overall worldwide pre–second-stage cesarean delivery rate was 17.94%, the second-stage cesarean delivery rate was 2.65%, and the second-stage cesarean delivery–to–assisted vaginal birth ratio was 0.19. The African studies had the highest second-stage cesarean delivery rate (5.14%) and second-stage cesarean delivery–to–assisted vaginal birth ratio (1.88), whereas the studies from East Asia and South Asia were opposite (0.94% and 0.11, respectively)