Morphological analysis and morphometry of the occipital condyle and its relationship to the foramen magnum, jugular foramen, and hypoglossal canal: implications for craniovertebral junction surgery.

Anatomical knowledge of the occipital condyle (OC) and its relationships to surrounding structures is important for avoiding injury during craniovertebral junction (CVJ) surgeries. This study was conducted to evaluate the morphology and morphometry of OC and its relationship to foramen magnum, jugular foramen (JF), and hypoglossal canal (HC). Morphometric parameters including length, width, height, and distances from the OC to surrounding structures were measured. The oval-like condyle was the most common OC shape, representing for 33.0% of all samples. The mean length, width and height of OC were 21.3±2.4, 10.5±1.4, and 7.4±1.1 mm, respectively. Moreover, OC was classified into three types based on its length. The most common OC length in both sexes was moderate length or type II (62.5%). The mean distance between anterior tips and posterior tips of OC to basion, and opisthion were 11.5±1.4, 39.1±3.3, 25.2±2.2, and 27.4±2.7 mm, respectively. The location of intracranial orifice of HC was commonly found related to middle 1/3 of OC in 45.0%. JF was related to the anterior 2/3 of OC in 81.0%, the anterior 1/3 of OC in 12.5%, and the entire OC length in 6.5%. These morphological analysis and morphometric data should be taken into consideration before performing surgical operation to avoid CVJ instability and neurovascular structure injury.

CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS.

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to Opisthorchis viverrini (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-ß was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases.

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells.

PURPOSE: The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. MATERIALS AND METHODS: ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. RESULTS: CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. CONCLUSION: Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.

Late administration of caffeine affects cardiac maturation in chick embryos: a combined two and threedimensional morphogenetic and gene analyses

Cardiac malformations are very prevalent and can be caused both by defective genes and envi-ronmental teratogens. Among the latter, caffeine causes malformations when exposed during early cardiac development, whereas its later effects are still unclear. We exposed three-day incubated (D3) chick embryos to 2 mg caffeine and analyzed them at D5, D7 and D9. The embryos were serially sec-tioned and analyzed two-dimensionally. Alternatively, the sections of D9 embryos were reconstructed three-dimensionally using Amira® software and analyzed volumetrically. The expres-sion of genes involved in endothelial-mesenchymal transformation (EMT) was studied by real-time PCR. Interestingly, caffeine treatment at D3 em-bryos did not induce cardiac malformations, but did delay growth, in particular that of the ventricles and ventricular trabeculae. Furthermore, it affected EMT in the endocardial cushion and atrioventricu-lar valves. Gene-expression analysis revealed that caffeine had a progressively deleterious effect on the expressions of GATA4, MMP2, SNAIL1, TWIST1, and VIMENTIN. The effect of late caf-feine administration on the chicken embryos would provide suggestive evident towards a possible heart developmental defect in humans, particularly heavy caffeine consumers during pregnancy

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Co-culture of males with late premolt to early postmolt female giant freshwater prawns, Macrobrachium rosenbergii resulted in greater abundances of insulin-like androgenic gland hormone and gonad maturation in male prawns as a result of olfactory receptors.

Insulin-like androgenic gland hormone (IAG) controls development of primary and secondary male sex-characteristics in decapod crustaceans. In male giant freshwater prawns, Macrobrachium rosenbergii, the IAG concentration correlates with male reproductive status and aggressiveness. When female prawns are co-cultured with males this can result in male size variations while this variation does not occur when males are cultured in monosex conditions. It was hypothesized that pheromone-like factors from female prawns may affect the abundance of IAG mRNA and protein in co-cultured males which would affect the pattern of sexual maturation of these males. In the present study, late premolt to postmolt females co-cultured with males for 7 days had a greater abundance of MrIAG mRNA transcript in all male phenotypes as well as for the gonad-somatic indexes (GSI). The abundance of MrIAG mRNA gradually increased from days 1 to 7 and using Western blot procedures MrIAG protein also increased in a similar pattern. Furthermore, with use of BrdU labeling, there was an increased cell proliferation in the spermatogenic zone of testicular tubules and in the spermatic duct epithelium during the 1 to 7 day co-culture period when there were increases in MrIAG mRNA and protein. In contrast, these effects were negated if short lateral antennules of males were ablated. Thus, results of the present study provide evidence that there might be female-molting factors which function as important regulators of androgenic gland function and gonadal maturation that were perceived by males via their short lateral antennules which are the olfactory organs.