•2-Fluorodeschloroketamine (2F-DCK) is a newly emerged psychoactive substance.•This ketamine analogue was identified in multiple poisoning patients.•2F-DCK was found to have similar metabolic and ...clinical profiles as ketamine.•Alarmingly, most patients had co-exposure to ketamine and multiple of its analogues.
New psychoactive substances (NPS) emerge continually, amongst which is a growing class of ketamine analogues with an arylcyclohexylamine backbone. Recently we reported a poisoning outbreak associated with 2-oxo-PCE (deschloro-N-ethyl-ketamine). The present report describes the emergence of another ketamine analogue, 2-fluorodeschloroketamine (2F-DCK). The compound was first detected in a patient’s urine, its identity confirmed by accurate mass analysis and comparison with reference standard. Four putative metabolites were identified, including nor-2F-DCK, dehydronor-2F-DCK (major metabolite) and two hydroxylated derivatives of nor-2F-DCK. Between January and July 2019, 20 cases of analytically confirmed 2F-DCK exposure were encountered. In 19 out of 20 cases, at least one more ketamine-type drug was detected concurrently with 2F-DCK, including ketamine (90%), deschloroketamine (DCK, 50%), 2-oxo-PCE (45%) and tiletamine (10%). In particular, six of the cases showed the presence of 4 ketamine-type drugs in the same urine sample. The clinical effects observed in patients exposed to 2F-DCK are predominantly neurological (impaired consciousness, agitation, abnormal behaviour) and cardiovascular (hypertension, tachycardia); five patients had loss of consciousness or convulsion. Management was mainly supportive; all patients recovered uneventfully. This is the first clinical case series involving 2F-DCK and frontline medical personnel are urged to be aware of this rapidly expanding class of NPS, in particular the co-ingestion of multiple ketamine analogues.
Acquired resistance to antiangiogenic drugs, such as sorafenib, is a major clinical problem. We studied development of a resistance to sorafenib in new preclinical models of human hepatocellular ...carcinoma (HCC) along with a strategy to delay such resistance—combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficient mice, and an orthotopic transplant in nude mice. The complementary DNA for the β-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allow recovery from toxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g., >42 days) at doses of 30 to 60 mg/kg. Transplantation of cell lines established from progressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance.
Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. ...Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.
Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to ...this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5AK50R. SNS01 exhibited significant antitumoral activity in both KAS-6/1 (95% inhibition; P < 0.05) and RPMI 8226 (59% inhibition; P < 0.05) multiple myeloma xenograft models following systemic administration. These results highlight the potential of using this approach as a new therapeutic strategy for multiple myeloma.
AIM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated ...in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinicopathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100p atients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469, P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P = 0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.
Amplification of 3q25-q26 was one of the most frequent chromosomal alterations in human ovarian carcinoma. A chromosome microdissection-hybrid selection method was applied to isolate transcribed ...sequences from a primary ovarian cancer containing high-copy-number amplification of 3q26 using 3q26 band-specific DNAs generated by chromosome microdissection. Using this method, we have isolated a novel candidate oncogene eIF-5A2 (eukaryotic initiation factor 5A2). eIF-5A2 shares 82% identity of amino acid sequence with eIF-5A including the minimum domain needed for eIF-5A maturation by hypusine modification at lysine-50 residue. Amplification and overexpression of eIF-5A2 was frequently detected in primary ovarian cancers and ovarian cancer cell lines. The proliferation-related function of eIF-5A supports that eIF-5A2 is a candidate oncogene related to the development of ovarian cancer.
To evaluate morphologic characteristics and cell viability of radiofrequency ablation zones in porcine liver.
Approval of the study protocol was obtained from the Ethics Committee on Use of Live ...Animals for Teaching and Research at University of Hong Kong. Internally cooled electrodes were used to produce 120 ablated zones ex vivo and 60 ablated zones in vivo with single electrodes (1-, 2-, and 3-cm exposed lengths) or clustered electrodes (1.0-, 2.0-, and 2.5-cm exposed lengths) at 4, 8, 12, and 16 minutes of ablation (ex vivo) and 8 and 12 minutes of ablation (in vivo). Morphologic measurements of each ablated zone were performed. Cell viability in each ablated zone was assessed qualitatively with histochemical staining and quantitatively with measurement of intracellular adenosine 5'-triphosphate (ATP) concentration.
Exposed length of electrode (coefficient = 0.79, standard error = 0.04, P < .001), duration of ablation (coefficient = 0.14, standard error = 0.01, P < .001), and clustered electrode design (coefficient = 1.21, standard error = 0.05, P < .001) were independent factors that affected minimal transverse diameter and volume of ablated zone in ex vivo study. Similar morphologic characteristics existed among ablated zones in in vivo study. Mean distance of ablation beyond the electrode tip remained constant (ex vivo, 1.0 cm +/- 0.08 standard deviation; in vivo, 0.5 cm +/- 0.05) regardless of different ablation conditions. Histochemical staining revealed no viable hepatocytes from center to margins of white zone in each ablated area. Mean intracellular ATP concentration in margins of white zone (9.5 x 10(-12) mol/microg DNA +/- 1.43) was lower than that in red zone (4088 x 10(-12) mol/microg DNA +/- 65.97, P < .001) and in adjacent normal liver (4528 x 10(-12) mol/microg DNA +/- 52.74, P < .001).
Distance of ablation beyond the tip of the electrode remained constant (ex vivo, 1.0 cm; in vivo, 0.5 cm) with different conditions of ablation. Complete and uniform cellular destruction was achieved in the white zone of ablated area.
High-level amplification of DNA sequence at 19q13.1 is one of the frequent genetic alterations in ovarian cancer. In an attempt to verify the minimal amplified region (MAR) at 19q13.1 and to identify ...the target oncogenes, 49 probes within a region from D19S425 to D19S907 ( approximately 19.5 cM) were used to survey the amplification status in four ovarian cancer cell lines that have been confirmed as containing amplification at 19q13.1. Two separated overlapping MARs, MAR1 (approximately 200 kb) and MAR2 (approximately 1.1 Mb), were identified at 19q13.1. Two candidate oncogenes, AKT2 and SEI-1, were identified in MAR2. Amplification and overexpression of these two genes in four ovarian cancer cell lines were confirmed by Southern and Northern blot analyses. The proliferation-related function of AKT2 and SEI-1 suggests that both genes are likely to be biological targets of an amplification event at 19q13.1 in ovarian cancer and to play important roles in ovarian tumorigenesis.
This study aims to clarify the role of heme oxygenase‐1 (HO‐1) in small‐for‐size liver transplantation. Transplantation was performed using 40% small‐for‐size or 100% whole liver grafts in rats. When ...no treatment was given, over‐expression of HO‐1 was detected predominantly in the small‐for‐size grafts at 6 hours after reperfusion as compared to whole grafts in both syngeneic and allogeneic combinations. Recombinant adenoviral vector encoding HO‐1 gene (AdHO‐1) administered to donors 48 hours before transplantation enhanced HO‐1 expression in both whole and small‐for‐size allografts, with a predominant augmentation in the small‐for‐size allografts, suggesting favorable conditions for the induction of HO‐1 expression in small‐for‐size allografts. In close relation to the expression level of HO‐1, AdHO‐1 significantly prolonged both whole and small‐for size allograft survivals, with a remarkable effect in the small‐for‐size allograft group. The prolongation of allograft survival was blocked by the HO‐1 inhibitor (zinc protoprophyrin IX). The non‐treated small‐for‐size allografts demonstrated impaired liver function during the early period after reperfusion, which could be improved by over‐expression of HO‐1, but reversed by the HO‐1 inhibitor. The markedly increase expression HO‐1 in small‐for‐size allografts was associated with lower levels of adhesion molecules and pro‐inflammatory cytokines in the early phase after reperfusion. These findings support the beneficial effects of HO‐1 on allograft survival. In conclusion, the ability of small‐for‐size grafts in the induction of HO‐1 expression might facilitate their own survival in liver transplantation. (Liver Transpl 2004;10:784–793.)
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