Enfortumab-vedotin use for urothelial carcinoma in two patients on hemodialysis.

Enfortumab vedotin (EV) is a novel treatment option for patients with advanced/metastatic urothelial carcinoma who have progressed after chemotherapy and immunotherapy. Two patients at two different New England tertiary cancer care centers were treated with EV while concurrently receiving hemodialysis (HD), where a complete response to EV in both patients was noted. The use of EV in patients requiring HD is extrapolated from the available pharmacokinetic and pharmacodynamic literature on monoclonal antibodies in patients requiring HD. There is a paucity of data for the use of antibody-drug conjugates like EV in patients needing dialysis.

Chlorogenic Acid Induced Neuroblastoma Cells Differentiation via the ACAT1-TPK1-PDH Pathway.

BACKGROUND: Chlorogenic acid (CHA) has been shown to have substantial biological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the pharmacological role of CHA in neuroblastoma has not yet been assessed. Neuroblastoma is a type of cancer that develops in undifferentiated sympathetic ganglion cells. This study aims to assess the antitumor activity of CHA against neuroblastoma and reveal its mechanism of action in cell differentiation. METHODS: Be(2)-M17 and SH-SY5Y neuroblastoma cells were used to confirm the differentiation phenotype. Subcutaneous and orthotopic xenograft mouse models were also used to evaluate the antitumor activity of CHA. Seahorse assays and metabolomic analyses were further performed to investigate the roles of CHA and its target ACAT1 in mitochondrial metabolism. RESULTS: CHA induced the differentiation of Be(2)-M17 and SH-SY5Y neuroblastoma cells in vivo and in vitro. The knockdown of mitochondrial ACAT1, which was inhibited by CHA, also resulted in differentiation characteristics in vivo and in vitro. A metabolomic analysis revealed that thiamine metabolism was involved in the differentiation of neuroblastoma cells. CONCLUSIONS: These results provide evidence that CHA shows good antitumor activity against neuroblastoma via the induction of differentiation, by which the ACAT1-TPK1-PDH pathway is involved. CHA is a potential drug candidate for neuroblastoma therapy.

[Intestinal absorption characteristics of Polygonum orientale extract in normal and isoproterenol-induced myocardial ischemia model rats via everted intestinal sac models].

The present study is to investigate the absorption characteristics of the main components in Polygonum orientale extract in normal and isoproterenol-induced myocardial ischemia model rats with everted intestinal sac models. Intestinal sac fluid samples were collected in different part of intestine(duodenum, jejunum, ileum, colon) at different time after administration of different concentration of P. orientale extract(5.0,10.0, 20.0 mg·mL~(-1)). An UPLC-TQD method was employed for the determination of six components including orientin, isoorientin, vitexin, protocatechuic acid, kaempferol-3-O-ß-D-glucoside and quercitrin in the intestinal sac samples. The absorption rate and cumulative absorption were calculated to analyze the intestinal absorption characteristics of six components in normal and myocardial ischemia model rats. The P-glycoprotein(P-gp) inhibitor was applied to investigate influence of intestinal absorption of six components in P. orientale extract. The results showed that the main absorption sites were concentrated on the duodenum at low concentration, while they were the colon at the medium concentration and the ileum at high concentration in control groups. In the condition of myocardial ischemia model, the main absorption sites focus on the ileum and jejunum at low concentration; the main absorption sites were in the ileum at the medium concentration and main absorption sites were the duodenum and ileum at high concentration. Compared with the normal group, the absorption rate and cumulative absorption of the six components significantly decreased in the model group. P-gp inhibitor markedly increased the absorption rate and cumulative absorption of six components in the model group, inferring that the 6 components may be the substrates of P-gp, and the mechanism needs further study. In this study, it is revealed that the six components of P. orientale extract can be absorbed into the intestinal sac, and it is an effective method to assess the intestinal absorption characteristics of P. orientale extract through everted intestinal sac model, providing data support for the clinical application and further development of P. orientale.

Th17 (IFNγ- IL17+) CD4+ T cells generated after burn injury may be a novel cellular mechanism for postburn immunosuppression.

BACKGROUND: The mechanism responsible for initiating and controlling the immunosuppressive response after burn injury remains unknown. Interleukin-17 (IL-17) secreting Th17 (interferon [IFN]γ IL17) cells are a novel subset of CD4 T cells associated with a weak, proinflammatory response that antagonizes the proinflammatory Th1 (IFNγ IL17) response. Given that transforming growth factor-ß and IL6 mediate Th17 cell development, we hypothesized that burn injury may generate Th17 cells that could mediate postburn immunosuppression. METHODS: After a 20% total body surface area burn in female C57BL/6 mice, wound-draining lymph nodes were harvested 3 days, 7 days, or 14 days after injury. CD4 T cells were enriched by magnetic selection, and flow cytometry was used to identify intracellular IL17 and IFNγ in CD3CD4 T cells. Additional purified CD3CD4 T cells were cultured with Th17 polarizing IL6 and transforming growth factor-ß for 4 days, and flow cytometry was again used to identify intracellular IL17 and IFNγ in CD4 T cells. RESULTS: The number and percentage of preformed Th17 cells was significantly greater in burn mice compared with sham at all time points. In addition, the ratio of Th17 cells to Th1 cells was always significantly higher in burn mice compared with sham. These differences were eliminated in Th17 polarizing conditions in vitro. CD4 T cells never generated both IL17 and IFNγ. CONCLUSION: These results demonstrate for the first time that Th17 cells (IFNγ IL17) are spontaneously generated after burn injury. Given that Th17 cells (IFNγ IL17) are antagonistic to Th1 (IFNγ IL17) cells, these results suggest a novel mechanism for initiating and controlling postburn immunosuppression that deserves further investigation.