Camrelizumab plus apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma (CAP 02): a single-arm, open-label, phase 2 trial.

BACKGROUND: Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma. METHODS: This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863. FINDINGS: Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred. INTERPRETATION: Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing. FUNDING: Jiangsu Hengrui Pharmaceuticals.

miR-384 suppressed renal cell carcinoma cell proliferation and migration through targeting RAB23.

microRNAs (miRNAs) are noncoding, short, and endogenous RNAs that play crucial roles in tumor progression at the post-transcriptional level. Here, we studied the role of miR-384 in the pathogenesis of renal cell carcinoma (RCC). We demonstrated that miR-384 expression was downregulated in the RCC specimens compared with nontumor specimens. Moreover, we showed that RAB23 expression was upregulated in the RCC tissues compared with nontumor tissues. Furthermore, we demonstrated that low expression of miR-384 was correlated with high levels of RAB23 in RCC tissues. We also demonstrated that the RAB23 was a direct target gene of miR-384 in RCC cells. In addition, overexpression of miR-384 suppressed RCC cell proliferation, cell cycle, and cell migration. Furthermore, ectopic expression of RAB23 promoted RCC cell proliferation, cell cycle, and cell migration. These data suggested that miR-384 played a tumor suppressor microRNA in the development of RCC partly through inhibiting RAB23 expression.

LncRNA CCAT2 promoted osteosarcoma cell proliferation and invasion.

Long non-coding RNA (lncRNA) plays important roles in tumour progression. Accumulating studies demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) acted as an oncogene in many tumours. However, the role of CCAT2 in the development of osteosarcoma has not been elucidated. In our study, we indicated that CCAT2 expression was up-regulated in osteosarcoma tissues and cell lines (SOSP-9607, MG-63, U2OS and SAOS-2). In addition, osteosarcoma cases with higher CCAT2 expression had a poorer disease-free survival and shorter the overall survival time compared to those with lower expression. Overexpression of CCAT2 promoted osteosarcoma cell proliferation, invasion and cell cycle. Furthermore, ectopic expression of CCAT2 increased the expression of mesenchymal markers N-cadherin, vimentin and snail and reduced the expression of N-cadherin marker E-cadherin. CCAT2 overexpression promoted the LATS2 and c-Myc expression in osteosarcoma cell. These data indicated that CCAT2 served as an oncogene in osteosarcoma and promoted osteosarcoma cell proliferation, cell cycle and invasion.

Difference in Uptake of Tetrodotoxin and Saxitoxins into Liver Tissue Slices among Pufferfish, Boxfish and Porcupinefish.

Although pufferfish of the family Tetraodontidae contain high levels of tetrodotoxin (TTX) mainly in the liver, some species of pufferfish, boxfish of the family Ostraciidae, and porcupinefish of the family Diodontidae do not. To clarify the mechanisms, uptake of TTX and saxitoxins (STXs) into liver tissue slices of pufferfish, boxfish and porcupinefish was examined. Liver tissue slices of the pufferfish (toxic species Takifugu rubripes and non-toxic species Lagocephalus spadiceus, L. cheesemanii and Sphoeroides pachygaster) incubated with 50 µM TTX accumulated TTX (0.99-1.55 µg TTX/mg protein) after 8 h, regardless of the toxicity of the species. In contrast, in liver tissue slices of boxfish (Ostracion immaculatus) and porcupinefish (Diodon holocanthus, D. liturosus, D. hystrix and Chilomycterus reticulatus), TTX content did not increase with incubation time, and was about 0.1 µg TTX/mg protein. When liver tissue slices were incubated with 50 µM STXs for 8 h, the STXs content was <0.1 µg STXs/mg protein, irrespective of the fish species. These findings indicate that, like the toxic species of pufferfish T. rubripes, non-toxic species such as L. spadiceus, L. cheesemanii and S. pachygaster, potentially take up TTX into the liver, while non-toxic boxfish and porcupinefish do not take up either TTX or STXs.

A novel function of vitellogenin subdomain, vWF type D, as a toxin-binding protein in the pufferfish Takifugu pardalis ovary.

Marine pufferfish of the Tetraodontidae family contain high levels of tetrodotoxin (TTX) in the liver and ovary. TTX is suggested to transfer from the liver to the ovary in female pufferfish during maturation. TTX in pufferfish eggs may act as a repellent against predators and as a sexual pheromone to attract male pufferfish. The toxification mechanism of the pufferfish ovary is poorly understood. Here we evaluated the chemical form of TTX and its related substances in the ovary of the panther pufferfish Takifugu pardalis by LC-ESI/MS. TTX and its analogs 4-epi-TTX, 4, 9-anhydroTTX, deoxyTTX, dideoxyTTX, and trideoxyTTX were detected in a low molecular weight fraction by Sephacryl S-400 column chromatography. The finding of an unknown TTX-related substance in a high molecular weight fraction from the Sephacryl S-400 column suggested the occurrence of toxin-binding protein in the ovary. The toxin-binding protein in the ovary was purified by ion-exchange HPLC, gel filtration HPLC, and SDS-PAGE. Amino acid sequencing and cDNA cloning revealed that the toxin-binding protein, TPOBP-10 (Takifugu pardalis ovary toxin-binding protein with a molecular mass of 10 kDa) was homologous with the predicted vitellogenin-1-like protein [Takifugu rubripes] subdomain, a von Willebrand factor type D domain. TPOBP-10 mRNA was highly expressed in the ovary and liver and less in other organs of female individuals based on RT-PCR. These findings reveal a novel function of the vitellogenin subdomain as binding with TTX-related substances, and its involvement in the toxification of the pufferfish ovary.