Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1-EEF1A1 Axis.

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

Oral administration of chicken NK-lysin or recombinant chicken IL-7 improves vaccine efficacy of Eimeria tenella elongation factor-1α (EF-1α) against coccidiosis in commercial broiler chickens.

The synergistic effects of orally-delivered chicken NK-lysin peptide 2 (cNK-2) or recombinant chicken IL-7 (rchIL-7) on vaccination with recombinant Eimeria elongation factor-1α (rEF-1α) against Eimeria maxima (E. maxima) infection was investigated in broiler chickens. Chickens were divided into six groups: control (CON, no Eimeria infection), non-immunized control (NC, PBS), Vaccination 1 (VAC 1, rEF-1α plus cNK-2), Vaccination 2 (VAC 2, rchIL-7 plus cNK-2), Vaccination 3 (VAC 3, rEF-1α/rchIL-7 plus cNK-2), and Vaccination 4 (VAC 4, rEF-1α/rchIL-7 plus cNK-2). All groups, except the CON and NC, were orally treated with cNK-2 for 5 days. The first immunization, except for the VAC 4 group, was performed intramuscularly on day 4, and the second immunization was given with the same concentration of components as the primary immunization one week later. The immunization of the VAC 4 group was carried out by an oral inoculation on the same days. On day 19, all chickens except the CON group, were orally challenged with E. maxima (1.0 × 104 oocysts/chicken). The in vivo vaccination results showed that the VAC 1 and VAC 3 groups produced high (p < 0.05) levels of serum antibody titers to rEF-1α, and the VAC 3 showed enhanced (p < 0.05) levels of serum IL-7. Furthermore, the VAC 3 group showed significantly (p < 0.01) greater body weight gains at 6- and 9-days post-E. maxima infection (dpi) with reduced oocyst shedding at 6 dpi. The average jejunal lesion score of the NC group was 2.5 whereas the VAC 1 group showed a significantly (p < 0.05) lower lesion scores at 6 dpi. E. maxima infection significantly (P < 0.05) up-regulated the expression levels of cytokines (IL-6, IL-10 and IFN-γ) in the jejunum at 4 dpi, but those expressions were down-regulated in VAC 1 or VAC 3 groups. Moreover, the gene expression levels of Jam 2 and Occludin, were significantly (P < 0.05) decreased following E. maxima infection in jejunum at 4 dpi (NC), but their expressions were increased in the VAC 3 group. Collectively, these results showed that the efficacy of rEF-1α vaccination was significantly enhanced when rEF-1α vaccine co-immunized with chIL-7 or cNK-2.

[A Case Report of Metachronous Multiple Cancers Including Triple Lung Cancers, Gastric Cancer, and Double Urothelial Cancers].

A male patient in his 60s at the time of the first medical examination had a smoking history of 50 years with 25 cigarettes a day. He was diagnosed with double urothelial cancers. In 200a, total left pelvic ureterectomy(pT2N0M0, Stage Ⅱ)and transurethral bladder tumorectomy(pTisN0M0, Stage Ⅰ)were performed. For his gastric cancer with malignant pleural effusion(cT3N0M1, Stage Ⅳb), in 200a plus 2, downstaging was acquired after chemotherapy. In 200a plus 5, subtotal gastrectomy D1 dissection was performed(W/D adenocarcinoma, pT2N0M0, Stage ⅠA, Ef 1). For the first lung cancer, in 200a plus 5, thoracoscopic lung wedge resection of the left lower lobe was performed(P/D adenocarcinoma, pT1aN0M0, Stage ⅠA1, R0, Ef 1). For the second lung cancer, in 200a plus 13, thoracoscopic lung wedge resection of the right upper lobe was performed after chemotherapy(P/D adenocarcinoma, pT1bN0M0, Stage ⅠA2, R0). For the third lung cancer, in 200a plus 17, immunotherapy was performed for the left upper lobe lung cancer(P/D adenocarcinoma, cT3N1M1a, Stage ⅢA). All the cancers were diagnosed as primary lesions by immunohistological examination. For the metachronous multiple cancers, multidisciplinary treatment was necessary for each cancer considering the patient's physical condition. Moreover, strict follow-up was necessary because of the high risk of carcinogenesis.

Genetically modified NT2N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury.

Human Ntera-2 (NT2) cells can be differentiated in vitro into well-characterized populations of NT2N neurons that engraft and mature when transplanted into the adult CNS of rodents and humans. They have shown promise as treatments for neurologic disease, trauma, and ischemic stroke. Although these features suggest that NT2N neurons would be an excellent platform for ex vivo gene therapy in the CNS, stable gene expression has been surprisingly difficult to achieve in these cells. In this report we demonstrate stable, efficient, and nontoxic gene transfer into undifferentiated NT2 cells using a pseudotyped lentiviral vector encoding the human elongation factor 1-alpha promoter and the reporter gene eGFP. Expression of eGFP was maintained when the NT2 cells were differentiated into NT2N neurons after treatment with retinoic acid. When transplanted into the striatum of adult nude mice, transduced NT2N neurons survived, engrafted, and continued to express the reporter gene for long-term time points in vivo. Furthermore, transplantation of NT2N neurons genetically modified to express nerve growth factor significantly attenuated cognitive dysfunction following traumatic brain injury in mice. These results demonstrate that defined populations of genetically modified human NT2N neurons are a practical and effective platform for stable ex vivo gene delivery into the CNS.