Surgical Treatment of Sacroiliac Pigment Villous Nodular Synovitis: A Case Report and Literature Review.

Pigmented villonodular synovitis (PNVS) is a rare and disabling disease that is thought to occur mostly in the knee joint. Here, the authors first present a unique case of PNVS occurring at the sacroiliac joint. The patient complained of sacroiliac joint pain with mild swelling. CT and MRI showed that the tumor was ~63 by 91 by 107 mm in size, and was considered to be a fibrous borderline or low-grade malignancy. Intraoperative macroscopic features of the synovitis during operation suggested PNVS, which was confirmed by histopathological examination. The clinical symptoms and signs of the disease, in this case, are not obvious, and radiological investigations, including MRI, suggest high aggressiveness. The author believes that it may be more likely to relapse and metastasis and recommends complete removal of the synovial membrane and regular follow-up, while preoperative or postoperative radiotherapy and molecular targeted therapy are not recommended for the time being.

A novel intracellular nanobody against HPV16 E6 oncoprotein.

Cervical cancer occurs as a result of the persistent infection of high-risk human papillomavirus (HPV). HPV16 oncoproteins E6 and E7 exert different and concerted pro-tumor actions in cell transformation and malignance maintenance in various m echanisms. Nanobody expressed as "intracellular antibodies" (intrabodies) can target intracellular antigens to hamper their function efficaciously and specifically. In this work, phage-display approach was employed to select the high affinity HPV16 E6-specific nanobody, nanobody Nb9 against HPV16 E6 was selected. Nb9 has high affinity (Kaff =6.3 × 108 M-) and can specifically bind endogenous HPV16 E6 protein in HPV16 positive CaSki and SiHa cells. In Nb9 overexpressed SiHa and CaSki cells, nucleus localization of HPV16 E6 was inhibited, p53 inactivation was prevented and increased apoptosis was observed. Moreover, tumor growth was inhibited in mouse xenograft model. Taken together, our results suggested that nanobody Nb9 could be a useful inhibitor for HPV16 E6 function and particularly appropriate for the treatment of HPV-associated disease.

Nanobody against PDL1.

Programmed death ligand 1 (PDL1, CD274, B7-H1) has been identified as the ligand for the immune inhibitory receptor programmed death 1 protein (PD1/PDCD1). PDL1 is a member of B7 family of immune molecules and this protein together with PDL2, are two ligands for PD1 expressed on activated lymphoid cells. By binding to PD1 on activated T cells, PDL1 may inhibit T cell responses by inducing apoptosis. Accordingly, it leads to the immune evasion of cancers and contribute to tumor growth, thus PDL1 is regarded as therapeutic target for malignant cancers. We selected PDL1 specific nanobodies from a high quality dromedary camel immune library by phage display technology, three anti-PDL1-VHHs were developed.

Nanobody against the E7 oncoprotein of human papillomavirus 16.

The persistent infection of high-risk human papillomavirus (HPV) is one of the most common causes of cervical cancer. It is well documented that expression of two oncogenes (E6/E7) plays a key role in tumor progression. HPV16E7 -targeting via nanobody (Nb) therefore could be beneficial for HPV16-associated cancer diagnosis and therapy. In this work, phage-display approach was employed to select the high affinity HPV16E7-specific Nb. Firstly; a high-quality immune library was constructed. After three round of biopanning, high-affinity HPV16 E7-specific nanobodies were retrieved. By phage ELISA and sequencing, four different sequences of anti- HPV16E7 nanobodies were selected. Then recombinant nanobody Nb2 was cloned and expressed in E. coli, and the specificity and thermal stability of purified Nb2 was evaluated. To examine the potential of Nb2 as an inhibitor of E7 function, Nb2 was expressed within HPV16 positive cells. Proliferation assay showed that the intracellular expressed Nb2 as an intrabody can decrease the growth of HPV16-positive cells. The results indicate that Nb2 as an intracellular antibody directed towards HPV oncoprotein E7 has great promise in applications for the therapy of HPV16-associated disease.

p73 coordinates with Δ133p53 to promote DNA double-strand break repair.

Tumour repressor p53 isoform Δ133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Δ133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, Δ133p53 lacks the transactivation domain of full-length p53, and the mechanism by which it exerts transcriptional activity independently of full-length p53 remains unclear. In this report, we describe the accumulation of high levels of both Δ133p53 and p73 (a p53 family member) at 24 h post γ-irradiation (hpi). Δ133p53 can form a complex with p73 upon γ-irradiation. The co-expression of Δ133p53 and p73, but not either protein alone, can significantly promote DNA DSB repair mechanisms, including homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). p73 and Δ133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a Δ133p53-responsive element (RE) and a p73-RE in the promoters of all three repair genes. In addition to its accumulation at 24 hpi, p73 protein expression also peaks at 4 hpi. The depletion of p73 not only reduces early-stage apoptotic frequency (4-6 hpi), but also significantly increases later-stage DNA DSB accumulation (48 hpi), leading to cell cycle arrest in the G2 phase and, ultimately, cell senescence. In summary, the apoptotic regulator p73 also coordinates with Δ133p53 to promote DNA DSB repair, and the loss of function of p73 in DNA DSB repair may underlie spontaneous and carcinogen-induced tumorigenesis in p73 knockout mice.

Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 promotes lung adenocarcinoma by directly interacting with specificity protein 1.

Metastasis-associated lung adenocarcinoma transcript 1 (malat1) is an oncogenic long non-coding RNA (lncRNA) which has been proven to be associated with various types of tumors. Transcription factor specificity protein 1 (SP1) is overexpressed in many types of cancers. Previously, we observed that malat1 expression level is regulated by SP1 in lung cancer. In the present study, we found that transfection of expression construct of malat1 5' end fragment M5 enhances stability and transcriptional activity of SP1. Various SP1 target genes are also upregulated following overexpression of malat1 M5 in lung adenocarcinoma cells. We also showed that malat1 M5 interacts with the C-terminal domain of SP1 by RNA immunoprecipitation (RIP) assay coupled with UV cross-linking. Malat1-SP1 association results in increase of SP1 stability. In turn, SP1 promotes malat1 transcription, thus forming a positive feedback loop. In conclusion, our data show that in lung adenocarcinoma cells, malat1 interacts with SP1 protein and promotes SP1-mediated transcriptional regulation of SP1 target genes.