BAP1 loss confers sensitivity to bromodomain and extra-terminal inhibitors in renal cell carcinoma.

The tumor suppressor gene BRCA1 associated protein-1 (BAP1) is frequently mutated in renal cell carcinoma (RCC). BAP1 loss-of-function mutations are associated with poor survival outcomes. However, personalized therapy for BAP1-mutated RCC is currently not available. Previously, we found that BAP1 loss renders RCC cells more sensitive to bromodomain and extra-terminal (BET) inhibitors, as demonstrated in both cell culture and xenografted nude mice models. Here, we demonstrate that BAP1 loss in murine RCC cells enhances sensitivity to BET inhibitors in ectopic and orthotopic allograft models. While BAP1 deletion suppresses RCC cell survival in vitro, it does not impede tumor growth in immunocompetent murine models. Thus, the effect of BAP1 loss on the interactions between tumor cells and host microenvironment plays a predominant role in RCC growth, highlighting the importance of utilizing immunocompetent animal models to assess the efficacy of potential anticancer therapies. Mechanistically, BAP1 deletion compromises DNA repair capacity, rendering RCC cells more vulnerable to DNA damage induced by BET inhibitors. Our results indicate that BET inhibitors show promise as targeted therapy for BAP1-deficient RCC.

Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors.

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.

[Effect of parthenolide on serum expressions of interleukin-1beta and tumor necrosis factor-alpha in rabbits with knee osteoarthritis].

OBJECTIVE: To observe the therapeutic effect of parthenolide (PTL) on rabbit knee arthritis (KOA) and its effects on serum expression of interleukin-1beta (IL-1beta) and contents of tumor necrosis factor-alpha (TNF-alpha). METHODS: Eight rabbits were randomly selected from 40 healthy pure-bred New Zealand rabbits as the normal control group. The KOA model was established in the rest 32 rabbits by plaster cast fixation of the right hind limb extension position. After modeling they were randomly divided into 4 groups, i.e., the model control group, the high dose PTL group, the middle dose PTL group, and the low dose PTL group, 8 in each group. Serum contents of IL-1beta and TNF-alpha were detected using enzyme-linked immunosorbent assay. RESULTS: Compared with the model group, IL-1beta and TNF-alpha concentration decreased in the 3 PTL groups (P < 0.01). The decrement was positively correlated with PTL concentrations (IL-1beta: r = 0.55, P < 0.01; TNF-alpha: r = 0.56, P < 0.01). The inhibition reached the peak when the PTL concentration arrived at 20 micromol/L. CONCLUSIONS: PTL could down-regulate the blood IL-1beta and TNF-alpha concentrations of KOA rabbits. Besides, the decrement was positively correlated with the PTL concentration.

[The effect of cyclophosphamide on cytokines in patients with primary Sjögren's syndrome-associated interstitial lung disease].

OBJECTIVE: To investigate the mechanisms of cyclophosphamide sequential therapy for patients with primary Sjögren's syndrome-associated interstitial lung disease (PSS-ILD). METHODS: This was a retrospective review of 15 patients (2005 - 2008) with PSS-ILD who underwent cyclophosphamide sequential therapy. Peripheral blood and bronchoalveolar lavage (BALF) were obtain before and 3, 6, 12, 24 months after the treatment. The TNF-α and TGF-ß(1)mRNA levels in peripheral blood were measured using reverse transcription-polymerase chain reaction (RT-PCR). Serum and BALF TNF-α, TGF-ß(1)and MMP-9 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: (1) The average levels of serum TNF-α (0.39 ± 0.22) and TGF-ß(1) (0.31 ± 0.18) mRNA in patients with PSS-ILD were higher compared with that in patients with PSS without ILD. TNF-α level (0.23 ± 0.19) was significantly decreased 3 months after cyclophosphamide treatment (t = 2.533, P < 0.05), and TGF-ß(1) (0.31 ± 0.18) level markedly decreased after 6 months of treatment (t = 2.617, P < 0.05). (2) The levels of serum TNF-α (11.2 ± 2.6) µg/L, TGF-ß(1) (72 ± 19) µg/L and MMP-9 (38 ± 9) µg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-ß(1) (36 ± 12) µg/L level decreased significantly after 3 months of treatment (t = 2.526, P < 0.05), and TNF-α level (7.1 ± 1.3) µg/L markedly decreased after 6 months of therapy (t = 2.578, P < 0.05). MMP-9 level (18 ± 4) µg/L decreased significantly after 12-month treatment (t = 2.329, P < 0.05). (3) The levels of BALF TNF-α (17.1 ± 3.5) µg/L, TGF-ß(1) (36 ± 17) µg/L and MMP-9 (27 ± 10) µg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-ß(1) (21 ± 14) µg/L level decreased significantly after 3-month treatment, and TNF-α level (9.4 ± 1.7) µg/L was decreased after 6 months of cyclophosphamide treatment (t = 2.215, P < 0.05). MMP-9 level (13 ± 5) µg/L decreased after 12 months of cyclophosphamide treatment (t = 2.576, P < 0.05). CONCLUSION: The mechanisms of cyclophosphamide treatment may be associated with its inhibition on production of TNF-α, TGF-ß(1)and MMP-9.