Hemostatic materials are of great importance in medicine. However, their successful implementation is still challenging as it depends on two, often counteracting, attributes; achieving blood coagulation rapidly, before significant blood loss, and enabling subsequent facile wound-dressing removal, without clot tears and secondary bleeding. Here we illustrate an approach for achieving hemostasis, rationally targeting both attributes, via a superhydrophobic surface with immobilized carbon nanofibers (CNFs). We find that CNFs promote quick fibrin growth and cause rapid clotting, and due to their superhydrophobic nature they severely limit blood wetting to prevent blood loss and drastically reduce bacteria attachment. Furthermore, minimal contact between the clot and the superhydrophobic CNF surface yields an unforced clot detachment after clot shrinkage. All these important attributes are verified in vitro and in vivo with rat experiments. Our work thereby demonstrates that this strategy for designing hemostatic patch materials has great potential.

Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy. Experimental Design: Isogenic ARID1A À/À and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A À/À tumors. Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of nonhomologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A À/À cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A À/À cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1Adeficient tumors. Conclusions: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1Adeficient malignancies.

Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1A WT and ARID1A KO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGFβ tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.