Summary The estimation of average treatment effects based on observational data is extremely important in practice and has been studied by generations of statisticians under different frameworks. Existing globally efficient estimators require non-parametric estimation of a propensity score function, an outcome regression function or both, but their performance can be poor in practical sample sizes. Without explicitly estimating either functions, we consider a wide class calibration weights constructed to attain an exact three-way balance of the moments of observed covariates among the treated, the control, and the combined group. The wide class includes exponential tilting, empirical likelihood and generalized regression as important special cases, and extends survey calibration estimators to different statistical problems and with important distinctions. Global semiparametric efficiency for the estimation of average treatment effects is established for this general class of calibration estimators. The results show that efficiency can be achieved by solely balancing the covariate distributions without resorting to direct estimation of propensity score or outcome regression function. We also propose a consistent estimator for the efficient asymptotic variance, which does not involve additional functional estimation of either the propensity score or the outcome regression functions. The proposed variance estimator outperforms existing estimators that require a direct approximation of the efficient influence function.

Purpose: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitinproteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-dependent lysosomal pathway occurs in response to UPS stress and proteasomal inhibition, and thus, ovarian cancer cell death can be triggered most effectively by coinhibition of both the proteasome-and HDAC6-dependent protein degradation pathways. Experimental Design: To address this hypothesis, we examined HDAC6 expression patterns in normal and cancerous ovarian tissues and used a novel HDAC6-specific inhibitor, NK84, to address HDAC6 function in ovarian cancer. Results: Abnormally high levels of HDAC6 are expressed by ovarian cancer cells in situ and in culture relative to benign epithelium and immortalized ovarian surface epithelium, respectively. Specific HDAC6 inhibition acts in synergy with the proteasome inhibitor Bortezomib (PS-341) to cause selective apoptotic cell death of ovarian cancer cells at doses that do not cause significant toxicity when used individually. Levels of UPS stress regulate the sensitivity of ovarian cancer cells to proteasome/HDAC6 inhibition. Pharmacologic inhibition of HDAC6 also reduces ovarian cancer cell spreading and migration consistent with its known function in regulating microtubule polymerization via deacetylation of a-tubulin. Conclusion: Our results suggest the elevation of both the proteasomal and alternate HDAC6-dependent proteolytic pathways in ovarian cancer and the potential of combined inhibition of proteasome and HDAC6 as a therapy for ovarian cancer.

Covariate balance is often advocated for objective causal inference since it mimics randomization in observational data. Unlike methods that balance specific moments of covariates, our proposal attains uniform approximate balance for covariate functions in a reproducing-kernel Hilbert space. The corresponding infinite-dimensional optimization problem is shown to have a finite-dimensional representation in terms of an eigenvalue optimization problem. Large-sample results are studied, and numerical examples show that the proposed method achieves better balance with smaller sampling variability than existing methods.

Purpose: Cervical cancer cells are addicted to the expression of the human papillomavirus (HPV) oncoproteins E6 and E7. The oncogencity of E6 is mediated in part by targeting p53 and PDZfamily tumor suppressor proteins for rapid proteasomal degradation, whereas the E7 oncoprotein acts in part by coopting histone deacetylases (HDAC)1/2. Here, we examine the hypothesis that inhibition of proteasome function and HDAC activity would synergistically and specifically trigger cervical cancer cell death by the interruption of E6 and E7 signaling. Experimental Design: The sensitivity and molecular responses of keratinocytes and HPVpositive and HPV-negative cervical cancer cells and xenografts to combinations of proteasome and HDAC inhibitors were tested. The expression of HDAC1/HDAC2 in situ was examined in cervical cancer, its precursors, and normal epithelium. Results: Cervical cancer cell lines exhibit greater sensitivity to proteasome inhibitors than do HPV-negative cervical cancers or primary human keratinocytes. Treatment of cervical cancer cells with bortezomib elevated the level of p53 but not hDlg, hScribble or hMAGI. Immunohistochemical analysis revealed elevated HDAC1/HDAC2 expression in cervical dysplasia and cervical carcinoma versus normal cervical epithelium. The combination of bortezomib and HDAC inhibitor trichostatin A or vorinostat shows synergistic killing of HPV-positive, but not HPV-negative, cervical cancer cell lines. Similarly, treatment of HeLa xenografts with the combination of bortezomib and trichostatin A retarded tumor growth significantly more effectively than either agent alone. Conclusions: A combination of proteasome and HDAC inhibitors, including bortezomib and vorinostat, respectively, warrants exploration for the treatment of cervical cancer.Persistent infection with an oncogenic-type human papillomavirus (HPV), most commonly HPV16 and HPV18, is a necessary but insufficient cause of cervical cancer (1). HPV DNA is detected in 99.7% of cervical cancers (2), as well as a large proportion of other anogenital cancers, and also in a subset of head and neck cancers. Although cytologic screening and HPV vaccines are effective preventive measures, there are currently no virus-specific therapies for cervical cancer, and the efficacy of standard surgical and chemo/radiotherapies is limited for advanced disease. Expression of two viral oncogenes, E6 and E7, is critical for the induction and maintenance of the transformed phenotype and is lacking from normal cells (3 -6). This suggests that E6 and E7 are logical targets for rational therapeutic approaches and that inhibitors should target the functions of both oncoproteins (4). Although neither has intrinsic enzymic activity, genetic and biochemical studies have defined key cellular partners through which these viral proteins transform cells (7,8).E6 exerts one important aspect of its oncogenic activity by binding to the HECT (homologous to the E6-AP Carboxyl Terminus) domain E3 ubiquitin ligase E6-AP (and possibly other ubiquitin lig...