Xiaoling Liu

BACKGROUND: Currently, the epidemic of coronavirus disease 2019 (COVID-19) has begun to spread worldwide. We aim to explore reliable evidence for the diagnosis and treatment of the COVID-19 by analyzing all the published studies by Chinese scholars on the clinical and imaging features in novel coronavirus pneumonia caused by SARS-CoV-2. METHODS: We searched five medical databases including two Chinese and three English databases for all published articles on COVID-19 since the outbreak. A random-effects model was designed, and the imaging and clinical data from all studies were collected for meta-analysis. RESULTS: Overall, 31 articles and 46 959 patients were included, including 10 English articles and 21 Chinese articles. The results of meta-analysis showed that the most common clinical manifestations were fever (87.3%; 0.838-0.909), cough (58.1%; 0.502-0.660), dyspnea (38.3%; 0.246-0.520), muscle soreness or fatigue (35.5%; 0.253-0.456), and chest distress (31.2%; -0.024 to 0.648). The main imaging findings were bilateral pneumonia (75.7%; 0.639-0.871) and ground-glass opacification (69.9%; 0.602-0.796). Among the patients, the incidence that required intensive care unit (ICU) was (29.3%; 0.190-0.395), the incidence with acute respiratory distress syndrome was (28.8%; 0.147-0.429), the incidence with multiple organ dysfunction syndrome was (8.5%; -0.008 to 0.179), and the case fatality rate of patients with COVID-19 was (6.8%; 0.044-0.093). CONCLUSION: COVID-19 is a new clinical infectious disease that mainly causes bilateral pneumonia and lung function deteriorates rapidly. Nearly a third of patients need to be admitted to the ICU, and patients are likely to present respiratory failure or even death.

PURPOSE: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin. EXPERIMENTAL DESIGN: We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventional cytotoxic drugs and the novel PARP inhibitor AZD2281. Finally, in vitro combination studies were done to investigate interaction between AZD2281 and cisplatin. RESULTS: Genetic, transcriptional, and functional analyses confirmed the successful isolation of BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines. Treatment of these cell lines with 11 different anticancer drugs or with gamma-irradiation showed that AZD2281, a novel and specific PARP inhibitor, caused the strongest differential growth inhibition of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Finally, drug combination studies showed synergistic cytotoxicity of AZD2281 and cisplatin against BRCA2-deficient cells but not against BRCA2-proficient control cells. CONCLUSION: We have successfully established the first set of BRCA2-deficient mammary tumor cell lines, which form an important addition to the existing preclinical models for BRCA-mutated breast cancer. The exquisite sensitivity of these cells to the PARP inhibitor AZD2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.

We have studied in vivo responses of "spontaneous" Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. Like human tumors, the response of individual mouse tumors varies, but eventually they all become resistant to the maximum tolerable dose of doxorubicin or docetaxel. The tumors also respond well to cisplatin but do not become resistant, even after multiple treatments in which tumors appear to regrow from a small fraction of surviving cells. Classical biochemical resistance mechanisms, such as up-regulated drug transporters, appear to be responsible for doxorubicin resistance, rather than alterations in drug-damage effector pathways. Our results underline the promise of these mouse tumors for the study of tumor-initiating cells and of drug therapy of human cancer.

PURPOSE: To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. EXPERIMENTAL DESIGN: CIP2A expression (mRNA and protein) was measured in three different sets of human mammary tumors and compared with clinicopathologic variables. The functional role of CIP2A in breast cancer cells was evaluated by small interfering RNA-mediated depletion of the protein followed by an analysis of cell proliferation, migration, anchorage-independent growth, and xenograft growth. RESULTS: CIP2A mRNA is overexpressed (n = 159) and correlates with higher Scarff-Bloom-Richardson grades (n = 251) in samples from two independent human breast cancer patients. CIP2A protein was found to be overexpressed in 39% of 33 human breast cancer samples. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity of the patients and with the expression of proliferation markers and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in breast cancer mouse models presenting mammary gland-specific depletion of p53 and either BRCA1 or BRCA2. Functionally, CIP2A depletion was shown to inhibit the expression of its target protein c-Myc. Loss of CIP2A also inhibited anchorage-independent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice. CONCLUSIONS: Our data show that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells. Thus, these results validate the role of CIP2A as a clinically relevant human oncoprotein and warrant further investigation of CIP2A as a therapeutic target in breast cancer treatment.