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Background:The epitope and the TNF␣ inhabitation mechanism of Adalimumab remain unclear. Results: The crystal structure of the TNF␣ in complex with Adalimumab is reported at a resolution of 3.1 Å. Conclusion:The epitope of Adalimumab provided information that Adalimumab may have clinical advantage compared with Infliximab. Significance: These data reveal the Adalimumab's mechanism of TNF␣ inhibition and its advantages compared with other TNF inhibitors in clinical practice. TNF␣-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNF␣ and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared withEtanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNF␣ and functions as a TNF␣ receptorbinding blocker. To further elucidate the variations between TNF␣ inhibitors, we solved the crystal structure of TNF␣ in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNF␣ and revealed the mechanism of Adalimumab inhibition of TNF␣ by occupying the TNF␣ receptor-binding site. The larger antigenantibody interface in TNF␣ Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab.TNF is an immunity-modulating cytokine required for immune processes. The unregulated activities of TNFs can lead to the development of inflammatory diseases. Excess amounts of TNF␣ expressed in cells are associated with the development of immune diseases, including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, and inflammatory bowel disease (1, 2). The function of TNF␣ requires smooth interaction with its two receptors, TNF receptor 1 (TNFR1) 4 and TNF receptor 2 (TNFR2). Blocking the interaction between TNF␣ and TNFRs has successfully been developed as a therapy in treating inflammatory or autoimmune diseases (3,4). TNF␣ neutralization therapies, including the use of a soluble TNFR2-Fc recombinant (Etanercept), a mouse-human chimera mAb (Infliximab), or a human mAb (Adalimumab), have been introduced in the past decades for the management of rheumatoid arthritis and other immune diseases (5).Although all of these TNF␣ blockers function by interrupting the TNF␣-TNFR interaction, information on whether the different TNF␣ inhibitors have similar clinical efficacy remains controversial because of the lack of randomized clinical trial meta-analyses. In the early stages of clinical usage of Infliximab, its discontinuation was reported to result in loss of response. This largely affected patients who received long term treatment and later discontinued use (6). Approximately 10% of...

It has come to our attention that we inadvertently swapped the headings on the two columns of Table S4. From left to right, the headings should read ''No AR peak amplification'' and then ''AR peak amplification''. Only the headings were swapped. The manuscript reports the correct result, and the statistical tests we performed on the values (two-by-two contingency table tests) are unchanged. The error has been corrected online, and we apologize for any confusion it may have caused.

To improve the general satisfaction level, policymakers must provide better pay and benefits and more opportunities for career development, particularly for village doctors.

The existing results show that patients who received hysteroscopic resection followed by progestin therapy achieved the highest CRR. Patients who received oral progestin only might be more likely to recur and have more systemic adverse effects. Recent intrauterine progestin therapy such as levonorgestrel-releasing intrauterine system combined with gonadotropin-release hormone receptor agonist/progestin have a satisfactory PregR and low ReR rate. Considering the inherent limitations of the studies we included, further well-designed, randomized controlled trials are necessary to confirm and update this analysis.

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Introduction Community‐acquired pneumonia (CAP) severity scores perform well in predicting mortality of CAP patients, but their applicability in influenza pneumonia is powerless. Objectives The aim of our research was to test the efficiency of PO2/FiO2 and CAP severity scores in predicting mortality and intensive care unit (ICU) admission with influenza pneumonia patients. Methods We reviewed all patients with positive influenza virus RNA detection in Beijing Chao‐Yang Hospital during the 2009–2014 influenza seasons. Outpatients, inpatients with no pneumonia and incomplete data were excluded. We used receiver operating characteristic curves (ROCs) to verify the accuracy of severity scores or indices as mortality predictors in the study patients. Results Among 170 hospitalized patients with influenza pneumonia, 30 (17.6%) died. Among those who were classified as low‐risk (predicted mortality 0.1%–2.1%) by pneumonia severity index (PSI) or confusion, urea, respiratory rate, blood pressure, age ≥65 year (CURB‐65), the actual mortality ranged from 5.9 to 22.1%. Multivariate logistic regression indicated that hypoxia (PO2/FiO2 ≤ 250) and lymphopenia (peripheral blood lymphocyte count <0.8 × 109/L) were independent risk factors for mortality, with OR value of 22.483 (95% confidence interval 4.927–102.598) and 5.853 (95% confidence interval 1.887–18.152), respectively. PO2/FiO2 combined lymphocyte count performed well for mortality prediction with area under the curve (AUC) of 0.945, which was significantly better than current CAP severity scores of PSI, CURB‐65 and confusion, respiratory rate, blood pressure, age ≥65 years for mortality prediction (P < 0.001). The scores or indices for ICU admission prediction to hospitalized patients with influenza pneumonia confirmed a similar pattern and PO2/FiO2 combined lymphocyte count was also the best predictor for predicting ICU admission. Conclusion In conclusion, we found that PO2/FiO2 combined lymphocyte count is simple and reliable predictor of hospitalized patients with influenza pneumonia in predicting mortality and ICU admission. When PO2/FiO2 ≤ 250 or peripheral blood lymphocyte count <0.8 × 109/L, the clinician should pay great attention to the possibility of severe influenza pneumonia.

The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TP L , retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TP L showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TP L potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TP L was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TP L treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TP L to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. Cancer Res; 73(21);