1,131 publications from this institution
<p>Supplementary Tables</p>
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models
3066 Background: BGB-A317 is a humanized IgG4 anti-PD-1 mAb with high specificity and affinity (KD = 0.15 nM) for PD-1. It blocks PD-L1 and PD-L2 binding, and inhibits PD-1-mediated negative signaling in T-cell lines and tumor growth in a number of allogeneic xenograft models. Methods: A phase I, multicenter study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of BGB-A317 in patients (pts) with advanced solid tumors. A 3+3 dose escalation design was undertaken. Pts received escalating doses of BGB-A317 intravenously biweekly (Q2W). Additional pts were treated at 2 and 5 mg/kg either Q2W or Q3W to explore alternate schedules. Results: As of 15 Dec, 2015, 61 patients were treated across 4 dose-escalating cohorts of BGB-A317 Q2W (0.5 mg/kg, n = 3; 2 mg/kg, n = 6; 5 mg/kg, n = 6 and 10 mg/kg, n = 6) and 4 dose-expansion cohorts (2 mg/kg, Q2W, n = 20; 2 mg/kg, Q3W, n = 2; 5 mg/kg Q2W, n = 17 and 5 mg/kg, Q3W, n = 1). One DLT (1/6) of grade 3 colitis was observed in the 5 mg/kg Q2W cohort. Maximum tolerated dose was not reached. The most common treatment-emergent adverse events (AEs) were grade (G) 1-2 fatigue (25%), diarrhea (20%), nausea (16%), rash (13%), pruritus (11%) and abdominal pain (11%). Treatment–related G3 AEs included diabetic ketoacidosis (n = 1, 2 mg/kg Q2W), hypotension (n = 1, 2 mg/kg Q2W), colitis (n = 2, 5 mg/kg Q2W), elevated ALT (n = 1, 2 mg/kg Q2W), hyperglycaemia (n = 1, 2 mg/kg Q2W) and fatigue (n = 1, 5 mg/kg Q2W). PKs of BGB-A317 show dose-proportional exposure increase from 0.5 to 10 mg/kg Q2W after the single dose administration with the elimination half-life of 11 to 17 days. Among 39 evaluable pts to date (10 ovarian, 6 colorectal, 6 RCC, 4 cutaneous SCC, 3 mesothelioma, 2 cervical, and 1 each of 8 others), 3 pts have partial response (2 to be confirmed) (1 gastric, 1 RCC and 1 cervical) and a further 13 pts exhibit stable disease. All 3 responding pts remain on treatment, ranging from 13 to 23 weeks. Conclusions: BGB-A317 demonstrates a favorable safety profile with AEs in keeping with the class effect. PKs are linear and early promising anti-tumor activity has been observed. The expansion cohorts are ongoing and an expanded phase IB study in selected cancer types is planned. Clinical trial information: NCT02407990.
Summary This paper investigates the behavior of high‐rise composite buildings with composite shear walls and concrete‐filled steel tubular (CFST) columns using a numerical model in OpenSees. In the model, the geometric and material nonlinearity of structural elements are captured by utilizing a fiber force‐based beam‐column elements with rigorously modified material stress–strain relationships. Besides, the confining effect of the concrete core, the semi‐rigid connections, and the coupling effect of composite shear walls is carefully taken into consideration. Finally, the case study of a 42‐storey composite building is conducted using the proposed model to provide a thorough understanding about the behavior of this kind of building. It shows that this innovative building has high loading capacity and significantly reduces the dimension of structural members (up to 50%) compared with the conventional RC building at the same loading capacity. Through the validation with test data, the suggested constitutive laws have shown the simplicity and high accuracy since the value of model error is only around 7%. In addition, the simulation results also indicate that the model can capture well the nonlinear behavior of tested specimens, especially, the failure and the formation of plastic hinges of coupling composite shear walls implicitly.
In order to optimize the performance of the steam turbine unit performance monitoring system, improve the reliability, stability and accuracy of the system, a new idea to establish target value surface and coal consumption growth surface in different load is presented. Take an imported supercritical steam turbine unit, which capacity is 600 MW, as an example to expound the design idea, the mathematic model and the construction process of these two types of surfaces.
Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned. CA Cancer J Clin 2011. © 2011 American Cancer Society.
