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Purpose: Therapeutic strategies against hormonal receptor–positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized.Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis.Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo.Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future “co-clinical” trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR.

Suppl Information Table S1. Clinical characteristics of COH-SC1 and COH-SC31 PDXs

Figure S1. Characterization of two HR+/HER2+ breast patient-derived xenografts (PDXs), COH-SC1 and COH-SC31. Figure S2. Uterus and tumor weight of mice bearing COH-SC1 and COH-SC31 tumors in respond to estrogen treatment. Figure S3. Observations of body weight in response to drug treatment in vivo. Figure S4: Pathway analysis of up-regulated loci in COH-SC1 and COH-SC31 transcriptomes. Figure S5: Expression patterns of up-regulated proteins in COH-SC1 and COH-SC31 PDXs assayed by RPPA. Figure S6 In vivo efficacy examination of trastuzumab and/or MLN0128 on COH-SC1 PDX.

Table S2. Highly expressed loci in COH-SC31 in relation to COH-SC1

Suppl Figure Legends

Image segmentation plays a significant role in image processing and scientific research. In this paper, we develop a novel approach, which provides effective and robust performances for image segmentation based on the region-based (block-based) graph instead of pixel-based graph. The modified Discrete Cosine Transform (DCT) is applied to obtain the Square Block Structures (DCT-SBS) of the image in the compressed domain together with the coefficients, due to its low memory requirement and high processing efficiency on extracting the block feature. A novel weight computation approach focusing on multi-feature fusion from the location, texture and RGB-color information is employed to efficiently obtain weights between the DCT-SBS. The energy function is redesigned to meet the region-based requirement and can be easily transformed into the traditional Normalized cuts (Ncuts). The proposed image segmentation algorithm is applied to the salient region detection database and Corel1000 database. The performance results are compared with the state-of-the-art segmentation algorithms. Experimental results clearly show that our method outperforms other algorithms, and demonstrate good segmentation precision and high efficiency.

The Mn-Bi-Te class of compounds are recently discovered topological insulators with broken time-reversal-symmetry, which host unique quantum anomalous Hall and axion insulator states. Their key characteristics are believed to be sufficiently understood by models in a single-particle picture. Here, we apply scanning tunneling microscopy to study the electronic properties of MnBi2Te4 and MnBi4Te7. Unexpectedly, our quasiparticle interference (QPI) results demonstrate that rotational symmetry of the crystal breaks, i.e. a nematic-like pattern arises, in certain energy range but persists in others. Moreover, our data in the presence of an external magnetic field rule out the possibility of the material magnetism as an origin of the C2 symmetric QPI pattern. This study reveals that the interaction in the Mn-Bi-Te class of topological materials may play an essential role in their electronic states, and thus opens a new path for investigating the interplay between wavefunction topology and symmetry breaking phases.

Anterior cervical fusion surgery is the first choice for spine surgeons in the treatment of cervical spine diseases. It has significant effects in treating cervical degenerative diseases, trauma and tumors and other cervical diseases. In anterior cervical fusion, it is necessary to use a distractor to properly distract the intervertebral space, so as to fully expose and relieve the compressive factors, restore the physiological height, curvature and stability of the lesion segment, and achieve the best surgical effect. However, there is currently no consensus on the standard distraction height for the intervertebral space during anterior cervical surgery. This article reviewsed the progress of intervertebral space height in anterior cervical fusion from three dimensions:the relationship between intervertebral space height and cervical disc degeneration mechanism, the selection of intervertebral space height during operation, the recovery of intervertebral space height and the postoperative effect, so as to provide theoretical basis and reference for spinal surgeons when performing intervertebral distraction during operation.

The critical adsorption and diffusion of a linear polymer chain on a heterogeneous surface with randomly distributed adsorption sites are studied using dynamic Monte Carlo simulations. Results show that the critical fraction of the adsorption sites at which critical adsorption takes place decreases exponentially with the increasing polymer-surface attraction strength and, at the same time, decreases with the increasing intra-polymer attraction strength. For adsorbed polymers with large intra-polymer attraction strength, we also find an adsorption-induced structural transition from a three-dimensional compact globule to a two-dimensional compacted pancake with an increasing fraction of adsorption sites. Anomalous sub-diffusion is observed for the adsorbed polymer diffusion on heterogeneous surfaces, in contrast to the normal diffusion on a homogeneous surface. The polymer on heterogeneous surfaces shows larger fluctuation in the total surface attraction energy and a longer waiting time.

The effect of the size of nanoparticles, σNP, on the glass transition temperature, Tg, of polymer nanocomposites is studied by using molecular dynamics simulations. The variation of Tg with σNP shows two distinct behaviours for polymer nanocomposites at low and high volume fractions of nanoparticles (fNP). At a low fNP, Tg decays almost exponentially with σNP, whereas at a high fNPTg shows a complex behaviour: it initially increases and then decreases with increasing σNP. The decrease in Tg with σNP is due to the significant decrease of adsorbed polymer monomers, while the increase in Tg with σNP is attributed to the slower diffusion of larger nanoparticles. We have also investigated the diffusion and relaxation of polymer chains at a temperature above Tg for both low and high fNPs. The diffusion constant and relaxation time of polymer chains are highly consistent with the behaviour of Tg.