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10520 Background: The ALK inhibitor crizotinib offers a new standard of care for patients with EML4-ALK fusion oncogene-positive advanced NSCLC. Two top priorities for its widespread clinical use a...

2578^ Background: As alkylating agents, platinum (Pt) analogs kill cancer cells mainly through induction of DNA damage. We hypothesize that low Pt-induced DNA damage is predictive of chemoresistanc...

3053 Background: New approaches to drug development in both the laboratory and clinic will be required to achieve the goal of personalized and molecular-based cancer therapy. Here we describe an in...

BACKGROUND: As alkylating agents, platinum (Pt) analogs kill cancer cells mainly through induction of DNA damage. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon with 10−18∼21 mole sensitivity. By measuring 14C bound to DNA, AMS detects carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin. METHODS: Cancer cells, mice bearing tumor xenografts and human cancer patients were treated with one microdose (1/100th the therapeutic dose) of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as pharmacokinetics (PK), drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy. RESULTS: In preclinical studies, the levels of microdose-induced DNA damage were linearly proportional to those caused by the therapeutic drug dose (R2=0.92, p We have opened a Phase 0 clinical trial because of the microdosing approach of the study. This trial takes a two-stage design. The first stage is similar to a Phase I trial to define the recommended Phase II dose (RP2D) of 14C-carboplatin. The second stage is similar to a Phase II trial to determine if low levels of microdosing carboplatin-induced DNA damage correlate with chemoresistance and determine some of the underlying chemoresistant mechanisms. So far, we have finished the first (Phase I) stage of the Phase 0 trial. One microdose of 14C-carboplatin was administered to human cancer patients. Pt-induced DNA damage and repair, and PK were measured and correlated with the response and toxicity of chemotherapy. The RP2D of 14C-carboplatin is 107 dpm/kg of body weight, less than 1% of the radiation exposure from an abdominal CT scan. The RP2D of carboplatin is 1% of therapeutic dose. No toxicity was observed. The PK of microdosing carboplatin was the same of the therapeutic dose. Slow drug metabolism correlated with high DNA damage. Molecular analysis of genes such as ERCC1 and RRM1 is being analyzed and will be compared with the Phase 0 results. All these results will be correlated with cancer response and patients' toxicity to chemotherapy. A parallel Phase 0 clinical trial in dogs with naturally occurring cancer will also be presented. CONCLUSION: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The microdosing trial is nontoxic to patients. The second stage of the trial is currently going on. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-403. doi:10.1158/1538-7445.AM2011-LB-403

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Non-small cell lung cancer (NSCLC) is the most common and lethal cancer worldwide. Erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is the first molecularly targeted agent that has demonstrated modest yet comparable survival benefit to chemotherapy in unselected patients with advanced NSCLC after failing first-line chemotherapy. However, all patients eventually die from disease progression and a cure does not currently exist, even in patients with NSCLC tumors harboring EGFR TKI-sensitive EGFR mutations and achieving an initially dramatic tumor response. We previously demonstrated that dysregulation of the EGFR/mTOR/AKT signaling pathway contributes primarily to the acquired resistance to erlotinib in an erlotinib-resistant clone H3255R#2 (EGFRWT/WT), which was derived from the parental, erlotinib-sensitive human lung adenocarcinoma cell line H3255 (EGFRL858R/WT). To gain further molecular insights into the resistance mechanisms, we explored genome-wide alterations in genomic DNA (gDNA) from erlotinib-resistant cells as compared to parental cells using the Affymetrix Human SNP 6.0 array platform, which contains approximately one million probes for the detection of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). We found that significant alterations were simultaneously present in several core functional pathways, including ErbB, mTOR/AKT, apoptosis, and cell cycle, as well as EMT, stem cell and metastasis related genes. Selected targets have been validated in vitro. Serum tumor DNA has emerged as an easily accessible and stable source of tumor biospecimens for advanced NSCLC patients and has been used for detecting somatic mutations in EGFR and K-Ras genes either directly or amplified by high fidelity whole genome amplification technology. We further determined whether this genome-wide array-based platform could be used to clinically assess the drug resistance mechanisms in advanced NSCLC patients. We analyzed the genomic alterations in two paired serum tumor DNA samples obtained before treatment and at treatment failure from NSCLC patients with primary or secondary resistance to erlotinib on a clinical trial (clinicaltrials.gov, identifier: [NCT00950365][1]). Of particular interest, we found that there were similar changes in the gDNAs from erlotinib-resistant patients’ sera and gDNA from R#2 cells within the mTOR/AKT pathway, including amplification of PI3K, AMPK, and VEGF genes, and deletion of RSK genes. Analyses on more banked, paired serum tumor DNA samples from patients enrolled in the same trial are ongoing. Our results support targeting the mTOR/AKT and/or VEGF pathway as a strategy to overcome clinical resistance to EGFR TKIs and serum tumor DNA could be a useful surrogate to assessing resistance mechanisms to therapy in advanced NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2011-5040 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00950365&atom=%2Fcanres%2F71%2F8_Supplement%2F5040.atom

Despite HER2-targeting agents having a reduced risk of distant relapse in early-stage breast cancer and improved systemic control in metastatic breast cancer, relapse or progression in the brain is a common and serious concern for mortality and morbidity in these HER2-positive breast cancer patients. Currently, radiation is the only effective therapy for these patients with various clinical outcomes. Thus, there is a significant unmet need to develop new therapeutic modalities to improve treatment efficacy for these patients, especially for patients who have failed radiation therapy. The objective of this project is to develop a novel nanoformulation of lapatinib for the treatment of HER2-positive breast cancer patients with brain metastasis. Lapatinib is the only FDA-approved small molecule tyrosine kinase inhibitor targeting both HER2 and epidermal growth factor receptor (EGFR). Lapatinib anecdotally induces objective response in HER2-positive breast cancer patients with brain metastasis. Current preclinical and clinic data suggest that lapatinib has limited and variable penetration through the blood-brain barrier, which is also affected by large inter-patient variations in the bioavailability of oral formulation of lapatinib. Dr. Lam's laboratory has developed a novel nanoparticle technology using oligocholic acid based micelles (telodendrimers) to load a high dose of hydrophobic drugs for cancer treatment. We have generated a stable nanoformulation of lapatinib with drug loading up to 10 mg per mL. The average particle size is less than 20 nm in diameter, which is desirable for tumor targeting due to the preferential drug accumulation at the tumor site via the enhanced permeation and retention (EPR) effect. We are currently optimizing and characterizing the physicochemical properties of several lapatinib-loaded nanoformulations. The most stable and efficacious nanoformulation of lapatinib will be selected for further preclinical testing using in vitro and in vivo models of HER2+ breast cancer. This nanoformulation of lapatinoib will be suitable for intrathecal injection as it is not affected by individual variations in oral bioavailability and penetration through the blood brain barrier. If successful, we would design a phase I/II clinical study to determine the safety and efficacy of this new nanoformulation of lapatinib for HER2+ breast cancer patients with refractory brain metastasis or meningeal disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4447. doi:10.1158/1538-7445.AM2011-4447

10529 Background: KRAS MTs have been associated with a diversity of biologic functions, and have both prognostic and predictive consequences in NSCLC and CRC. Little data exist comparing the specif...

2543 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS), an ultrasensitive method for measuring radiocarbon, can detect [14C]carboplatin bound to the DNA of cancer cells from cell culture, mice bearing tumor xenografts and patients receiving subtoxic microdoses of compound. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Relevant parameters such as drug influx/efflux, intracellular drug inactivation, DNA damage and repair, were measured and correlated with response to chemotherapy. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung or bladder transitional cell cancers who are planning to receive Pt-based chemotherapy. One microdose of [14C]carboplatin is administered to these patients 4 hours before biopsy. Pt-induced DNA damage and repair in tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Results: Preclinical studies showed that AMS can detect Pt-DNA damage when cancer cells and mice with tumor xenografts are exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage are directly proportional to the damage caused by a therapeutic drug dose (p [Table: see text]

Endocrine disruptors (EDs) are of global concern owing to their widespread occurrence and adverse effect on reproductive systems of animals and humans. The sorption behaviour of EDs is of fundamental importance in determining their transport and fate, but the influence of solution chemistry (ion species and concentration) on the sorption process is poorly understood. In the present study, the effects of Ca2+ and Na+ on the sorption of three selected EDs (bisphenol A, 17β-oestradiol and 17α-ethynylestradiol) to sediments were investigated. Fluorescence spectra of EDs were measured to reveal the interactions of ions with EDs. The sorption of EDs to sediments increases with rising ion concentration, and Ca2+ has a greater influence on sorption than Na+. Two characteristic excitation–emission peaks were found in the three-dimensional fluorescence spectra. For the selected EDs, a strong reduction in intensity of these two peaks was observed after the addition of ions. These results indicate that solution chemistry has a major influence on the sorption of selected EDs to sediments; greater sorption occurs with higher ion concentration.

19096 Background: The primary objective of this study was to determine the complete, partial response rate and stable disease rate of bortezomib as a first line therapy in advanced NSCLC. Methods: ...

1037 Background: Tipifarnib and fulvestrant both have single agent activity in hormone receptor-positive (HR+) metastatic breast cancer (MBC), and tipifarnib enhances the activity of anti-estrogens in HR+ breast cancer cell lines. Methods: Eligibility criteria: measurable HR+ MBC, postmenopausal status, ECOG PS of 0–2, and no prior chemotherapy for MBC. Treatment: fulvestrant 250 mg IM on day 1 plus oral tipifarnib 300 mg BID on days 1–21 every 28 days (defined as one cycle). Response was evaluated by RECIST criteria every 3 cycles. The study was suspended for efficacy/futility analysis after 33 of 46 patients were accrued. It was designed to detect an improvement in clinical benefit rate (CBR; defined as objective response or stable disease for at least 24 weeks) from 50% to 70% (90% power, type I error 10%), and would require at least 26 of 42 eligible/evaluable patients to have clinical benefit (CB). The expected CBR for fulvestrant alone is 30% in aromatase inhibitor (AI) resistant disease (Ingle, 2006), 45% in tamoxifen (tam)-resistant disease (Osborne, 2002), and 60% when used as first line endocrine therapy (ET) (Howell, 2004). Results: Of 33 patients enrolled, 28 are currently assessable for CBR (2 were ineligible, and 3 have stable disease for < 6 months and remain on treatment). Grade 3/4 toxicity: neutropenia (15%), pain (11%) and gastrointestinal toxicity (11%). Tipifarnib was either reduced in dose (N=10) or discontinued (N=8) due to toxicity or non-compliance. The overall CBR is shown; should accrual continue, all 14 evaluable patients must have CB in order to meet the pre-specified efficacy objective. For the ET-resistant group, 18 were resistant to AI therapy (or AI plus tam in 5) and 2 to tam. * Number eligible/evaluable for CBR. Conclusions: The tipifarnib-fulvestrant combination is not likely to produce a CBR of at least 70%. The 45% CBR in ET-resistant disease may merit further evaluation in this setting. [Table: see text] No significant financial relationships to disclose.

Sediment transport is one of the main concerns in a river system with hyper-concentrated flows. Therefore, the water use for sediment transport must be considered in study on the water demand for river ecosystem. The conventional methods for calculating the Minimum Water Demand for River Ecosystem (MWDRE) are not appropriate for rivers with high sediment concentration. This paper studied the MWDRE in wet season, dry season and the whole year under different water-and-sediment conditions in the Lower Yellow River, which is regarded as a typical river with sediment-laden flows. The characteristics of MWDRE in the river are analyzed. Firstly, the water demand for sediment transport (WDST) is much larger than the demands for other riverine functions, the WDST accounts for the absolute majority of the MWDRE. Secondly, in wet season when the WDST is satisfied, not only most of the annual incoming sediment can be transported downstream, but also the water demands for other river functions can be satisfied automatically, so that the MWDRE in wet season is identical to the WDST. Thirdly, in dry season, when the WDST is satisfied, the water demands for other river functions can also be satisfied, but the low sediment transport efficiency results in significant waste of water resources. According to these characteristics and aiming at decreasing sediment deposition in the riverbed and improving the utilization efficiency of water resources, hydrological engineering works can be used to regulate or control flow and sediment so that the sediment incoming in dry season can be accumulated and be transported downstream intensively and thus efficiently in wet season.

This paper presents the characteristics of sediment transport by flood in the Lower Yellow River with the reach from Huayuankou to Gaocun, which is regarded as a typical braided pattern. The Artificial Neural Network Model on Water Use for Sediment Transport (WUST) by flood was established based on the measured data from 1980 to 1998. Consequently, simulations of controlling process of sediment transport by flood were made in terms of the control theory under different scenarios. According to the situation of sediment transport by flood in the Lower Yellow River, Open-Loop control system and feedback control system were adopted in system design. In the Open-Loop control system, numerical simulations were made to reveal the relationship between average discharge of flood and the WUST with varying sediment concentrations. The results demonstrate that sediment concentration has significant influence on the controlling process of flood flow to WUST. It is practical and efficient to control WUST if sediment concentration is less than 20 kg/m3. In the feedback control system, controlling processes of sediment concentration and flood discharge for sediment transport were simulated respectively under given conditions, and it was found that sediment transport process could be controlled completely by sediment concentration and discharge at the inlet of the reach from Huayuankou to Gaocun. Using the same method, controlling processes of sediment transport by flood in other reaches in the Lower Yellow River were also simulated. For the case of sediment concentration being 20 kg/m3, the optimized controlling discharge ranges from 2390 to 2900 m3/s in the lower reach of Huayuankou. This study is also of significance to flood control and flushing sediment in the Lower Yellow River with proper operation modes of Xiaolangdi Reservoir.

In view of river functions and the Minimum Water Demand for River Ecosystem (MWDRE), the water resources in the Lower Yellow River is further divided into three portions, i.e. water available for ecosystem (WE), water exploitable for socioeconomic purposes (WS) and excess flood water (WF). Corresponding conceptions and practical significances are expounded in details. The annual amount of the three portions of water resources from 1950 to 2001 is worked out on the basis of the daily hydrologic data, and the division of different portions is discussed. The results indicate that although the essential water demand for river functions is considered preferentially, the amount of the WE has decreased dramatically while its proportion increased gradually since the 1950s, and the shortage to the MWDRE increased markedly; both the amount and the proportion of the WS decreased notably. Since the 1990s, the actual water consumption for socioeconomic purposes in the lower reaches of the river basin has already exceeded the maximum amount of the WS and has to take over the WE which is already insufficient, hence not only the normal river functions are further disturbed and the river course shrinks greatly, but also the proportion and potential danger of the WF show no decreasing tendency in spite of the sharp decrease of upstream runoff.

In this paper, the Cauchy problem of the isothermal hydrodynamic model for semiconductor devices is investigated. The existence of global weak entropy solutions with large initial data is obtained by using a modified fractional step Lax–Friedrichs scheme and the theory of compensated compactness. As a byproduct, the existence of entropy solutions to the Cauchy problem of the isentropic hydrodynamic model for a semiconductor with infinite mass is also proved.

INTRODUCTION: The objective of this study was to identify and characterize echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase fusion (EML4-ALK+) cancers by variant-specific, quantitative reverse transcription polymerase chain reaction (RT-PCR) assays in a large cohort of North American non-small-cell lung cancer (NSCLC) patients. METHODS: We developed a panel of single and multiplex RT-PCR assays suitable for rapid and accurate detection of the eight most common EML4-ALK+ variants and ALK gene expression in archival formalin-fixed, paraffin-embedded NSCLC specimens. EGFR and KRAS genotyping and thymidylate synthase RNA level by RT-PCR assays were available in a subset of patients. RESULTS: Between December 2009 and September 2012, 7344 NSCLC specimens were tested. An EML4-ALK+ transcript was detected in 200 cases (2.7%), including 109 V1 (54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and three V5a (1.5%) variants. Median age was 54.5 years (range, 23-89), and 104 patients (52.0%) were women. The great majority (n=188, 94.0%) of EML4-ALK+ NSCLC tumors had adenocarcinoma histology. ALK expression level varied significantly among different EML4-ALK+ variants and individual tumors. Only one case each of concurrent EGFR or KRAS mutation was detected. The median thymidylate synthase RNA level from 85 EML4-ALK+ cancers was significantly lower compared with that of EML4-ALK-negative lung adenocarcinomas (2.02 versus 3.29, respectively, p

Figure S1. (PPTX 1336 kb)

© 2017 The Author(s). Background: Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors have quickly become standard of care for patients with advanced non-small cell lung cancer and increasing numbers of other cancer types. In this report, we discuss the clinical history, pathological evaluation, and genomic findings in a patient with metastatic lung squamous cell cancer (SCC) who developed severe nivolumab-induced pneumonitis preceding durable clinical remission after three doses of nivolumab. Case presentation: A patient with chemotherapy-refractory, metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab treatment, concurrently with onset of a potent antitumor response. Despite discontinuation of nivolumab after three doses and the use of high dose oral corticosteroids for grade 3 pneumonitis, continued tumor response to a complete remission by 3 months was evident by radiographic assessment. At the time of this submission, the patient has remained in clinical remission for 14 months. High PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar macrophages and viable tumor cells in the pneumonitis and recurrent tumor specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome sequencing revealed a very high tumor mutation burden (TMB) corresponding to 95-96 percentile in lung SCC, i.e., 87.4-91.0 and 82.9 mut/Mb, respectively, in pre- and post-nivolumab tumor specimens. Except for one, the 13 functional genomic alterations remained the same in the diagnostic, recurrent, and post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the patient’s immune system against one or more preexisting tumor-associated antigens (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in which an oncogenic promoter -146C>T mutation was detected. Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides. Conclusions: Nivolumab could quickly reset and sustain host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC patient. Further mechanistic studies are needed to characterize the effective immune cells and define the HLA-restricted TAA(s) and the specific T cell receptor clones responsible for the potent antitumor effect, with the aim of developing precision immunotherapy with improved effectiveness and safety.

CA-ANN models which integrate Cellular Automata (CA) and Artificial Neural Networks (ANNs) for simulating land use change, usually urban and non-urban, predict the final land use type of a cell by the greatest similarity or probability after model parameters were defined in the training stage. In this study, the Monte Carlo approach was introduced into a CA-ANN model to simulate multiple land use changes with a case study in Shenzhen, China. The final land use type of a cell was jointly determined by the Monte Carlo approach and artificial neural network. The model performance were evaluated based on cell-to-cell comparison between simulated maps and actual ones by overall accuracy and kappa coefficient. The input maps of 1996, 2000 and 2004 were combined into three scenarios, the overall accuracies and kappa coefficients were all greater than 81.91% and 0.71 respectively. The land use maps of from 2004 to 2020 with 4 years interval were simulated and the results showed that build up will increase steadily while woodland will decrease. The impacts of spatial variables, neighborhood size and cell size on model performance were obtained by sensitive analysis. The simulation performance were all acceptable compared with the existing studies. The model performance would increase slightly as either neighborhood size or cell size increased, and that proximities to railways and city center were the main factors driving the dynamics of land use change in the study area.

Methods S1–S4. (DOCX 1572 kb)

Background α3β1 integrin is overexpressed in several types of human cancer and is associated with poor prognosis, metastasis, and resistance to cancer treatment. We previously identified a cyclic peptide ligand LXY1 that specifically binds to the α3β1 integrin on human glioblastoma U-87MG cells. Here, we optimized LXY1 through one-bead one-compound combinatorial library screening and site-specific modifications to improve its in vivo binding property. Methods Three bead libraries were synthesized and whole-cell binding assays were performed. The binding capacity of individual peptide ligands against different tumor cells was determined by flow cytometry and confirmed by optical imaging. A complex joining biotinylated ligand with streptavidin-Cy5.5 was used for in vivo target imaging in both subcutaneous and orthotopic U-87MG xenograft mouse models. Results LXY30, a cyclic peptide with the sequence cdG-Phe(3,5-diF)-G-Hyp-NcR, emerged as the most potent and selective ligand for the α3 subunit of α3β1 integrin with improved in vitro and in vivo tumor-targeting effects compared to LXY1 in U-87MG cells. LXY30 is considerably stable in plasma as demonstrated in an in vitro stability study in 90 % human plasma. LXY30 also binds to several other known α3β1 integrin-expressing glioblastoma, lung, and breast cancer cell lines with various affinities. Conclusions Our data support further investigating the role of LXY30 as a human tumor-targeting peptide ligand for systemic and intracranial delivery of imaging agents and cancer therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0165-z) contains supplementary material, which is available to authorized users.

Figure S1. (PPTX 1336 kb)

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Methods S1–S4. (DOCX 1572 kb)