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Vertical-structure photodetectors usually have the advantages of fast response speed and low driving voltage, but suffer from the high dark current that suppresses the detectivity of the devices. Introducing hole/electron-transporting or blocking layers has thus been widely considered to reduce the dark current, but may simultaneously cause the undesirable loss of photocurrent. Herein, we apply photo-switchable electron-transporting layers into vertical-structure photodetectors, which effectively reduces the dark current without sacrificing photocurrent for achieving the high detectivity. Organic dye molecules, perylene bisimides (PBI-H), are doped into the matrix of zinc oxide (ZnO) to achieve the photo-switchable layer (ZnO:PBI-H), which is less conductive in the dark for the inserted low-conductivity organic molecules but highly conductive under light irradiation due to the photo-induced electron transfer from PBI-H to ZnO. Perovskite is used as the photoactive layer in the photodetectors, and a thin layer of polyethylenimine ethoxylated (PEIE) is inserted between the ZnO:PBI-H layer and the perovskite layer in order to inhibit the decomposition of perovskite caused by ZnO. The optimized photodetector based on a ZnO:PBI-H electron-transporting layer shows the highest detectivity up to 2.5 × 1013 cm Hz1/2 W−1 (Jones) at zero bias (light intensity of 126 μW cm−2), which is more than doubled when compared with the device based on ZnO. In addition, the photoresponse stability of the device is also improved by the photo-switchable layer. The primary result sheds new light on the great potential of photo-switchable materials for the development of high-performance photodetectors.

Background Parental attitudes towards the vaccines play a key role in the success of the herd immunity for the COVID-19. Psychological health seems to be a controversial determinant of vaccine hesitancy and remains to be investigated. This study attempted to measure parental psychological distress, attitudes towards the COVID-19 vaccine, and to explore the potential associations. Methods An online survey using convenience sampling method was conducted among parents within the school public health network of Shenzhen. Demographic information and attitudes towards COVID-19 vaccination were collected. The Patient Health Questionnaire (PHQ-4) was applied to measure psychological distress. Results Overall, 4,748 parents were included (average age: 40.28, standard deviation: 5.08). More than one fifth of them demonstrated psychological distress, in which only 3.3% were moderate to severe symptom. The proportions of COVID-19 vaccine hesitancy for themselves, their spouses, and their children were 25.2%, 26.1%, and 27.3%, respectively. Parents with psychological distress were more likely to suffer vaccine hesitancy for themselves (OR: 1.277, 95%CI: 1.091~1.494), for their spouses (OR:1.276, 95%CI: 1.088~1.496) and children (OR:1.274, 95%CI: 1.092~1.486). These associations tended to be more significant among parents with mild or severe psychological distress. Limitation Non-random sampling limited the generalization of our findings to all parents. Conclusion Parents had a low level of psychological distress but relatively high willingness of COVID-19 vaccination when there was no local epidemic but persistent risk of imported cases. Targeted health education and intervention strategies should be provided to people with vaccine hesitancy, especially for those who are susceptible to psychological distress.

Terahertz (THz) photonic waveguides are of great importance in THz integrated technology, especially for versatile signal processing. However, in THz photonics, very few fundamental “building blocks” equivalent to those used in muti-functional electronics circuits exist. This study proposes a photonics-inspired micro-ring whispering gallery mode resonator (WGMR) waveguide with a standard waveguide-compatible package on silicon platform. A gradual taper is integrated on the same chip to improve the coupling efficiency and reduce transmission loss. The packaged WGMR waveguide with an operating range of 0.360 to 0.440 THz had a maximum measured extinction ratio of 32 dB at 0.390 THz, with a Q factor of 385 and an insertion loss of 2.6 dB. The compact and standard waveguide-compatible packaged WGMR can easily be integrated into practical terahertz application systems for THz signal processing and as a tool for the study of fundamental THz science.

From September 1 to October 27, 2015, an outbreak of bacillary dysentery occurred in the Shenzhen Children Welfare Institute (SCWI). The shigellosis was uncommon in Shenzhen and no related outbreak was reported during the last 5 years. An epidemiological investigation was conducted and the children and nursing workers in SCWI were surveyed for gastrointestinal symptoms; 28 of children reported having a diarrheal illness. Rectal swabs or fecal specimens from 14 case patients and 24 nursing workers or cook, as well as 17 swabs from implicated items were collected and examined for Shigella, Vibrio parahaemolyticus, and Salmonella. Susceptibility testing and pulse-field gel electrophoresis (PFGE) were performed on the Shigella isolates.The multiple-antibiotic-resistant Shigella flexneri 2a was isolated from 10 ill children aged less than 5 years. The source of the outbreak was most likely a new welfare child transferred from an institute in another county and the secondary transmission of the illness was facilitated by the limited activity space and the cohabiting of ill and well residents. The outbreak was controlled after quarantine of ill residents, introduction of new antibiotics and the improvements of hygienic condition. This was the first time that shigellosis outbreak was reported at such settings in Shenzhen and the results of this investigation underscored the need for adequate precautions to prevent secondary transmission of multiple-antibiotic-resistant strain in the welfare setting. Keywords: Outbreak, Shigellosis, Children Welfare Institute, Multiple-antibiotic-resistant, Shigella flexneri 2a

Molecular profiling of prostate cancer with liquid biopsies, such as circulating tumor cells (CTCs) and cell-free nucleic acid analysis, yields informative yet distinct data sets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We conducted an initial proof-of-principle study aimed at piloting this multiparametric approach. Peripheral blood samples from men with metastatic castrate-resistant prostate cancer were analyzed simultaneously for CTC enumeration, single-cell copy number variations, CTC DNA and matched cell-free DNA mutations, and plasma cell-free RNA levels of androgen receptor (AR) and AR splice variant (ARV7). In addition, liquid biopsies were compared with matched tumor profiles when available, and a second liquid biopsy was drawn and analyzed at disease progression in a subset of patients. In this manner, multiparametric liquid biopsy profiles were successfully generated for each patient and time point, demonstrating the feasibility of this approach and highlighting shared as well as unique cancer-relevant alterations. With further refinement and validation in large cohorts, multiparametric liquid biopsies can optimally integrate disparate but clinically informative data sets and maximize their utility for molecularly directed, real-time patient management.

The slow response speed and instability of the lateral photodetectors (L-PDs), often caused by the persistence of the excess minority carriers in the long channel after the termination of the illumination (called Persistent Photoconductivity effects) are the main factors that hinder the practical application of this type of device. In this research, two types of ZnO with different work functions, including ZnO nanoparticles (ZnO-NPs) doped in bulk heterojunction (BHJ) and thermal annealed ZnO nanocrystalline film (ZnO–NF), are incorporated into the L-PDs to construct an energy gradient, which could facilitate the quick transfer of the minority carriers and restrict their release into the active layer. The structure of L-PDs are optimized as quartz/ZnO–NF/PffBT4T-2OD:PC61BM:ZnO-NPs (component ratio = 5:6:1)/Au–Au electrodes. Compared with the control device, the test results show that the optimized L-PDs exhibit higher stability with much lower fall time (3.7 ms, boosted 200-fold) and gentler rise slope of dark current versus time (Kdark) (8.3 × 10−6 nA/s, reduced four orders of magnitude). Meanwhile, the very low dark current (

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. Methods: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0–1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120–360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. Results: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

e16587 Background: CTCs have the potential to reflect not only genomic alterations but also cancer-relevant transcriptomic phenotypes. However, CTC gene expression has been hampered by signal-to-noise: rare CTC-derived transcripts are drowned out by abundant leukocyte-derived RNA. To date, a few specialized labs have achieved CTC RNAseq by capturing and analyzing single cells, a laborious and expensive approach not suitable for routine analysis of numerous samples. To address this need, we developed and validated a simple, rapid method for enrichment of live CTCs for RNAseq. Methods: Blood was drawn with informed consent under an IRB-approved protocol. Prostate cancer cell line spike-in samples were used to optimize live CTC enrichment by sequential leukocyte depletion (RosetteSep, Stem Cell Technologies) and size-based enrichment (Parsortix, Angle). Cancer-specific gene expression was first measured by multiplexed prostate specific qRT-PCR and subsequently by whole transcriptome amplification (WTA, SMARTer V2, Clontech) and RNAseq. Four patient samples were similarly analyzed by enrichment and RNAseq, along with spike-in positive controls and matched unenriched buffy coat negative controls. Results: Processing “from patient to RNA” took < 3 hrs. and achieved mean CTC recovery of 30% (range 28-33%) and mean leukocyte background of 100 (range 47-179), a 100,000-fold enrichment. Prostate specific genes (AR, PSA, PSMA) were consistently detected by qRT-PCR from enriched samples but not from unenriched samples. When analyzed by RNAseq, patient samples clustered with spike-in positive controls and away from matched buffy coat controls by principle component analysis and by unsupervised hierarchical clustering. Differential gene expression (enriched vs. matched buffy coat) identified prostate cancer-relevant transcripts. Conclusions: We developed a simple and efficient method for live CTC enrichment and expression profiling, applicable to large numbers of patient samples. This approach can be used serially over time to detect known cancer-specific transcripts and to discover new gene expression signatures that reflect tumor biology and inform disease management.

BACKGROUND. Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. METHODS. Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. RESULTS. Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. CONCLUSIONS. Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.

INTRODUCTION AND OBJECTIVES: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and clinical outcomes in localized disease. METHODS: Radical prostatectomy (RP) specimens (þ/disease recurrence) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Univariable and multivariable associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts and in-silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa proliferation, invasion and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. In external cohorts and in silico, low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. In vitro and in vivo, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice (Figure). CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. Based on these novel roles in PCa, AXIN2 may represent a new putative biomarker and potential therapeutic target in this disease.

274 Background: Molecular profiling of prostate cancer using liquid biopsies such as CTC capture and cell-free nucleic acid analysis yield informative yet distinct datasets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We have conducted an initial proof of principle study aimed at piloting this multi-parametric approach. Methods: Blood was drawn under an IRB-approved protocol from 20 mCRPC patients. Samples were analyzed simultaneously for the following: CTC enumeration and single CTC and matched white blood cell capture for whole genome amplification and low-pass copy number variation; CTC DNA and matched cfDNA for somatic single nucleotide variant analysis; plasma cfRNA extraction and qRT-PCR for AR, AR-V7, and PCA3. When available, liquid biopsies were compared with matched tumor profiles. Results: Fifteen of 20 patients (75%) had detectable CTCs by CellSearch (range: 1-692/7.5mL, median: 16.5/7.5mL). Thirteen of 20 patients (65%) had detectable SSNVs in CTC DNA and/or matched cfDNA, including mutations in TP53, PIK3CA, HRAS, and EGFR. Matched CTC DNA and cfDNA demonstrated both shared and distinct SSNVs. Copy number analysis of single CTCs was performed in 2 patients, and both had CNVs in multiple cancer relevant genes. A majority of CNVs were present in matched solid tumor profiles, but some were exclusive to the liquid biopsies. Plasma PCA3 and AR transcripts were detected in 18/20 (90%) and AR-V7 in 4/20 (20%) cfRNA samples. Unique SSNVs were detected at second time points at disease progression (more are being collected). Conclusions: In this pilot cohort, simultaneous multi-parametric profiling was feasible for CTC DNA mutations and CNVs, and matched plasma cfDNA mutations and cfRNA gene expression. These disease-specific molecular profiles were often concordant with tumor tissues but also contained new, potentially actionable alterations unique to CTC DNA or cfDNA. Expanded studies will build upon this approach to optimally leverage liquid biopsies for molecularly directed patient management.

271 Background: CTC RNA analysis currently involves single cell recovery that is laborious and expensive, or alternatively lysis of preserved whole blood which yields RNA predominantly from leukocytes which vastly outnumber CTCs. To effectively characterize gene expression in large patient cohorts, new enrichment methodologies are needed that yield high purity CTC populations while preserving RNA integrity. Here we describe a simple yet robust method for enrichment of prostate CTCs for gene expression analysis. Methods: Blood was drawn with informed consent under an IRB-approved protocol. For initial optimization, CFSE-stained PCa cells were spiked into healthy blood and recovered using various combinations of 2 methods: microfluidic enrichment (Parsortix™ system) and CD45 depletion. For assay qualification, a prostate-specific multiplexed qRT-PCR gene expression panel was developed. Enrichment and gene expression were tested initially using PCa cell lines spiked into healthy blood, then metastatic castrate resistant prostate cancer (mCRPC) blood samples in parallel with CellSearch enumeration. Results: Optimal enrichment of live cells was achieved with CD45 depletion followed by microfluidic enrichment, resulting in an average spiked cell recovery of 30% and approximately 100 contaminating background leukocytes. Using this enrichment method, prostate specific genes were detectable by multiplexed qRT-PCR down to 25 cells spiked into 7.5 ml whole blood, and transcripts were not measurable in matched healthy blood controls. When applied to mCRPC patient blood containing CTCs by CellSearch, multiplexed qRT-PCR successfully detected prostate specific genes in all samples. Conclusions: We developed a novel enrichment method capable of rapidly and efficiently recovering live CTCs with high purity, free of magnetic beads and with very few background leukocytes. Captured cells yielded high-quality RNA with high sensitivity and specificity for prostate-specific transcripts. This approach is applicable to high throughput gene expression profiling assays and offers an alternative to laborious single cell recovery or non-cancer-specific whole blood fixation.

11516Background: Novel hormonal therapies recently approved for metastatic castration resistant prostate cancer (mCRPC) are now being tested in hormone sensitive disease (mHSPC), prompting evaluati...

Introduction: Precision oncology care is predicated upon detecting actionable genomic aberrations. Obtaining tissue that accurately reflects the genomic landscape of prostate cancer (PCa) is a challenge, though circulating tumor cells (CTCs) represent a promising tissue source. We demonstrate the feasibility of high throughput targeted sequencing of CTCs across multiple PCa disease states and compare the genomic variation among different cancer substrates (CTCs, cell free DNA [cfDNA], primary tumors, metastasis) in matched patient samples. Methods: Under IRB approval, 7.5ml of peripheral blood was obtained from healthy controls and patients with PCa. CTCs were enriched using LiquidBiopsy® (Cynvenio Biosystems), a CLIA-certified immunoaffinity-based microfluidic platform. CTCs were defined as EpCAM+CK+DAPI+CD45. Amplicon libraries covering 50 cancer genes were generated (AmpliSeq 2.0, Life Technology) and sequenced on an Ion Proton System. Somatic single nucleotide variants (SSNV), occurring in >1% of DNA in a sample, were identified based on their presence in CTCs and absence from WBC. When available, matched cfDNA, primary tumors and metastatic tissue were sequenced in parallel. Results: Peripheral blood was collected from healthy controls (n = 31) and PCa patients (n = 26) at various disease states: localized (n = 2), biochemical recurrence (n = 4), metastatic hormone sensitive (n = 16), and castration resistant (n = 4). In patients with PCa, the median PSA was 3.32 ng/dl (range Conclusion: Targeted sequencing of CTCs was feasible across the spectrum of PCa and SSNVs identified in CTCs were not concordant with SSNVs in matched cfDNA or tumor DNA, likely reflecting cellular heterogeneity, clonal evolution, and tissue-specific extraction methodologies. Expanded matched sample cohorts are needed to elucidate how these DNA sources - used alone or in combination - can best inform clinical decisions in prostate cancer. Citation Format: Brian Hu, Stephen Liu, Yucheng Xu, Paul Dempsey, William Strauss, Kristopher Wentzel, Tong Xu, Jacek Pinski, Tanya Dorff, Jessamine Winer-Jones, David I. Quinn, Amir Goldkorn. Targeted sequencing of prostate cancer circulating tumor cells in comparison with matched cell free DNA and prostate tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1587. doi:10.1158/1538-7445.AM2015-1587

29 Background: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor cancer phenotype impact PCa biology and clinical outcomes in localized disease. Methods: Genes associated with self-renewal, drug resistance, and tumorigenicity were analyzed by qRT-PCR on PCa mRNA from radical prostatectomy (RP) specimens (+/- disease recurrence). Wilcoxon rank sum two-sample test, multivariable recursive partitioning, and bootstrap internal validation measured and confirmed associations with recurrence. Further validation was conducted in external cohorts and in-silico, as well as in vitro and in vivo using siRNA knockdown and lentiviral overexpression to determined the effect of gene expression on PCa proliferation, invasion and tumor growth. Results: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. Validation in external cohorts demonstrated low AXIN2 expression was associated with more aggressive prostate cancer and was independently associated with biochemical recurrence (BCR) and metastasis-free survival (MFS) after RP. In vitro, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice. Conclusions: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts. AXIN2 expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. AXIN2 represents a putative biomarker and potential therapeutic target in early prostate cancer.

e22033 Background: Circulating tumor cells (CTC) have been associated with outcome in epithelial malignancies, but conventional immunoaffinity capture has not been amenable to HCC given the rare ex...

11040 Background: Recently a succession of new hormonal therapies has emerged, highlighting the need for biomarkers to guide the management of HSPC. Biomarker development in HSPC has been hampered by the absence of primary tumor tissue in men who undergo radiation or present with metastatic disease. CTCs can address this challenge by providing real-time cancer tissue for biomarker analysis in HSPC. To test this approach we conducted a pilot of CTC capture and targeted NGS in HSPC. Methods: Under IRB approval, blood samples from patients with HSPC were labeled with EpCAM ferrofluid and placed into the LiquidBiopsy platform (Cynvenio Biosystems, Inc.), an immunoaffinity-based microfluidic device tailored to query genomic events. CTCs were identified by CK, CD45 and DAPI expression. A matched WBC pellet served as a control representing germline sequence. Amplicon libraries were generated using Life Technologies AmpliSeq 2.0 and sequenced on an Ion Torrent platform. Somatic single nucleotide variants (SNV) present in CTCs but not in WBC were identified. Results: CTCs were detected in all 8 patients with HSPC (CTC median 64.5, range 17-217). Germline variants were consistently detected in matched CTC and WBC samples. Significant SNVs (occurring in > 1% of DNA in a sample) were found in 4 of 8 CTC samples (range 1-5 SNVs/sample, frequency 1.2%-11.9% with 620X-14,422X coverage). Notably, 3 patients had biochemical recurrence only (no clinical metastases) yet still yielded CTCs associated with SNVs in KIT, APC, RET, SMAD4 and PTEN. One patient who had untreated metastatic disease had the highest number of CTCs which harbored 4 SNVs. Conclusions: This pilot demonstrates the feasibility of using CTCs as real-time disease relevant substrate for NGS to identify personalized genomic targets in HSPC. A high number of CTCs were detectable in all patients and CTC germline variants correlated with matched WBC controls. Encouragingly, even with a relatively narrow, primary tumor-derived AmpliSeq platform, cancer relevant SNVs were detected in half of the patients including those with only biochemical recurrence, making targeted NGS of CTCs a promising approach for biomarker discovery and validation in HSPC.