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An effective approach to solving complex problems is to decompose them and integrate dedicated solvers for those subproblems. We introduce a hybrid decomposition that incorporates: (1) a quantum annealer that samples from the configuration space of a relaxed problem to obtain strong candidate solutions, and (2) a classical processor that maintains a global search tree and enforces constraints on the relaxed components of the problem. Our framework is the first to use quantum annealing as part of a complete search. We consider variants of our approach with differing amounts of guidance from the quantum annealer. We empirically test our algorithm and compare the variants on problems from three scheduling domains: graph-coloring-type scheduling, simplified Mars Lander task scheduling, and airport runway scheduling. While we were only able to test on problems of small sizes, due to the limitation of currently available quantum annealing hardware, the empirical results show that results obtained from the quantum annealer can be used for more effective search node pruning and to improve node selection heuristics when compared to a standard classical approach.

This article examines the predominately Asian American “Anti-Phandom” community on GuruGossiper.com to explore how anti-fans of YouTube star Michelle Phan engage with ideologies of beauty cultures within Asian diasporic contexts. For many, Anti-Phandom provides an online space where personal concerns about female Asian beauty standards can be negotiated through Michelle Phan. Within these conversations, I argue Anti-Phans display forms of resistance to Phan's postfeminist forms of female empowerment on racial and ethnic terms. However, these counters to Phan's notions of beauty also produce a rubric of the beautiful Asian woman which renders difference as ugly, creating idealized definitions of racial beauty and Asian/American cultures based on essentialized categories that police diasporic women.

Debuting in the fall of 2017, the Second Wave podcast follows host Thanh Tan as she explores the experiences and challenges of U.S.-born Vietnamese Americans. Similar to many children of Vi...

Brain metastases (BM) are a leading cause of cancer death and prognosis remains poor despite treatment advances at other sites. Models are central to therapeutic development, but few orthotopic patient-derived xenograft (PDX) models of BM exist. To represent diversity across BM types, we established a program to create orthotopic PDX at scale from all BM patients. To date BM were received from 100 patients and PDX attempted by direct brain injection (PDX, n=89) or injection of low passage patient-derived cell lines (PDCLX, n=11). We created 65 successful BM PDX from 13 cancers: 17 lung (55% take), 15 breast (68%), 6 melanoma (75%), 5 CNS lymphoma (83%), 3 gastrointestinal (75%), 2 esophageal (40%), 2 ovarian (67%), 1 sarcoma (100%), 1 laryngeal (100%), 1 prostate (100%), 1 pancreatic (100%), 1 uterine adenosarcoma (100%), and 1 yolk sac tumor (100%). Take rate was similar for models derived from patients with prior chemotherapy-only versus immune/targeted therapy-only (63 vs 58%). Fifteen patients had live tumor and matching PBMCs archived for modeling in vitro immunotherapy responses. Mean time to moribund among different cancer types ranged from 27 days (yolk sac tumor) to 177.5 days (ovarian). BM PDX had a favorable timeline for preclinical study (90% moribund at 180 days). All PDX retained high fidelity to the patient driver SNVs and copy aberrations, even at >P4. No significant differences noted by immunodeficient strain (SCID versus NSG) or injection site (orthotopic versus heterotopic). Explants from BM PDX were able to generate long-term cell lines (60%) or short-term cultures with qualitative concordance of model-to-patient responses to targeted therapy (Osimertinib, EGFRi) and immunotherapy (Pembrolizumab, PD1i). Genomic and clinical data were used to create the DFCI BM PDX cBioPortal for public release and models distribution will be available through the DFCI Center for Patient Derived Models.

Impaired adipose tissue function and lower levels of high density lipoprotein cholesterol (HDL-C) have been implicated in the development of vascular dementia, and metabolic diseases such as hypertension, atherosclerosis, type 2 diabetes (T2D) and metabolic syndrome. Interestingly, both the substrate fluxes in adipose tissue and HDL-C concentration differ between men and women. Moreover, adipose tissue cholesterol efflux has been implicated in modulation of HDL-C levels. Thus, we aimed to determine if the association between serum estradiol levels and adipose tissue cholesterol efflux is sex-dependent.We evaluated the serum estradiol levels and adipose tissue cholesterol efflux in young healthy men (n=5) and women (n=3). Adipose tissue cholesterol efflux was determined using subcutaneous microdialysis probes. Linear regression analyses were used to determine the relationship between the parameters, p0.05 was considered as statistically significant.Our data demonstrated that serum estradiol levels directly associated with adipose tissue cholesterol efflux; however, the relationships may be sex-dependent. We discussed our results in the context of currently available data regarding sex-dependent variability in adipose tissue function and HDL-C metabolism as a potential contributor to higher rates of vascular dementia in men. Further research is required to understand the sex-dependent and -independent variabilities in adipose tissue metabolism to determine novel targets for interventions to prevent the development of vascular dementia.

We investigate solvable-unsolvable phase transitions in the single-machine scheduling (SMS) problem. SMS is at the core of practical problems such as telescope and satellite scheduling and manufacturing. To study the solvability phase transition, we construct a variety of instance families parameterized by the set of the processing times, the window size (deadline minus release time), and the horizon. We empirically establish the phase transition and look for an easy-hard-easy pattern for this family using several common solvers. While in many combinatorial problems a phase transition coincides with typically hard instances, whether or not that is the case with SMS remains an open question, and merits further study.

The GEO-Stationary Coastal and Air Pollution Events (GEO-CAPE) mission plans to put a visible spectrum imaging instrument on a satellite in geo-stationary orbit to perform ocean color remote sensing. Two different instrument designs, Filter Radiometer (FR) and COastal Ecosystems Dynamic Imager (COEDI), with different shape for the imaged area and image acquisition time, are being evaluated. Scheduling observations for either instrument requires optimizing science objectives in the presence of predicted cloud cover and available daylight. We model this scheduling problem as both Mixed Integer Linear Program (MILP) and Constraint Programming (CP) problems, and compare these two formulations for FR and COEDI using real cloudiness data collected at different times throughout the year. Our results show that MILP is the more suitable technique, and the schedule quality metric shows FR is the preferred design. We have reported our results to the GEO-CAPE mission team to assist them making an informed decision for the next step in formulating this mission.

Lymphomas of the central nervous system (CNSL) are rare tumors with few treatment options; however, recent genomic studies have uncovered several druggable targets. To facilitate novel treatment discovery, we sought to establish patient-derived xenograft (PDX) models and cell lines from patients with newly diagnosed or recurrent CNSL. PDX models were attempted from fresh tumor samples from 18 consented patients for whom rich clinical annotation was available. Orthotopic intracranial injections were performed via stereotactic injection. Cell line generation was attempted from both primary tumors (PDCL) and PDX samples (PDXCL). Characterization included histopathology, targeted exome sequencing, low-pass whole-genome sequencing for copy number evaluation, and expression profiling of matched patient tumors and PDXs. Drug response testing was performed using CellTiterGlo. From 18 samples attempted, 8 PDX models were successfully generated: 2 primary CNS diffuse large B-cell lymphoma (DLBCL), 5 secondary CNS DLBCL, and 1 secondary cutaneous T-cell lymphoma (CTCL). Mean time to moribund was 66 days. All 8 PDXs grew successfully as orthotopic models, and 4 also grew in subrenal capsule. Additionally, 6 PDCL and 2 PDXCL were established (> P3). Models faithfully represented primaries, showing nearly identical histopathology, immunoprofiles, and genomic signatures. To support expanded and rapid preclinical use of these models in drug testing we documented that PDX could be explanted to create short-term cell preparations or long-term cell lines with a 100% and 40% success rate, respectively. Proof of principle testing showed that explanted DLBCL PDX cells and cell lines showed sensitivity to copanlisib and venetoclax, which were not efficacious in the CTCL PDX. These findings showcase a diverse collection of CNSL models demonstrating high fidelity to primary tumors at the genomic and phenotypic levels, emphasizing their utility for preclinical studies and as patient avatars to rapidly determine sensitivities to existing and novel regimens prior to initiation of therapy.

Brain metastases (BM) are a leading cause of cancer death and prognosis remains poor despite treatment advances at other sites. Models are central to therapeutic development, but few orthotopic patient-derived xenograft (PDX) models of BM exist. To represent diversity across BM types, we established a program to create orthotopic PDX at scale from all BM patients. To date BM were received from 100 patients and PDX attempted by direct brain injection (PDX, n=89) or injection of low passage patient-derived cell lines (PDCLX, n=11). We created 65 successful BM PDX from 13 cancers: 17 lung (55% take), 15 breast (68%), 6 melanoma (75%), 5 CNS lymphoma (83%), 3 gastrointestinal (75%), 2 esophageal (40%), 2 ovarian (67%), 1 sarcoma (100%), 1 laryngeal (100%), 1 prostate (100%), 1 pancreatic (100%), 1 uterine adenosarcoma (100%), and 1 yolk sac tumor (100%). Take rate was similar for models derived from patients with prior chemotherapy-only versus immune/targeted therapy-only (63 vs 58%). Fifteen patients had live tumor and matching PBMCs archived for modeling in vitro immunotherapy responses. Mean time to moribund among different cancer types ranged from 27 days (yolk sac tumor) to 177.5 days (ovarian). BM PDX had a favorable timeline for preclinical study (90% moribund at 180 days). All PDX matched the patient driver SNVs and copy aberrations, even at >P4. No significant differences noted by immunodeficient strain (SCID versus NSG) or injection site (orthotopic versus heterotopic). Explants from BM PDX were able to generate long-term cell lines (60%) or short-term cultures with qualitative concordance of model-to-patient responses to targeted therapy (Osimertinib, EGFRi) and immunotherapy (Pembrolizumab, PD1i). Genomic and clinical data were used to create the DFCI BM PDX cBioPortal for public release and models distribution will be available through the DFCI Center for Patient Derived Models.

PurposeWe explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing.Materials and methodsA total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing.ResultsMedian circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity.ConclusionsThis study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.

This article uses scaled entity search (SES), a data mining technique and interpretive framework, to study the historically dynamic role of local radio broadcasters in the United States. The authors model the technique by searching for more than two thousand individual radio call letters and discussing the call signs with the highest number of page hits, with critical attention to the meaning of those results within the 1.6 million page digitized corpus of the Media History Digital Library. They also detail the strategies of one of the top-trending stations, WCCO Minneapolis, to distinguish itself in the broadcasting marketplace through the trade press. The authors conclude that WCCO’s emphasis on various aspects of the local market through facts and figures, constructions of local market identity, and relationships with sponsors instantiated a larger trend on the part of local broadcasters to position themselves favorably to advertisers and other industry participants.

Background and Objectives: To identify the effects of global health electives over a decade in a pediatric residency program. Methods: This was an anonymous email survey of the Boston Combined Residency alumni funded for global health electives from 2002 to 2011. A test for trend in binomial proportions and logistic regression were used to document associations between elective and participant characteristics and the effects of the electives. Qualitative data were also analyzed. Results: Of the 104 alumni with available email addresses, 69 (66%) responded, describing 94 electives. Elective products included 27 curricula developed, 11 conference presentations, and 7 academic publications. Thirty-two (46%) alumni continued global health work. Previous experience, previous travel to the site, number of global electives, and cumulative global elective time were associated with postresidency work in global health or with the underserved. Conclusions: Resident global electives resulted in significant scholarship and teaching and contributed to long-term career trajectories.

e13002Background: Next generation sequencing (NGS) of blood-derived nucleic acids is an emerging paradigm for determining the mutational status of cancer patients over time. Circulating tumor cells...

e16607Background: Next generation sequencing (NGS) of blood-derived nucleic acids is an emerging paradigm for determining the mutational status of cancer patients over time. Circulating tumor cells...