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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Dosing schedule figure Dose reduction table

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein–Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%–91.9%). Overall response rate (ORR) was 92% (95% CI, 64%–100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273–81. ©2018 AACR.

PDF file - 636KB, Supplemental Table S1: information of the GBM lines used in this paper. Supplemental Table S2: information of the patient clinical data for Figure 1. Supplemental Table S3: Percentage of cells positive for staining with PRMT5 in spontaneous high grade astrocytoma from Mut3 strain (GFAP-cre; cisNf1-/+; P53-/-) and normal brain tissue from wild-type control mouse stained by PRMT5 and ki-67 antibody. Supplemental table S4. GBM cell line (U251) was transfected by scramble control or si-PRMT5. Affymetrix microarray genechip was performed in three independent experiments to evaluate genes up-regulated with PRMT5 silencing.

PDF file - 1690KB, Supplemental Figure S1. PRMT5 is over-expressed in human GBM cell lines. Supplemental Figure S2: High grade astrocytomas Supplemental Figure S3: efficacy and specificity of PRMT5 knock-down by lead siRNA. Supplemental Figure S4: PRMT5 Knockdown promotes cell death of human GBM cells Supplemental Figure S5: si-PRMT5 induced cell death is P53-independent Supplemental Figure S6: Decreased ST7 expression correlates with worse survival in all glioma patients (grade I-IV). Supplemental Figure S7: Over-expression of ST7 in three GBM cell lines was confirmed by real-time PCR and western blot (top panels).

Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. Cancer Res; 74(6); 1752–65. ©2014 AACR.

Sclerotinia sclerotiorum is a devastating pathogen that infects a broad range of host plants. The mechanism underlying plant defence against fungal invasion is still not well characterized. Here, we report that ANGUSTIFOLIA (AN), a CtBP family member, plays a role in the defence against S. sclerotiorum attack. Arabidopsis an mutants exhibited stronger resistance to S. sclerotiorum at the early stage of infection than wild-type plants. Accordingly, an mutants exhibited stronger activation of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) responses, including mitogen-activated protein kinase activation, reactive oxygen species accumulation, callose deposition, and the expression of PTI-responsive genes, upon treatment with PAMPs/microbe-associated molecular patterns. Moreover, Arabidopsis lines overexpressing AN were more susceptible to S. sclerotiorum and showed defective PTI responses. Our luminometry, bimolecular fluorescence complementation, coimmunoprecipitation, and in vitro pull-down assays indicate that AN interacts with allene oxide cyclases (AOC), essential enzymes involved in jasmonic acid (JA) biosynthesis, negatively regulating JA biosynthesis in response to S. sclerotiorum infection. This work reveals AN is a negative regulator of the AOC-mediated JA signalling pathway and PTI activation.

The Phasmatodea population evolution algorithm (PPE) is a novel metaheuristic algorithm proposed in recent years, which simulates the evolutionary trend of stick insect population. In this article, a multigroup-based Phasmatodea population evolution algorithm with mutistrategy (MPPE) is proposed to further improve the overall performance of PPE. During the initialization period, the stick insect population is divided into multiple groups, and the step factor of the flower pollen algorithm is introduced into the population growth model of no more than half of the groups. This makes the population evolution trend diversified and prevents the algorithm from falling into the local optimal solution to a certain extent. In terms of intergroup communication, two communication strategies are adopted to mutate and replace the inferior particles, respectively, which improves the convergence speed and search ability of the algorithm. In the MPPE performance test, we compared it with PPE, five standard algorithms, and other parallel algorithms in CEC 2013 Benchmark Suite. Finally, this algorithm is applied to the IoT based electric bus scheduling for urban waterlogging situation, and the excellent performance of MPPE is verified comprehensively.

We are investigating the relation between premature birth and face memory, taking into consideration other factors known to be related to face memory, such as gender and race/ethnicity and to birth status such as birth weight. Study 1, which was not pre-registered, was completed in April 2023. In Study 1, with data from over 900 undergraduate students attending a large Canadian university we found no difference in memory for faces for adults who were born preterm versus full term. We did, however, replicate a well-established finding with respect to race/ethnicity: White participants had significantly better memory for White faces than participants of other races. Now, for Study 2 and 3, we want to replicate and extend Study 1. For Study 2, we want to replicate the premature finding from Study 1, but with a non-university sample. Using Prolific, we will recruit White adults from Canada, USA, Great Britain, and Australia and use Bayesian statistics to see if we can again find evidence for our null hypothesis (i.e., there is no difference in face memory for adults who were born preterm versus fullterm). For Study 3, we will more closely investigate the effects of gender and ethnicity. In Study 1, the original Cambridge Face Memory Test (CFMT), which only consists of White male faces, was administered to all participants. For Study 3, we will further investigate any influences of gender and race/ethnicity on face memory by including three versions of the CFMT: Original, Female, and Chinese.

Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.

Millions of people suffer from bone loss and diseases each year, which give rise to bone-related medical treatments. Multi-material coatings composed of Silicon Substituted Hydroxyapatite (Si-HA) and Silver Substituted Hydroxyapatite (Ag-HA) potentiated its usage as an ideal bone implant material with favourable biological response and antibacterial properties, respectively. Each patient has different conditions (e.g. bone ages, bone density, position, and infection status) and specific bone implant requirement, thus requiring specific designs of Si-HA and Ag-HA bone implant material ratios. In this paper, a recommender system which took advantage of Wide&Deep recommendation architecture and DenseNet architecture was provided and a semi-supervised training process was utilized to recommend appropriate bone implant material ratio (Si-HA:Ag-HA) for each patient to improve the bone disease treatment and recovery. The proposed recommendation system could achieve high accuracy ( $$92.2\%$$ ) and efficiency (using only $$10\%$$ of labeled data) on test dataset, which could be potentially utilized in future clinical usages and provide doctors with decision support to make better clinical decisions.

The textual similarity task, which measures the similarity between two text pieces, has recently received much attention in the natural language processing (NLP) domain. However, due to the vagueness and diversity of language expression, only considering semantic or syntactic features, respectively, may cause the loss of critical textual knowledge. This paper proposes a new type of structure tree for sentence representation, which exploits both syntactic (structural) and semantic information known as the weight vector dependency tree (WVD-tree). WVD-tree comprises structure trees with syntactic information along with word vectors representing semantic information of the sentences. Further, Gaussian attention weight is proposed for better capturing important semantic features of sentences. Meanwhile, we design an enhanced tree kernel to calculate the common parts between two structures for similarity judgment. Finally, WVD-tree is tested on widely used semantic textual similarity tasks. The experimental results prove that WVD-tree can effectively improve the accuracy of sentence similarity judgments.

Online training is necessary for public fire escaping with the development of WebVR (Virtual Realization on Web). However, the online real-time fire training could not implemented in WebVR for the large-scale public scenario because of the huge size of VR fire scenario data, the low network transmission speed, and the slowly rendering ability of Web browser. To solve these bottlenecks, we propose a suite of solution for WebVR online fire training. Firstly, we implement a series of lightweight technologies to compress the large-scale scene data. The huge BIM (Building Information Modeling) volume data could be compressed by as much as 10 times. Then, we propose a kind of FDS (Fire Dynamic Simulator) smoking data lightweight mechanism to compress huge volume smoke data, which can be reduced by as much as 30 times. Thirdly, we adopt the multithread loading mechanism to accelerate WebVR fire scenario lightweight data. Finally, we collect the escape traces from history fire evacuation of the public, who wear the VR devices. Based on the valuable traces, we propose the TC-eACO algorithm to plan crowd optimal evacuation paths. At the same time, we implement a prototype system based on TC-eACO for WebVR fire evacuation training, with which the user just needs to surf the internet and take part in the fire evacuation training. The experimental results demonstrate that the solutions we proposed are feasible for online fire evacuation training not only in subway stations but also in other types of buildings.

Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody–drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor–positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.

Virtual training of metro fire evacuation definitely becomes considerably more efficient and convenient immigration of trainees from the PC desktop to mobile web browsers. However, web browsers face extreme difficulty in sustaining online visualization of large-scale building information modeling (BIM) data on metro, FDS smoking data, crowding passengers, and planning of fire evacuation path simultaneously due to the weak rendering capability and limited networking bandwidth. Herein, a novel lightweight Web3D technology roadmap is proposed to address these problems. First, the lightweight preprocessing of metro BIM data is performed by semantic and geometric retrieval of repetitive entities. Second, crowding passengers are visualized online by reusing several avatars and behavior randomly in terms of textures and scales in a lightweight manner. Third, substantial smoking data are reduced by redundancy elimination and voxel normalization and rendered online with spirit texture particle. Finally, the backbone escape paths are extracted by clustering the virtual evacuation traces that are collected by virtual reality devices, such as HTC VIVE, as initial heuristics, and a lightweight metro fire evacuation planning evacuation based on adaptive ant colony optimization is realized on mobile web browsers. Numerous tests have been conducted online, and experimental results show that the proposed method can be loaded remotely in a few seconds and visualized on mobile web browsers smoothly.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor–positive (ER+) metastatic breast cancer. We tested whether (18)F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. (18)F-fluoroestradiol PET and (18)F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline (18)F-fluoroestradiol uptake was associated with longer progression-free survival. (18)F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and (18)F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher (18)F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of (18)F-fluoroestradiol PET.

According to architectural structure of underground station and condition of passengers, the emergency evacuations are extremely important during emergency accidents caused in the stations. Based on the architectural features and situation of passengers in the station, Multi-Agent system is proposed to analyze passengers’ behavior and elements which affect passengers’ behavior. Base on the crowd mentality, the model of selective behavior of passengers’ route was established to simulate passengers’ actions during emergency accidents. It is feasible to find out the influence brought by crowd mentality affect the emergency evacuations, and the influence of remitting the situation from external factor through WebVR. At last, it provides references for emergency evacuation strategy.

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein–Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy. Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry. Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%–91.9%). Overall response rate (ORR) was 92% (95% CI, 64%–100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy. Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273–81. ©2018 AACR.

Background & Objective: Substantial progress has been made in treating HR+ metastatic breast cancer patients with CDK4/6, mTOR and PIK3CA inhibitors (all FDA approved), but there are no current available therapies to directly restore sensitivity to endocrine therapy once patients’ cells develop epigenetic suppression of ER pathways. CCCTC-binding factor (CTCF), which regulates higher-order chromatin organization and estrogen reception (ER) transcription, is altered by hemizygous deletion or mutation in more than 50% of HR+ luminal type breast tumors. The goal of this project is to characterize an epigenetic signature in CTCF-altered breast cancers to identify novel epigenetic targets for therapeutics development. Targeting CTCF influenced pathways with or without its chaperones may restore sensitivity to endocrine therapy in patients with HR+ breast cancer. Methods: We identified patient-derived cell lines from the Cancer Cell Line Encyclopedia (CCLE) with known CTCF gene copy number. Selected cell lines were tested for proliferation with a custom siRNA library targeting 1,300 genes involved in epigenetic regulation while in the presence of different concentrations of estradiol, tamoxifen and fulvestrant. We confirmed presence of CTCF protein by western blot and mRNA expression by real-time PCR. Proliferation of the lines in vitro was quantified by the MTT assay. Further functional annotation and pathway enrichment analysis of the identified genes were performed by using the g:ProfileR package. Results: We have screened more than 60 breast cancer cell lines and focused on six HR+ luminal (3 each “a” and “b” type) lines with different levels of CTCF copy number; a normal breast epithelial line was used as control. We observed that cell growth responded to anti-estrogen therapy differently based on the copy number of CTCF. Cells with high copy number of CTCF are resistant to endocrine therapy, the sensitivity was restored by silencing CTCF using siRNA. We then selected two cell lines with low and high copy number of CTCF for further high-throughput screening with the epigenetic siRNA library. A total of 67 and 35 candidate sensitizer target genes, and 56 and 44 candidate enhancer target genes were prioritized in cells with low and high copy number of CTCF, respectively. Functional annotation and pathway enrichment analysis of the identified genes showed that cells with low copy number of CTCF had apoptosis related hits, such as BCL family and caspase genes; however, cells with high copy number of CTCF were found to relate to other epigenetic regulators such as DNMTs and CHD. This suggests that CTCF might form complexes with other epigenetic proteins to form abnormal chromatin configuration with abnormal regulation of ER pathway as consequence. Conclusions: To our knowledge, this is the first epigenetic library screen of HR+ luminal breast cancer cells with responses categorized by differential CTCF copy number status. We have confirmed CTCF as an important protein in predicting response to endocrine therapy and identified possible interactions between CTCF, DNMT and CHD. We conclude that development of therapeutics against targets identified in our screen to reverse endocrine resistance may be achievable for treatment of luminal breast cancers that undertake epigenetic deregulation. Keywords: Breast cancer; Hormone receptor positive; epigenetic screening Citation Format: Fengting Yan, Olga Nikolova, VK Gadi. High-throughput epigenetic screening in hormone receptor positive (HR+) breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-04-03.

Practical 3D printing application always encounters motor motion confliction and warping of ugly product. This paper presents the proper ways to solve these problems. Firstly, to be assured precise motion controlling, safety and 3D printing process stabilization, we present motion mutex approach with Karnaugh map for real time monitoring motor motion status, and its algorithm of motion mutex, based on this way to make motor motion coordination working to accomplish precise process controlling. Secondly, to obtain reliable and precise product with smooth surface and to reduce the time of fabrication product, we propose comprehensive path planning to achieve this purpose, which integrated contour offset scanning and short linear scanning. Finally, with these methods in the practice we have produced the beautiful statuette of warrior.

Mobile-WebVR based real-time fire evacuation suffers from the limitation of the cache and the computing of the Web-browser. This paper proposes a lightweight and intelligent solution for popular fire evacuation. Firstly, lightweighting the scenario objects; secondly, lightweighting the collision detection of avatars; thirdly, lightweighting the optimal path planning for real-time evacuation. At last, a lightweight evacuation system is created with fire flattering the Mobile-WebVR (Lightweighting Fire Evacuation system, LFE system). The system uses the real data (the static scenario metro station BIM data, and the dynamic smoke data). The object data are reduced to 0.3%; 220 avatars as agents take part the fire evacuation on Mobile-Web showing the FPS value is 26; the heuristic ACO (Ant Colony Optimization) is used in the virtual reality metro station for each agent to plane path, and the LFE path planning is real-time and an effective solution.

It would be a horrible scene when a fire breaks out in any underground metro station, which could result in high human casualties. Therefore, the training of fire evacuation is highly necessary for the public. Among various current training methods, online fire evacuation training is a very popular one, owing to its low-cost and convenience. However, due to the huge size of data of both the representation of the metro station and the fire scenario, the limited bandwidth of network, and the weak rendering ability of web browser, the online fire evacuation training simulation usually runs extremely slow or is not able to run at all. This paper proposes a new virtual reality online training system for metro station fire evacuation. Firstly, a method based on semantic and voxelization component checking is introduced for light-weighting the large-scale metro station static scene, and the BIM (Building Information Modeling) data can be reduced by as much as 10 times. Next, we propose a smoke redundant-removing and normalization method, which is used for substantially light-weighting the dynamic FDS (Fire Dynamics Simulator) smoking data (as much as 200 times in our experiments). With the above methods, the metro station and smoke data can transmit through the internet quickly, and real-time rendering can be achieved on web pages by using a multi-thread mechanism. Finally, we present our eACO (evacuation based on adaptive Ant Colony Optimization) algorithm which can be used for the planning of mass fire evacuation. A prototype system based on eACO is implemented for VR (Virtual Realization) the fire evacuation training on Web, with which the user just needs to surf the internet (without loading and installing plug-ins) and take part in the fire evacuation training. The experimental results demonstrate that the proposed solution is feasible for online training in metro station fire evacuation. The technologies developed are also suitable for fire simulation and evacuation training in other urban infrastructures.

We report a case of platypnea-orthodeoxia syndrome resulting from multiple inter-atrial communications with right-toleft shunting in a 73 year old woman. Our patient presented with progressive shortness of breath over the last eighteen months. She was on 10 liters of high flow oxygen at time of presentation to our hospital and was bed bound owing to severe dyspnea. Her history of chronic pulmonary emboli despite therapeutic coumadin levels and ulcerative colitis initially led to an exhaustive hepatopulmonary work-up. On clinical exam, she was noted to have normal oxygen saturation with lying down, but with sitting up or walking she developed significant hypoxia and respiratory distress. With no evidence of lung parenchymal or vascular diseases, right heart catheterization was performed and revealed normal right sided pressures. Intracardiac echocardiography confirmed a typical appearing patent foramen ovale (PFO) with atrial septal aneurysm and bidirectional shunting, and a small inferior secundum atrial septal defect (ASD). Although the ASD was congenital, aortic dilation with ageing could have altered the location of the atrial septum which facilitated laminar blood flow from the inferior vena cava to the left atrium. We proceeded to close both defects with an Amplatzer Cribiform Occluder. Her symptoms dramatically improved 48 hours following closure and she was ambulating on room air at time of discharge. One month follow-up was notable for no recurrence of symptoms. PFOs and small ASDs are generally innocuous but could cause right to left shunting even in the absence of elevated right sided pressures. Excluding other causes of platypnea-orthodeoxia, and closing the atrial communications can lead to resolution of symptoms. Key words: Multiple Atrial Communications, Platypnea-Orthodeoxia Syndrome.

In mountain battlefield, the path planning of the army needs many detail scene information which based on the semantic information (SI) of the mountain terrain. This paper basing on SI addresses a kind of mACO(mountain Ant Colony Optimal) path planning method to compute an optimal path in the mountain terrain for Web3D. A series of solutions proposed inhere: abstracting the mountain information including ray stone, round wood, entrenchment, bamboo nails trap and the fire power semantic information, then mapping every weapon's destruction value into every mountain terrain and use the value to compute the pheromones, which will be reused in the process of path planning. And at last, a leader-follower idea is used for the army marching basing on the optimal path. The mACO algorithm is compared with the classical ACO algorithm and the A star algorithm, and the experimental results show that the mACO algorithm is real-time and its optimal path is shorter than the others.

Clinical trials and correlative laboratory research are increasingly reliant upon archived paraffin-embedded samples. Therefore, the proper processing of biological samples is an important step to sample preservation and for downstream analyses like the detection of a wide variety of targets including micro RNA, DNA and proteins. This paper analyzed the question whether routine fixation of cells and tissues in 10% buffered formalin is optimal for in situ and solution phase analyses by comparing this fixative to a variety of cross linking and alcohol (denaturing) fixatives. We examined the ability of nine commonly used fixative regimens to preserve cell morphology and DNA/RNA/protein quality for these applications. Epstein-Barr virus (EBV) and Bovine Papillomavirus (BPV)-infected tissues and cells were used as our model systems. Our evaluation showed that the optimal fixative in cell preparations for molecular hybridization techniques was “gentle” fixative with a cross-linker such as paraformaldehyde or a short incubation in 10% buffered formalin. The optimal fixatives for tissue were either paraformaldehyde or low concentration of formalin (5% of formalin). Methanol was the best of the non cross-linking fixatives for in situ hybridization and immunohistochemistry. For PCR-based detection of DNA or RNA, some denaturing fixatives like acetone and methanol as well as “gentle” cross-linking fixatives like paraformaldehyde out-performed other fixatives. Long term fixation was not proposed for DNA/RNA-based assays. The typical long-term fixation of cells and tissues in 10% buffered formalin is not optimal for combined analyses by in situ hybridization, immunohistochemistry, or -if one does not have unfixed tissues - solution phase PCR. Rather, we recommend short term less intense cross linking fixation if one wishes to use the same cells/tissue for in situ hybridization, immunohistochemistry, and solution phase PCR.

Infection by the human papillomavirus (HPV) is a cause of cervical intraepithelial neoplasia (CIN) and cancer. microRNA (miRNA) in situ analysis of the transformation zone epithelia, the site of initial cervical HPV infection, showed that miRNAs let-7c, — 99a, 26a, and 125b were the most abundantly expressed. In situ testing of CIN 1 showed a dramatic reduction in miR-125b expression in the koilocytes, the cytologic marker of productive HPV infection. A marked reduction in miR-125b was likewise observed in the HPV-infected cells of the condyloma acuminatum, verruca vulgaris, and epidermodysplasia verruciformis. Reverse transcriptase in situ polymerase chain reaction (PCR) showed that the pre-miRNA 125b was present in the koilocyte, suggesting direct inactivation of the mature miRNA. HEK cells transfected with only the antimiR-125b showed perinuclear halos equivalent to HPV-infected koilocytes. NIH 3T3 cells transfected with the HPV 16 full-length genome and mimetic miR-125b showed a marked reduction in viral DNA and protein synthesis by quantitative PCR and in situ-based analyses, respectively (P=0.002). Alternatively, cotransfection with anti-miR-125b and HPV 16 markedly increased HPV DNA (P=0.002). Sequence analyses showed strong homology between L2 of different HPV genotypes and miR-125b. Transfection with HPV 16 L2 resulted in a marked reduction in miR-125b levels in the NIH 3T3 cells. HPV L2-induced inactivation of miR-125b is associated with the classic cytologic changes of the koilocyte, and the exogenous application of mimetic miR-125b markedly inhibits HPV DNA synthesis.

Recurrent metastatic breast cancer is difficult to treat and patients often exhaust standard-of-care regimens. P.A.R.I.S. is a CLIA certified high throughput chemosensitivity test developed by SEngine Precision Medicine. (Seattle, WA USA) Tumor cells derived from patient breast tissue are expanded as mammospheres, and challenged with a library of 123 clinically actionable, targeted drugs. These results are integrated with patient genomic data and reported to the oncologist to prioritize treatment options. To date, we have performed over 100 such drug screens using low passage patient-derived tumor cells in 70 independent replicate pairs. Of 18 viable primary breast tumor samples received to date, we have successfully derived organotypic cultures in 13 cases. (72%) Of these, 7 were challenged to the full 123 agent library. Three of the seven cases were HER2 positive and demonstrated clear sensitivity to HER2 kinase inhibitors. Overall, patients can be separated into two groups, characterized by families of drug sensitivities. Patients in group one respond preferentially to inhibitors of signaling pathways such as IGF1R, ALK, FGFR and EGFR. Patients in the second group responded to therapies targeting epigenetic modifiers, cell cycle control and apoptosis. Presented here is a premenopausal female, diagnosed in 2010 as pT2N0M0 (stage IIA), ER+ PR+ HER2+. This patient underwent surgery and received adjuvant chemotherapy, followed by tamoxifen. Upon progression to metastatic disease, biopsy of her recurrent lesion showed loss of ER and PR expression, but remained positive for HER-2 amplification. Sequencing of this biopsy exposed a PIK3CA G106R mutation and amplification of unknown significance. Tumor cells were isolated from ascites, cultured and the P.A.R.I.S. test was performed. Patient derived tumor cells were sensitive to HER2 targeting agents, concordant with the patient's HER2 amplification. Of these, the non-reversible inhibitor neratinib exhibited a significantly enhanced effect and achieved maximum growth inhibition of 80% over the duration of the assay. Two different AKT inhibitors, afuresertib and AZD5363, demonstrated activity in the patient cells consistent with the activating PIK3CA mutation. Also consistent with the loss of ER/PR expression, the patient derived tumor cells no longer responded to anti-estrogen therapies nor to chemotherapies the patient had been refractory to prior: cyclophosphamide, docetaxel, doxorubicin, gemcitabine, and paclitaxel.The PARIS assay is a robust ex vivo screening platform to objectively quantify patient specific sensitivities to a panel of 123 clinically actionable oncology drugs. We show here concordance with both genomic data and prior treatments the patient received in the course of disease however the same approach may be used to successfully identify unique sensitivities in the absence of established biomarkers. Citation Format: Michael J. Churchill, Franz X. Schaub, Hallie A. Swan, Rachele Rosati, Fengting Yan, Reid C. Shaw, Kay E. Gurley, Robert L. Diaz, Shalini C. Pereira, Carla Grandori, Christopher J. Kemp, Vijayakrishna K. Gadi. Patient derived tumor organoids identify actionable targets in heavily pretreated metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1603.

Family summer travel packages designing should consider the demands of different families, such as the number of people, the cost, the time and the other factors. It is important to decide how to choose the scenic spot in order to make the trip to scenic spots as much as possible, as far as possible. This problem can be abstracted as a multi-objective programming problem. Therefore, we can make use of multi-objective optimization model to filter scenic spots. Keywords-intelligent filter; multi-objective programming model; traveling salesman problem; genetic algorithm This is a classical traveling salesman problem, and we can make use of Genetic Algorithm and other algorithms to solve a specific line of travel. In view of a tourist city, Shanghai for example, there is numerous of scenic spots and several of choices of completing the tour. We can calculate the attractions of some districts in Shanghai and put forward a concept of degree dense according to the Shanghai attractions to partition scenic spots, and then filtered each partition attractions. In this way, we can save calculate and make the calculation to be more operability and practicability. We use Genetic Algorithm to find the optimal route. This method can greatly reduce the amount of calculation, and our solutions are more comprehensive. It can meet the demands of various customers. Different level demands of different family can be divided respectively: (1) there is no cost constraint, but time limitation; (2) there is cost limitation, and a time limitation; (3) there is cost limitation, but no cost restriction. The first and the third are two special circumstances, and the second is a common condition. In this case, different levels of requirement should have different optimal routes. In view of different levels of demand analysis, such as different scenic spot category, natural folk, entertainment and leisure, cultural sports class, we can plan the daily schemes.

Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)–induced B-cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV+ lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first-in-class, small-molecule PRMT5 inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA-sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV-driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas. This work was supported by grants from the American Society of Hematology/European Hematology Association (L.Alinari), the Leukemia & Lymphoma Society Translational Research Project (LLS TRP) (R.A.B.), Friends of Jason Gould Foundation (R.A.B., P.L.S., J.T.P.), The Ohio State University Drug Development Institute (R.A.B., C.L.), National Institutes of Health, National Institute of Neurological Disorders and Stroke grant R21NS071346 (R.A.B., C.L.) and National Cancer Institute grant R01CA116093 (S.S., R.A.B.).

The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL.