Ray: A Distributed Execution Engine for the Machine Learning Ecosystem

In recent years, growing data volumes and more sophisticated computational procedures have greatly increased the demand for computational power. Machine learning and artificial intelligence applications, for example, are notorious for their computational requirements. At the same time, Moores law is ending and processor speeds are stalling. As a result, distributed computing has become ubiquitous. While the cloud makes distributed hardware infrastructure widely accessible and therefore offers the potential of horizontal scale, developing these distributed algorithms and applications remains surprisingly hard. This is due to the inherent complexity of concurrent algorithms, the engineering challenges that arise when communicating between many machines, the requirements like fault tolerance and straggler mitigation that arise at large scale and the lack of a general-purpose distributed execution engine that can support a wide variety of applications.In this thesis, we study the requirements for a general-purpose distributed computation model and present a solution that is easy to use yet expressive and resilient to faults. At its core our model takes familiar concepts from serial programming, namely functions and classes, and generalizes them to the distributed world, therefore unifying stateless and stateful distributed computation. This model not only supports many machine learning workloads like training or serving, but is also a good t for cross-cutting machine learning applications like reinforcement learning and data processing applications like streaming or graph processing. We implement this computational model as an open-source system called Ray, which matches or exceeds the performance of specialized systems in many application domains, while also offering horizontally scalability and strong fault tolerance properties

Qd-tree: Learning Data Layouts for Big Data Analytics

Corporations today collect data at an unprecedented and accelerating scale, making the need to run queries on large datasets increasingly important. Technologies such as columnar block-based data organization and compression have become standard practice in most commercial database systems. However, the problem of best assigning records to data blocks on storage is still open. For example, today's systems usually partition data by arrival time into row groups, or range/hash partition the data based on selected fields. For a given workload, however, such techniques are unable to optimize for the important metric of the number of blocks accessed by a query. This metric directly relates to the I/O cost, and therefore performance, of most analytical queries. Further, they are unable to exploit additional available storage to drive this metric down further. In this paper, we propose a new framework called a query-data routing tree, or qd-tree, to address this problem, and propose two algorithms for their construction based on greedy and deep reinforcement learning techniques. Experiments over benchmark and real workloads show that a qd-tree can provide physical speedups of more than an order of magnitude compared to current blocking schemes, and can reach within 2X of the lower bound for data skipping based on selectivity, while providing complete semantic descriptions of created blocks.Comment: ACM SIGMOD 202

Systemic Optimization of Booster Stations - From Data Collection to Validation

In the past, great efforts have been made to optimize pumps in the sense of a Product Approach: The energy efficiency at the pump's point of optimal operation was maximized by improving its design. While this has enabled considerable improvements in the optimal efficiency, in practical applications, where one finds oversizing or varying loads, 90% of the pumps are operated at partial load and thus not at their best operating point [1]. This insight has led to the Extended Product Approach [2], which considers pump and motor as part of a system with various operating points. A further step towards practically relevant energy assessment is the System Approach: here, the interactions of several components in the surrounding system are taken into account. This is of high relevance, since 85% of the energy consumption associated with pumps are actually dissipated in the system [1]. To address this, the systemic optimization of fluid systems was investigated in a joint project of TU Darmstadt, MLU Halle and KSB SE & Co. KGaA [3]. Employing the methodology Technical Operations Research (TOR), algorithms from discrete optimization were used to design optimal systems. In a current project of VDMA pumps+systems TOR is applied to a booster station for water supply in skyscrapers - a typical example of a fluid system. In this paper, we present the application of all steps of the TOR-methodology for a downscaled booster station. This includes data collection for modeling, global optimization as well as validation through simulations and experiments. First, the function of the system is described using load profiles that have to be fulfilled. Then the aim of the optimization - minimization of life cycle costs - is defined. For modeling the set of possible components, we use manufacturer's data. Based on this, a mathematical optimization model is developed. Only simplified models, e.g. without transient start-up procedures, can be considered within the optimization. For this reason, a simulation with Modelica is carried out in the next step. Afterwards, the optimal configuration is set up on a test rig and the feasibility of the configuration is checked. The fluid-system test rig is 6-meter-high and has five outlets to ambient pressure on different levels, which represents the downscaled water supply in a skyscraper. In total, 13 speed-controlled pumps are available, of which up to six can be operated and measured simultaneously as a booster station. A modular piping system allows the simple set-up of different system configurations. If shortcomings emerge either in simulation or experiment, the optimization program can be adapted

Bactericidal Efficacy of Cold Plasma at Different Depths of Infected Root Canals In Vitro

Objectives: Cold plasma (CP) has been shown to be effective even against multiresistant microorganisms. As previous investigations on the effect of CP in root canals showed promising results, the aim of the present study was to analyze the bactericidal efficacy of CP in different depths of infected dentin. Methods: 32 standardized root canals of human mandibular premolars were infected with Enterococcus faecalis and incubated for one week. Specimens were randomly selected for one of four disinfection methods: control (5mL NaCl), 5mL chlorhexidine (CHX), CP alone (CP), and a combination of 5mL CHX and cold plasma (CHX+CP). CHX was ultrasonically activated for 30s, while cold plasma was used for 60s in the root canals. Dentin samples at depths of 300, 500 and 800 µm were obtained and diluted serially. Colony forming units (CFUs) were counted on agar plates after 24h of incubation. Results: The highest overall logarithmic reduction factors (RF) were obtained from CHX+CP (log RF 3.56 p<0.01; Mann-Whitney U test), followed by CP (log RF 3.27 p<0.01) and CHX alone (log RF 2.65 p<0.01) related to the control. All disinfection methods showed significantly lower CFU counts compared to the control group in 300 µm and 800 µm (both p<0.01, Kruskal-Wallis test). Discussion: The adjuvant use of CP might be beneficial in highly infected root canals to improved disinfection. However, the disinfection effect against Enterococcus faecalis of CP is comparable to ultrasonically activated CHX

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration

Purpose: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. Methods: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. Results: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 +/- 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. Conclusion: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes

Splenic switch-off as a predictor for coronary adenosine response: validation against 13N-ammonia during co-injection myocardial perfusion imaging on a hybrid PET/CMR scanner

BACKGROUND Inadequate coronary adenosine response is a potential cause for false negative ischemia testing. Recently, the splenic switch-off (SSO) sign has been identified as a promising tool to ascertain the efficacy of adenosine during vasodilator stress cardiovascular magnetic resonance imaging (CMR). We assessed the value of SSO to predict adenosine response, defined as an increase in myocardial blood flow (MBF) during quantitative stress myocardial perfusion 13 N-ammonia positron emission tomography (PET). METHODS We prospectively enrolled 64 patients who underwent simultaneous CMR and PET myocardial perfusion imaging on a hybrid PET/CMR scanner with co-injection of gadolinium based contrast agent (GBCA) and 13N-ammonia during rest and adenosine-induced stress. A myocardial flow reserve (MFR) of  > 1.5 or ischemia as assessed by PET were defined as markers for adequate coronary adenosine response. The presence or absence of SSO was visually assessed. The stress-to-rest intensity ratio (SIR) was calculated as the ratio of stress over rest peak signal intensity for splenic tissue. Additionally, the spleen-to-myocardium ratio, defined as the relative change of spleen to myocardial signal, was calculated for stress (SMR$_{stress}$) and rest. RESULTS Sixty-one (95%) patients were coronary adenosine responders, but SSO was absent in 18 (28%) patients. SIR and SMR$_{stress}$ were significantly lower in patients with SSO (SIR: 0.56 ± 0.13 vs. 0.93 ± 0.23; p < 0.001 and SMR$_{stress}$: 1.09 ± 0.47 vs. 1.68 ± 0.62; p < 0.001). Mean hyperemic and rest MBF were 2.12 ± 0.68 ml/min/g and 0.78 ± 0.26 ml/min/g, respectively. MFR was significantly higher in patients with vs. patients without presence of SSO (3.07 ± 1.03 vs. 2.48 ± 0.96; p = 0.038), but there was only a weak inverse correlation between SMR$_{stress}$ and MFR (R = -0.378; p = 0.02) as well as between SIR and MFR (R = -0.356; p = 0.004). CONCLUSIONS The presence of SSO implies adequate coronary adenosine-induced MBF response. Its absence, however, is not a reliable indicator for failed adenosine-induced coronary vasodilatation

Correlation of Perfusion MRI and F-18-FDG PET Imaging Biomarkers for Monitoring Regorafenib Therapy in Experimental Colon Carcinomas with Immunohistochemical Validation

Objectives To investigate a multimodal, multiparametric perfusion MRI/F-18-fluoro-deoxyglucose (F-18-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation. Materials and Methods Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group;n = 7 control group) female athymic nude rats (Hsd: RH-Foxn1(mu)). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/F-18-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV,%) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In F-18-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67). Results Regorafenib significantly (p<0.01) suppressed PF (81.1 +/- 7.5 to 50.6 +/- 16.0 mL/100mL/min), PV (12.1 +/- 3.6 to 7.5 +/- 1.6%) and PS (13.6 +/- 3.2 to 7.9 +/- 2.3 mL/100mL/min) as well as TTB (3.4 +/- 0.6 to 1.9 +/- 1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0 +/- 2.4 vs. 16.1 +/- 5.9) and tumor cell proliferation (Ki-67, 434.0 +/- 62.9 vs. 663.0 +/- 98.3) in the therapy group. Perfusion MRI parameters Delta PF, Delta PV and Delta PS showed strong and significant (r = 0.67-0.78;p<0.01) correlations to the PET parameter Delta TTB and significant correlations (r = 0.57-0.67;p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55;p<0.05). Conclusions A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and F-18-FDG-PET validated by immunohistochemistry

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

Objectives To investigate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring therapy effects of regorafenib on experimental colon carcinomas in rats with correlation to dynamic contrast-enhanced MRI (DCE-MRI) and immunohistochemistry. Materials and Methods: Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n =21 (n = 11 therapy group;n = 10 control group) female athymic nude rats (Hsd: RH-Foxn1 (mu)). Animals were imaged at baseline and after a one-week daily treatment with regorafenib or a placebo (10 mg/kg bodyweight), using CEUS with VEGFR2-targeted microbubbles and DCE-MRI. In CEUS tumor perfusion was assessed during an early vascular phase (wash-in area under the curve = WiAUC) and VEGFR2-specific binding during a late molecular phase (signal intensity after 8 (SI8min) and 10 minutes (SI10min)), using a conventional 15L8 linear transducer (transmit frequency 7 MHz, dynamic range 80 dB, depth 25 mm). In DCE-MRI functional parameters plasma flow (PF) and plasma volume (PV) were quantified. For validation purposes, CEUS parameters were correlated with DCE-MRI parameters and immunohistochemical VEGFR2, CD31, Ki-67 and TUNEL stainings. Results: CEUS perfusion parameter WiAUC decreased significantly (116,989 +/- 77,048 a.u. to 30,076 +/- 27,095a.u.;p = 0.005) under therapy with no significant changes (133,932 +/- 65,960 a.u. to 84,316 +/- 74,144 a.u.;p = 0.093) in the control group. In the therapy group, the amount of bound microbubbles in the late phase was significantly lower in the therapy than in the control group on day 7 (SI8min: 283 +/- 191 vs. 802 +/- 460 a.u.;p = 0.006);SI10min: 226 +/- 149 vs. 645 +/- 461 a.u.;p = 0.009). PF and PV decreased significantly (PF: 147 +/- 58 mL/100 mL/min to 71 +/- 15 mL/100 mL/min;p = 0.003;PV: 13 +/- 3% to 9 +/- 4%;p = 0.040) in the therapy group. Immunohistochemistry revealed significantly fewer VEGFR2 (7.2 +/- 1.8 vs. 17.8 +/- 4.6;p < 0.001), CD31 (8.1 +/- 3.0 vs. 20.8 +/- 5.7;p < 0.001) and Ki-67 (318.7 +/- 94.0 vs. 468.0 +/- 133.8;p = 0.004) and significantly more TUNEL (672.7 +/- 194.0 vs. 357.6 +/- 192.0;p = 0.003) positive cells in the therapy group. CEUS parameters showed significant (p < 0.05) correlations to DCE-MRI parameters and immunohistochemistry. Conclusions CEUS with VEGFR2-targeted microbubbles allowed for monitoring regorafenib functional and molecular therapy effects on experimental colorectal adenocarcinomas with a significant decline of CEUS and DCE-MRI perfusion parameters as well as a significant reduction of specifically bound microbubbles under therapy, consistent with a reduced expression of VEGFR2

A randomized controlled trial to investigate the influence of low dose radiotherapy on immune stimulatory effects in liver metastases of colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases.</p> <p>Methods/Design</p> <p>This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I/II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastasis. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on, tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome.</p> <p>Discussion</p> <p>This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastasis infiltrating T cells and thus potentially enhance the antitumor immune response.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01191632">NCT01191632</a></p

18F–FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma

Background: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by F-18-FDG-PET/CT and diffusionweighted MRI (DW-MRI). Methods: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by 18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12;dabrafenib, 20 mg/kg/d;ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq F-18-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density -CD31;tumor cell proliferation -Ki-67). Results: Tumor glucose uptake was significantly suppressed under therapy (Delta TTLTherapy -1.00 +/- 0.53 vs.Delta TTLControl 0.85 +/- 1.21;p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (Delta ADC(Therapy) 0.12 +/- 0.14 x 10(-3) mm(2)/s;Delta ADCControl -0.12 +/- 0.06 x 10(-3) mm(2)/s;p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 +/- 48 vs. 287 +/- 92;p = 0.001) and proliferation (Ki-67, 3718 +/- 998 vs. 5389 +/- 1332;p = 0.007) in the therapy compared to the control group. Conclusion: A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by F-18-FDG-PET/CT and DW-MRI