Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effect of Different Linkers on Target Cell Catabolism and Pharmacokinetics/Pharmacodynamics of Trastuzumab Maytansinoid Conjugates

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody–drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the in vitro and in vivo activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examined. Both ADCs showed high in vitro potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. In vitro target cell processing of T-DM1 and T-SPP-DM1 produced lysine-Nϵ-MCC-DM1, and lysine-Nϵ-SPP-DM1 and DM1, respectively; in vivo studies confirmed these results. The in vitro processing rates for the two conjugate to their respective catabolites were similar. In vivo, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concentrations (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chemical nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor. Mol Cancer Ther; 11(5); 1133–42. ©2012 AACR.
Host Integrity Protection Through Usable Non-discretionary Access Control

Existing non-discretionary access control systems (such as Security Enhanced Linux) are difficult to use by ordinary users. We identify several principles for designing usable access control system and introduce the Host Integrity Protection Policy (HIPP) model that adds usable non-discretionary access control to operating systems. The HIPP model is designed to defend against attacks targeting network server and client programs and to protect the system from careless mistakes users might make. It aims at not breaking existing applications or existing ways of using and administering systems. HIPP has several novel features to achieve these goals. For example, it supports several types of partially trusted programs to support common system administration practices. Furthermore, rather than requiring file labeling, it uses information in the existing discretionary access control mechanism for non-discretionary access control. We also discuss our implementation of the HIPP model for Linux using the Linux Security Modules framework, as well as our evaluation results.
The First Hypertension Trial Comparing the Effects of Two Fixed‐Dose Combination Therapy Regimens on Cardiovascular Events: Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH)

Current recommendations for the treatment of hypertension clarify the need to achieve lower blood pressure levels in the general population (<140/90 mm Hg) and in specific high‐risk patient groups such as patients with diabetes or chronic renal disease (<130/80 mm Hg). Further, it is evident that to reach appropriate blood pressure control, most patients with high blood pressure will require two or more antihypertensive agents. There is scarce clinical trial outcome evidence to guide clinicians in the selection of optimal combinations of antihypertensive classes for high‐risk hypertensive patients. A new clinical trial, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is the first large clinical trial to directly compare cardiovascular mortality and morbidity rates for two fixed‐dose combination therapies. Results from ACCOMPLISH should provide much‐needed guidance for selecting optimal combination therapy for high‐risk hypertensive patients.
Effect of binder and mixture variables on glass transition behavior of asphalt mixtures

The thermal coefficient of contraction of asphalt mixtures is one of the required properties in the prediction of thermal cracking of asphalt pavements. Due to the significant influence of asphalt binders on asphalt mixtures' thermal properties, asphalt mixtures are expected to show a significant glass transition behavior. In current practice, however, the thermal coefficient of contraction of mixtures is assumed to be linear, and determined from a simplistic relationship with binders that takes into account volumetric and physical mixture properties. Although measuring thermal properties of asphalt mixtures has been a long-standing research topic for the last decade, a limited number of studies have explored the methods for the direct measurements of these properties. Using the findings of previous studies, a system was developed in this project for the direct measurement of change in temperature. The system was used to show the significant glass transition experienced by mixtures and to evaluate the effect of mix variables on the thermal properties. The investigation included the thermal properties of 23 mixture specimens produced from six types of asphalt binders, two sources of aggregates, and two levels of gradation. In the test, a wide temperature range from +40 degrees C to -90 degrees C induced a thermal change in the specimens. In order to study the effect of cooling rates on the properties of interest, two different cooling rates were applied while the specimens' thermal contraction was continuously measured. The measured data allowed an estimation of the Glass Transition and thermal coefficient of contractions above and below the Glass Transition for each mixture. Statistical analysis was conducted to relate the mix variables with the thermal properties. The results indicated the developed system is practical and repeatable, offering a means for reliable evaluations of glass transition of the asphalt mixtures. The results showed the need for considering dual thermal coefficients of contraction and that such an approach would provide more accurate results in the prediction of thermal stress. The results also indicated that the asphalt binder glass transition temperature and aggregate type appeared to have important effects on the thermal properties.
Improving CNN Performance Accuracies With Min–Max Objective

We propose a novel method for improving performance accuracies of convolutional neural network (CNN) without the need to increase the network complexity. We accomplish the goal by applying the proposed Min–Max objective to a layer below the output layer of a CNN model in the course of training. The Min–Max objective explicitly ensures that the feature maps learned by a CNN model have the minimum within-manifold distance for each object manifold and the maximum between-manifold distances among different object manifolds. The Min–Max objective is general and able to be applied to different CNNs with insignificant increases in computation cost. Moreover, an incremental minibatch training procedure is also proposed in conjunction with the Min–Max objective to enable the handling of large-scale training data. Comprehensive experimental evaluations on several benchmark data sets with both the image classification and face verification tasks reveal that employing the proposed Min–Max objective in the training process can remarkably improve performance accuracies of a CNN model in comparison with the same model trained without using this objective.
The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.

Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha-APA derivative) and HBY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HBY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant.
What Is Breast in the Bone?

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%–50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural “recycling” of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.
Increasing Use of Elective Mastectomy and Contralateral Prophylactic Surgery Among Breast Conservation Candidates: A 14-year Report From a Comprehensive Cancer Center

Background: First-line surgical options for early-stage breast cancer include breast-conserving surgery (BCS) or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. Methods: We analyzed the rates of mastectomy and BCS for 1634 women who underwent upfront surgical treatment for AJCC stage 0, I, or II breast cancer between 1995 and 2008 using data from the University of Louisville James Graham Brown Cancer Center Tumor Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Results: Overall, 65.9% of women received BCS, and 34.1% received mastectomy over a 14-year period (annual BCS rate range, 38.6% to 77.7%). The mastectomy rate substantially decreased from 43.5% in 1995 to 22.5% in 2004 (P=0.0007) but then increased to 51.7% in 2008 (P<0.0001). During the years between 2004 and 2008 (vs. 1995 to 2003), there was a significant increase in the rates of mastectomy performed in conjunction with immediate reconstruction (IR: 35.7% vs. 8.4%; P<0.0001) and/or contralateral prophylactic mastectomy (CPM: 22.9% vs. 3.3%; P<0.0001). On the basis of the multivariate analysis, the rate of receiving mastectomy was drastically higher for patients treated since 2004 (vs. before 2004), uninsured and government-insured (vs. privately insured) patients, patients with pT2 disease (vs. pTis or pT1), patients with pN1 disease (vs. pNX or pN0). Conclusions: In this longitudinal registry study, major independent determinants of mastectomy for early-stage breast cancer include year of diagnosis, insurance status, and stage. Mastectomy rates declined until 2004, but have since increased in conjunction with immediate reconstruction and contralateral prophylactic mastectomy. Additional study is needed to identify the underlying reasons for and unintended consequences of the reemergence of radical surgery for early-stage breast cancer in the era of multidisciplinary care.
The natural course of unruptured cerebral aneurysms in a Japanese cohort.

BACKGROUND The natural history of unruptured cerebral aneurysms has not been clearly defined. METHODS From January 2001 through April 2004, we enrolled patients with newly identified, unruptured cerebral aneurysms in Japan. Information on the rupture of aneurysms, deaths, and the results of periodic follow-up examinations were recorded. We included 5720 patients 20 years of age or older (mean age, 62.5 years; 68% women) who had saccular aneurysms that were 3 mm or more in the largest dimension and who initially presented with no more than a slight disability. RESULTS Of the 6697 aneurysms studied, 91% were discovered incidentally. Most aneurysms were in the middle cerebral arteries (36%) and the internal carotid arteries (34%). The mean (±SD) size of the aneurysms was 5.7±3.6 mm. During a follow-up period that included 11,660 aneurysm-years, ruptures were documented in 111 patients, with an annual rate of rupture of 0.95% (95% confidence interval [CI], 0.79 to 1.15). The risk of rupture increased with increasing size of the aneurysm. With aneurysms that were 3 to 4 mm in size as the reference, the hazard ratios for size categories were as follows: 5 to 6 mm, 1.13 (95% CI, 0.58 to 2.22); 7 to 9 mm, 3.35 (95% CI, 1.87 to 6.00); 10 to 24 mm, 9.09 (95% CI, 5.25 to 15.74); and 25 mm or larger, 76.26 (95% CI, 32.76 to 177.54). As compared with aneurysms in the middle cerebral arteries, those in the posterior and anterior communicating arteries were more likely to rupture (hazard ratio, 1.90 [95% CI, 1.12 to 3.21] and 2.02 [95% CI, 1.13 to 3.58], respectively). Aneurysms with a daughter sac (an irregular protrusion of the wall of the aneurysm) were also more likely to rupture (hazard ratio, 1.63; 95% CI, 1.08 to 2.48). CONCLUSIONS This study showed that the natural course of unruptured cerebral aneurysms varies according to the size, location, and shape of the aneurysm. (Funded by the Ministry of Health, Labor, and Welfare in Japan and others; UCAS Japan UMIN-CTR number, C000000418.).
Analyzing natural-language artifacts of the software process

Software teams, as they communicate throughout the life-cycle of their projects, generate a substantial stream of textual data. Through emails and chats, developers discuss the requirements of their software system, they negotiate the distribution of tasks among them, and they make decisions about the system design, and the internal structure and functionalities of its code modules. The software research community has long recognized the importance and potential usefulness of such textual information. In this paper, we discuss our recent work on systematically analyzing several textual streams collected through our WikiDev2.0 tool. We use two different text-analysis methods to examine five different sources of textual data. We report on our experience using our method on analyzing the communications of a nine-member team over four months.
Ieee Transactions on Visualization and Computer Graphics 1 Creature Control in a Fluid Environment

—In this paper, we propose a method designed to allow creatures to actively respond to a fluid environment. We explore various objective functions in order to determine ways to direct the behavior of our creatures. Our proposed method works in conjunction with generalized body forces as well as both one-way and two-way coupled fluid forces. As one might imagine, interesting behaviors can be derived from minimizing and maximizing both drag and lift as well as minimizing the effort that a creature's internal actuators exert. A major application for our work is the automatic specification of secondary motions, for example, certain joints can be animated while others are automatically solved for in order to satisfy the objective function.
A Prototype for Automating Ontology Learning and Ontology Evolution

Ontology learning supports ontology engineers in the complex task of creating an ontology. Updating ontologies at regular intervals greatly increases the need for expensive expert contribution. This naturally leads to endeavors to automate the process wherever applicable. This paper presents a model for automated ontology learning and a prototype which demonstrates the feasibility of the proposed approach in learning lightweight domain ontologies. The system learns ontologies from heterogeneous sources periodically and delegates all evaluation processes, eg. the verification of new concept candidates, to a crowdsourcing framework which currently relies on Games with a Purpose. Furthermore, we sketch ontology evolution experiments to trace trends and patterns facilitated by the system. (authors' abstract)
Every microsecond counts: tracking fine-grain latencies with a lossy difference aggregator

Many network applications have stringent end-to-end latency requirements, including VoIP and interactive video conferencing, automated trading, and high-performance computing---where even microsecond variations may be intolerable. The resulting fine-grain measurement demands cannot be met effectively by existing technologies, such as SNMP, NetFlow, or active probing. We propose instrumenting routers with a hash-based primitive that we call a Lossy Difference Aggregator (LDA) to measure latencies down to tens of microseconds and losses as infrequent as one in a million. Such measurement can be viewed abstractly as what we refer to as a coordinated streaming problem, which is fundamentally harder than standard streaming problems due to the need to coordinate values between nodes. We describe a compact data structure that efficiently computes the average and standard deviation of latency and loss rate in a coordinated streaming environment. Our theoretical results translate to an efficient hardware implementation at 40 Gbps using less than 1% of a typical 65-nm 400-MHz networking ASIC. When compared to Poisson-spaced active probing with similar overheads, our LDA mechanism delivers orders of magnitude smaller relative error; active probing requires 50--60 times as much bandwidth to deliver similar levels of accuracy.
Product families and process families

Product lines or families represent an important way of organizing software products. Product families might include, for example, successive revisions of a single application, versions of an application for different host platforms, or versions with varying features, e.g., different levels of security. A software product family can thus be viewed as a collection of products that are similar in some important respects yet systematically different in others. The family viewpoint emphasizes both the commonality among family members and the differences between them, and it draws attention to their interrelationships. Our work in software processes has lead us to conclude that software processes also can be usefully viewed in terms of families. As software process engineers, we also naturally view products in terms of the processes that create them and, conversely, we view processes in terms of the products they create. This suggests that product families and process families should be closely interrelated. Consequently, both products and processes may benefit from analysis in terms of families and family relationships. We begin to sketch out such an analysis and some of the issues that it raises.
Combustion and gasification in fluidized beds

INTRODUCTION Background Fluidized Bed Equipment Features of Fluidized Beds Fluidized Bed and Other Clean Coal Options HYDRODYNAMICS Regimes of Fluidization Fast Fluidized Bed Hydrodynamic Regimes in a CFB Hydrodynamic Structure of Fast Beds Gas-Solid Mixing Scale-Up FLUIDIZED BED GASIFICATION Types of Gasifiers Theory Effect of Operating Parameters on Gasification Effect of Feed Properties on Gasification Fluidized Bed Gasification Examples of Some Fluidized Bed Gasifiers Gas Cleaning Design Methods Modeling of Fluidized Bed Gasification Appendix 3A: Estimating Equilibrium Gas Composition Appendix 3B: An Example of a Fluidized Bed Biomass Gasifier COMBUSTION Stages of Combustion Factors Affecting Combustion Efficiency Combustion in Bubbling Fluidized Bed Boilers Combustion in Circulating Fluidized Bed Boilers Biomass Combustion EMISSIONS Air Pollution Sulfur Dioxide Emission Nitrogen Oxide Emission Nitrous Oxide Emission Mercury Emission Carbon Monoxide Emission Carbon Dioxide Emission Emission of Trace Organics Particulate Emission HEAT TRANSFER Gas-to-Particle Heat Transfer Heat Transfer in Circulating Fluidized Beds Heat Transfer in Bubbling Fluidized Bed Freeboard Heat Transfer in Bubbling Fluidized Beds Heat Transfer in Commercial-Size CFB Boilers BUBBLING FLUIDIZED BED BOILER Description of a BFB Boiler Features of BFB Boilers Thermal Design of Bubbling Fluidized Bed Boilers Combustion in Bubbling Fluidized Bed Furnace Design Start-Up Procedure and Control Some Operational Problems and Remedies Design of Feed Systems for BFB Bed Boiler CIRCULATING FLUIDIZED BED BOILER General Arrangement Types of CFB Boilers Non-CFB Solid Circulation Boilers Combustion in a Circulating Fluidized Bed Furnace Design of CFB Boilers Furnace Design Design of Heating Surfaces Auxiliary Power Consumption Control of CFB Boilers Supercritical CFB Boiler MATERIAL ISSUES Material Selection Criteria Erosion Potential Corrosion Potentials Steels Used in Fluidized Bed Boilers Refractory and Insulations Expansion Joints SOLID HANDLING SYSTEMS FOR FLUIDIZED BEDS Solid Handling Systems Biomass Handling Systems Feed System for Bubbling Beds Feed System for Circulating Fluidized Beds Design of Pneumatic Transport Lines for Solids AIR DISTRIBUTION GRATE Distributor Plates Operation of Distributors Design Methods Practical Considerations GAS-SOLID SEPARATORS Cyclones Impact Separator Inertial Separators SOLID RECYCLE SYSTEMS Types of Non-mechanical Valves Principles of Operation Design of Loop-Seal Design of L-Valve Practical Considerations Nomenclature References APPENDIX 1: CHARACTERISTICS OF SOLID PARTICLES APPENDIX 2: STOICHIOMETRIC CALCULATIONS APPENDIX 3: SIMPLIFIED MODEL FOR SULFUR CAPTURE APPENDIX 4: TABLES OF DESIGN DATA