gebhart/patrepeval huggingface dataset:
Targetable Pathways in Advanced Bladder Cancer: FGFR Signaling (2021)

Bladder cancer is the 10th most commonly diagnosed cancer in the world, accounting for around 573,000 new cases and 213,000 deaths in 2020. The current standard treatment for locally advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. The significant progress being made in the genomic and molecular understandings of bladder cancer has uncovered the genetic alterations and signaling pathways that drive bladder cancer progression. These developments have led to a dramatic increase in the evaluation of molecular agents targeting at these alterations. One example is Erdafitinib, a first-in-class FGFR inhibitor being approved as second-line treatment for locally advanced or metastatic urothelial carcinoma with FGFR mutations. Immunotherapy has also been approved as second-line treatment for advanced and metastatic bladder cancer. Preclinical studies suggest targeted therapy combined with immunotherapy has the potential to markedly improve patient outcome. Given the prevalence of FGFR alternations in bladder cancer, here we review recent preclinical and clinical studies on FGFR inhibitors and analyze possible drug resistance mechanisms to these agents. We also discuss FGFR inhibitors in combination with other therapies and its potential to improve outcome.
Small-molecule agonists and antagonists of F-box protein–substrate interactions in auxin perception and signaling (2008)

The regulation of gene expression by the hormone auxin is a crucial mechanism in plant development. We have shown that the Arabidopsis F-box protein TIR1 is a receptor for auxin, and our recent structural work has revealed the molecular mechanism of auxin perception. TIR1 is the substrate receptor of the ubiquitin-ligase complex SCF(TIR1). Auxin binding enhances the interaction between TIR1 and its substrates, the Aux/IAA repressors, thereby promoting the ubiquitination and degradation of Aux/IAAs, altering the expression of hundreds of genes. TIR1 is the prototype of a new class of hormone receptor and the first example of an SCF ubiquitin-ligase modulated by a small molecule. Here, we describe the design, synthesis, and characterization of a series of auxin agonists and antagonists. We show these molecules are specific to TIR1-mediated events in Arabidopsis, and their mode of action in binding to TIR1 is confirmed by x-ray crystallographic analysis. Further, we demonstrate the utility of these probes for the analysis of TIR1-mediated auxin signaling in the moss Physcomitrella patens. Our work not only provides a useful tool for plant chemical biology but also demonstrates an example of a specific small-molecule inhibitor of F-box protein-substrate recruitment. Substrate recognition and subsequent ubiquitination by SCF-type ubiquitin ligases are central to many cellular processes in eukaryotes, and ubiquitin-ligase function is affected in several human diseases. Our work supports the idea that it may be possible to design small-molecule agents to modulate ubiquitin-ligase function therapeutically.
FCP (2013)

Transport protocols must accommodate diverse application and network requirements. As a result, TCP has evolved over time with new congestion control algorithms such as support for generalized AIMD, background flows, and multipath. On the other hand, explicit congestion control algorithms have been shown to be more efficient. However, they are inherently more rigid because they rely on in-network components. Therefore, it is not clear whether they can be made flexible enough to support diverse application requirements. This paper presents a flexible framework for network resource allocation, called FCP, that accommodates diversity by exposing a simple abstraction for resource allocation. FCP incorporates novel primitives for end-point flexibility (aggregation and preloading) into a single framework and makes economics-based congestion control practical by explicitly handling load variations and by decoupling it from actual billing. We show that FCP allows evolution by accommodating diversity and ensuring coexistence, while being as efficient as existing explicit congestion control algorithms.
Microbial–stem cell interactions in periodontal disease (2022)

Periodontitis is initiated by hyper-inflammatory responses in the periodontal tissues that generate dysbiotic ecological changes within the microbial communities. As a result, supportive tissues of the tooth are damaged and periodontal attachment is lost. Gingival recession, formation of periodontal pockets with the presence of bleeding, and often suppuration and/or tooth mobility are evident upon clinical examination. These changes may ultimately lead to tooth loss. Mesenchymal stem cells (MSCs) are implicated in controlling periodontal disease progression and have been shown to play a key role in periodontal tissue homeostasis and regeneration. Evidence shows that MSCs interact with subgingival microorganisms and their by-products and modulate the activity of immune cells by either paracrine mechanisms or direct cell-to-cell contact. The aim of this review is to reveal the interactions that take place between microbes and in particular periodontal pathogens and MSCs in order to understand the factors and mechanisms that modulate the regenerative capacity of periodontal tissues and the ability of the host to defend against putative pathogens. The clinical implications of these interactions in terms of anti-inflammatory and paracrine responses of MSCs, anti-microbial properties and alterations in function including their regenerative potential are critically discussed based on literature findings. In addition, future directions to design periodontal research models and study <i>ex vivo</i> the microbial-stem cell interactions are introduced.
Spatially resolved generation profiles for onshore and offshore wind turbines: A case study of four Dutch energy transition scenarios (2022)

In line with the Dutch Climate Agreement, multiple energy transition scenarios have been constructed for 2030 and 2050. To various extents, they project a shift towards decentralized and intermittent renewable electricity generation (wind and solar) and widespread deployment of electric vehicles and heat pumps. These developments impose challenges regarding electricity supply-demand mismatch and grid congestion. In order to gain an understanding of when and where such problems are likely to occur, temporally and spatially resolved interpretations of the energy transition scenarios are required. This paper focuses on Dutch wind energy supply and shows construction of geodatabases of scenario-specific, hourly onshore and offshore wind electricity generation profiles on an individual turbine level. For the geographical distribution of turbine capacity, datasets on historically operational turbines, planned wind parks and suggested future turbine distributions are utilized. Turbine electricity generation profiles are constructed using a high resolution 3D meteorological dataset and power curves of commercially available turbine models. They are corrected for air pressure deviations and a multitude of loss factors, including wake effects. Compared to the present-day situation, yearly country-level electricity generation is projected to be a factor 16.6, 24.6 or 12.8 higher in 2050 when following the Regional, National or International Steering scenarios, respectively. In comparison to both the present-day and 2030 situation, onshore electricity generation is projected to be more evenly spread over different parts of the country in 2050. All offshore wind exploration areas considered in this research are projected to be completely utilized by 2050.
Abstract A194: A QT/QTc and multi-dose pharmacokinetic (PK) study of abiraterone acetate (AA) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). (2011)

Abstract Background: AA is the prodrug of abiraterone (A), an androgen biosynthesis inhibitor that selectively inhibits CYP17, thereby blocking testicular, adrenal, and prostatic intratumoral androgen biosynthesis. In a phase 3 study, AA+P demonstrated survival improvements in post-docetaxel mCRPC pts (De Bono ESMO 2010). ADT with an LHRH analog (LHRHa) has been associated with median QTc interval prolongation of 9–21 msec (Garnick ASCO 2004). Primary objective: effects of AA+P on QT/QTc interval duration in mCRPC pts receiving LHRHa. Secondary objectives: pharmacokinetics (PK) of AA and abiraterone (A) after single/multiple doses of AA. Methods: In this open-label, single-arm phase 1b study (COU-AA-006/NCT00910754), 33 mCRPC pts with disease progression after failure of GnRH hormone therapy, a PSA ≥2 ng/mL and ≤1 course of prior chemotherapy, received AA 1000mg orally QD + P 5mg orally BID. ECGs were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle (C)1 Day (D)-1. Serial ECG recordings and time-matched PK blood samples were collected over 24 hrs on C1D1 and C2D1. Serial PK blood samples were also collected over 24 hrs on C1D8. Results: After AA administration, the upper bound of the 2-sided 90% CI for the mean baseline-adjusted QTcF change was &amp;lt;10 msec; no subjects discontinued due to QTc prolongation or AEs. Most AA plasma concentrations were below the quantification limit; thus AA PK analysis was not performed. A linear mixed-effects model showed no apparent relationship between change in QTcF and A plasma concentrations (estimated slope [90%CI): 0.0031 [−0.0040, 0.0102]). Exposure to A after multiple AA dosing on C1D8 and C2D1 increased versus exposure after single dose on C1D1; accumulation ratios for C1D8 (1.8–2.0) and C2D1 (2.0–2.2) were similar. The most commonly reported treatment-emergent AE (TEAE) was dizziness (12%); all TEAEs were grade 1; except 1 grade 3 AE (increased ALP) with no grade 4 TEAEs. Conclusions: There is no significant effect of AA+P on the cardiac QT/QTc interval in mCRPC pts. No relationship between change in QTcF and A plasma concentration was observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A194.
Techniques for measuring the common mode current and voltage of ASIC devices (2008)

With the increasing numbers of transistors in todaypsilas die as well as incorporating mixed technology (i.e. analog, RF, digital, and power), large scale devices with their large switching currents create internal voltage drops due to the package design (i.e. wire bond or flip-chip) that can be a source of common mode noise. The normal lumped components, the printed circuit boards, the harnessing, and the packaging are well known contributors and there are various measurement techniques to identify these noise sources. However, what is lacking are some measurement techniques applicable specifically for determining if a large scale integrated circuit type devices could be a noise source. This paper will look at a couple of proposed techniques specifically for the chip level.
Dietary supplementation with omega-3 polyunsaturated fatty acid-rich oils protects against visible-light-induced retinal damagein vivo (2018)

The effects of administering omega-3 (ω-3) polyunsaturated fatty acid (PUFA)-rich oils on visible-light-induced retinal damage were investigated in rabbits. The mole percentages of α-linolenic acid in sea buckthorn berry oil, sea buckthorn oil (SO), sea buckthorn seed oil and flaxseed oil (FO) were 2.12%, 12.98%, 31.56% and 55.41%, respectively. Algal oil (AO) contains 33.34% docosahexaenoic acid. SO has the highest total phenolic content (63.42 ± 0.59 mg SAE per 100 g) amongst these oils. The administration of SO, FO and AO provided structural and functional protection to the retina. In the retina, we observed a significant increase in the levels of DHA in the AO group compared with the normal group. The mechanism of retinal protection by SO, FO and AO involves up-regulating the expression of nuclear factor erythroid-2 related factor 2 and haem oxygenase-1. The levels of interleukin-1 β, tumour necrosis factor-alpha, interleukin-8, and cyclooxygenase 2 in the retina were significantly reduced with AO treatment. The administration of AO resulted in the down-regulation of nuclear factor kappa B mRNA expression. In addition, the treatment with AO significantly attenuated the light-induced apoptosis and angiogenesis in the retina. These results suggest that dietary ω-3 PUFA-rich oils protect against visible-light-induced retinal damage.
Evaluation of DNA repair biology signatures to predict specific carboplatin (C) versus docetaxel (D) benefit in advanced triple-negative breast cancer (aTNBC). (2020)

1074 Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 &amp; DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT &amp; recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 &amp; 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT &amp; REC. CIN70 increased from PT to REC, DDRD (non-significantly) &amp; PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 &amp; DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]
Enhancement Test of Critical Clearing Time of One-Machine Infinite Bus Transmission System by Use of SFCL (2018)

A transformer type field shielding superconducting fault current limiter (SFCL), which is made of rare-earth barium-copper-oxide (REBCO) for primary and secondary windings, is designed and made for demonstration of not only fault current limiting but also power system stability improvement performance. A lab-scale test power system consists of one machine (18.26 kVA, 200 V) and double transmission route to an infinite bus. The simulated fault occurs at the sending end of one of the transmission route and after a certain time (fault clearing time), the fault route was rejected by circuit breakers. While the clearing time is short, the generator can continue to operate with one healthy transmission route, however, it becomes longer than a certain time critical clearing time (CCT), the generator loses its synchronism and fails into step out. The test SFCL was installed at the generator side bus of the fault route. The peak fault current was reduced to less than half of that without SFCL and the generator terminal voltage did not fall below 20% of rated voltage. It was confirmed experimentally that CCT can be enhanced by introducing the SFCL. It is confirmed that the SFCL cannot only limit the fault current but also improve the system stability.
ChemInform Abstract: Serial Radical Cyclization of Pyranose‐Derived Dienes in the Stereocontrolled Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward′s Reserpine Precursor. (1995)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Probabilistic Weather Prediction with an Analog Ensemble (2013)

Abstract This study explores an analog-based method to generate an ensemble [analog ensemble (AnEn)] in which the probability distribution of the future state of the atmosphere is estimated with a set of past observations that correspond to the best analogs of a deterministic numerical weather prediction (NWP). An analog for a given location and forecast lead time is defined as a past prediction, from the same model, that has similar values for selected features of the current model forecast. The AnEn is evaluated for 0–48-h probabilistic predictions of 10-m wind speed and 2-m temperature over the contiguous United States and against observations provided by 550 surface stations, over the 23 April–31 July 2011 period. The AnEn is generated from the Environment Canada (EC) deterministic Global Environmental Multiscale (GEM) model and a 12–15-month-long training period of forecasts and observations. The skill and value of AnEn predictions are compared with forecasts from a state-of-the-science NWP ensemble system, the 21-member Regional Ensemble Prediction System (REPS). The AnEn exhibits high statistical consistency and reliability and the ability to capture the flow-dependent behavior of errors, and it has equal or superior skill and value compared to forecasts generated via logistic regression (LR) applied to both the deterministic GEM (as in AnEn) and REPS [ensemble model output statistics (EMOS)]. The real-time computational cost of AnEn and LR is lower than EMOS.
Involvement of cannabinoid receptor type 2 (CB2) to dendritic cell population on inflammatory and allergic response (2022)

Cannabinoid receptor type 2 (CB2) is one of the major receptors for cannabis, which is expressed all over the body especially on the immune-related cells. It is considered that CB2 can work as a regulator in the immune system, particularly to suppress inflammatory responses in macrophages and microglias when activated. However no other immune cells have been studied whether and how they get modulated by CB2 activity. The objective of this experiment is to search for the other immune cell that can be affected by CB2 activity, and reveal the detailed mechanism of CB2-involved immune regulation.
Enhancing Oral Vaccine Potency by Targeting Intestinal M Cells (2010)

The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells.
Influence of storage of milk on casein distribution between the micellar and soluble phases and its relationship to cheese-making parameters (1980)

Summary The influence of storage time and temperature on the distribution of individual milk proteins between the micellar and soluble phases has been examined. Storage at 4 or 7 °C is accompanied by a dissociation of micellar caseins, particularly β-casein, into the soluble phase during the first 48 h, but on further storage there is a partial reversal of this process. At higher storage temperatures (10–20 °C) the contents of all the individual caseins in the soluble phase decrease throughout storage. During cheese–making, losses of fat and curd fines in whey were greater with increased soluble phase casein and clotting times were prolonged. Curd structure was weaker, curds were more moist and slightly lower cheese yields were obtained in stored milks with elevated soluble–phase casein. When milks were stored for up to 3 d at 4 °C cheese gradings were virtually unaffected by storage, but higher temperatures (10–15 °C) led to cheeses being downgraded, largely for body and texture defects but also for flavour after 3 d. Attempts to reverse the pattern of casein dissociation and to minimize the detrimental effects of milk storage on subsequent cheese-making showed that a heat treatment of 30 min at 60 °C was the most beneficial.
Industry‐Driven Rapid Prototyping for Comparing Nonlinear Control Schemes in Pyomo (2020)

Abstract With ongoing digitalization, fast simulation of process dynamics offers new opportunities for model‐based control schemes. This is eased by the availability of high‐level, open‐access, easy‐to‐use software able to simulate and optimize chemical processes, making rapid prototyping possible also for the chemical engineer. In this study, the capabilities of the Python‐based open‐source software package Pyomo towards industrial application is illustrated in modeling and comparing different control schemes for a simple Williams‐Otto process. It is shown how to simulate the process dynamics and how to compute optimal control trajectories for minimizing waste and maximizing yield. Two approaches to setpoint tracking are compared: one based on proportional‐integral feedback control and one based on optimal open‐loop control.