gebhart/patrepeval huggingface dataset:
A first-in-class HDM2-inhibitor (JNJ-26854165) in phase I development shows potent activity against multiple myeloma (MM) cells in vitro and ex vivo (2008)

14694 Mutation of p53 in MM is often associated with refractory disease, indicating the important role of p53 in MM. HDM2 is a key regulator of p53, mediating its rapid degradation. Blockade of HDM2 provides an attractive treatment strategy to restore/enhance p53 activity. HDM2 binds also other partners (e.g. p73, E2F1, p21) and may thus affect MM growth through different mechanisms. Therefore, we explored the antitumoral/proapoptotic capacity of a novel first-in-class HDM2 inhibitor, JNJ-26854165, that recently entered Phase I development, In Vitro and Ex Vivo (primary MM samples) to assess its potential value for treatment of MM. Kill curves for JNJ-26854165 or Nutlin-3a were established for a panel of MM cell lines and apoptosis was measured by Annexin V-FITC/PI staining. Primary MM cells were prepared from diagnostic bone marrow (BM) aspirates by CD138-positive selection and kept in co-culture with BM stromal cells prior to challenge with either drug. MM cell lines showed different sensitivities for apoptosis induction by JNJ-26854165. 6 lines were sensitive (EC50 < 8 μM, EC90 < 20 μM) and 3 lines comparatively insensitive (EC50 > 15 μM, EC90 not reached at 25 μM). While all insensitive cell lines are known to express mutant p53, this was also true for two of the sensitive lines. In contrast, all p53 mutant cell lines were insensitive to Nutlin-3a. JNJ-26854165 (10 μM) reduced the viability of primary MM cells by over 50% in 9/18 samples. At 20 μM, 9/10 (JNJ- 26854165) vs. 6/9 (Nutlin-3a) MM samples showed less than 50% viability. Interestingly, two Nutlin-3a resistant samples were highly sensitive to JNJ-26854165. JNJ-26854165 was shown to be effective against MM In Vitro and Ex Vivo. This compound may represent a promising approach to restore p53 function and to potentially impact other HDM2 dependent pathways. While the activity pattern suggests a distinct role of p53 status for response, sensitivity of some p53 mutant and Nutlin-3a resistant samples points towards involvement of additional mechanisms, and allow for use in p53 mutated MM. JNJ-26854165 may open a novel treatment strategy for MM, specifically for aggressive disease with altered p53 status. Phase I development is currently ongoing in the clinics. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ortho Biotech Ortho Biotech
Angiopoietin-2–Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits Immunotherapy in Melanoma (2023)

ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.
Optical stimulation of the cavernous nerves in the rat prostate (2008)

Laser nerve stimulation has recently been studied as an alternative to electrical stimulation in neuroscience. Advantages include non-contact stimulation, improved spatial selectivity, and elimination of electrical stimulation artifacts. This study explores laser stimulation of the rat cavernous nerves, as a potential alternative to electrical nerve mapping during nerve-sparing radical prostatectomy. The cavernous nerves were surgically exposed in a total of 10 male rats. A Thulium fiber laser stimulated the nerves, with a wavelength of 1870 nm, pulse energy of 7.5 mJ, radiant exposure of 1 J/cm<sup>2</sup>, pulse duration of 2.5 ms, pulse rate of 10 Hz, and 1-mm laser spot diameter, for a stimulation time of 60 s. A significant increase in the intracavernosal pressure was detected upon laser stimulation, with pressure returning to baseline levels after stimulation. This study demonstrates the feasibility of non-contact laser stimulation of the cavernous nerves using near-infrared laser radiation.
Push-pull polyenes with enhanced quadratic nonlinear susceptibilities (1994)

Organic molecules have been extensively studied in view of their potential applications for second-harmonic generation and electrooptic modulation in nonlinear optics. 1 Molecules bearing a donor- acceptor (or push-pull) substituted π electron system can yield significant quadratic hyperpolarizabilities β. In addition, early experimental studies on para disubstituted polyenic systems have shown superlinear dependences of β with the length of the conjugation path linking the electron-donating and electron-accepting end groups. 2−4 Also semiempirical calculations conducted on two series of push-pull polyene series predicted a rapid increase in β with the number n of double bonds, the effect per unit volume saturating beyond n = 20. 5 Clearly longer push-pull polyenes are relevant candidates for the design of compounds with dramatically enhanced nonlinearities.
Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth (2021)

With the emergence of multi-drug-resistant strains of <i>Mycobacterium tuberculosis,</i> there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular <i>in vitro</i> activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound <b>3</b> was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (<b>1-2</b>) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against <i>M. tuberculosis</i>. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead <b>29</b>, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to <b>29</b>, and under replicating conditions, <b>29</b> demonstrated bactericidal activity against <i>M. tuberculosis</i>. Unfortunately, compound <b>29</b> had no efficacy in an acute model of TB infection; this was most likely due to the <i>in vivo</i> exposure remaining above the minimal inhibitory concentration for only a limited time.
Development of a Simulation Model for Fluorescence-Guided Brain Tumor Surgery (2019)

<b>Objective:</b> Fluorescence dyes are increasingly used in brain tumor surgeries, and thus the development of simulation models is important for teaching neurosurgery trainees how to perform fluorescence-guided operations. We aimed to create a tumor model for fluorescence-guided surgery in high-grade glioma (HGG). <b>Methods:</b> The tumor model was generated by the following steps: creating a tumor gel with a similar consistency to HGG, selecting fluorophores at optimal concentrations with realistic color, mixing the fluorophores with tumor gel, injecting the gel into fresh pig/sheep brain, and testing resection of the tumor model under a fluorescence microscope. The optimal tumor gel was selected among different combinations of agar and gelatin. The fluorophores included fluorescein, indocyanine green (ICG), europium, chlorin e6 (Ce6), and protoporphyrin IX (PpIX). The tumor model was tested by neurosurgeons and neurosurgery trainees, and a survey was used to assess the validity of the model. In addition, the photobleaching phenomenon was studied to evaluate its influence on fluorescence detection. <b>Results:</b> The best tumor gel formula in terms of consistency and tactile response was created using 100 mL water at 100°C, 0.5 g of agar, and 3 g of gelatin mixed thoroughly for 3 min. An additional 1 g of agar was added when the tumor gel cooled to 50°C. The optimal fluorophore concentration ranges were fluorescein 1.9 × 10<sup>-4</sup> to 3.8 × 10<sup>-4</sup> mg/mL, ICG 4.9 × 10<sup>-3</sup> to 9.8 × 10<sup>-3</sup> mg/mL, europium 7.0 × 10<sup>-2</sup> to 1.4 × 10<sup>-1</sup> mg/mL, Ce6 2.2 × 10<sup>-3</sup> to 4.4 × 10<sup>-3</sup> mg/mL, and PpIX 1.8 × 10<sup>-2</sup> to 3.5 × 10<sup>-2</sup> mg/mL. No statistical differences among fluorophores were found for face validity, content validity, and fluorophore preference. Europium, ICG, and fluorescein were shown to be relatively stable during photobleaching experiments, while chlorin e6 and PpIX had lower stability. <b>Conclusions:</b> The model can efficiently highlight the "tumor" with 3 different colors-green, yellow, or infrared green with color overlay. These models showed high face and content validity, although there was no significant difference among the models regarding the degree of simulation and training effectiveness. They are useful educational tools for teaching the key concepts of intra-axial tumor resection techniques, such as subpial dissection and nuances of fluorescence-guided surgery.
Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses (2015)

Filoviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross-protective immunotherapeutics are urgently needed. Here, we describe monoclonal antibodies with cross-reactivity to several filoviruses, including the first report of a cross-neutralizing antibody that exhibits protection against Ebola virus and Sudan virus in mice. Our results further describe a novel combination of antibodies with enhanced protective efficacy. These results form a basis for further development of effective immunotherapeutics against filoviruses for human use. Understanding the cross-protective epitopes are also important for rational design of pan-ebolavirus and pan-filovirus vaccines.
ChemInform Abstract: Phosphonium‐Mediated Cyclization of N‐(2‐Aminophenyl)thioureas: Efficient Synthesis of 2‐Aminobenzimidazoles. (2011)

Abstract Conditions A) allow the synthesis of a broad spectrum of benzimidazole structures with good to excellent yields within ~1h.
Ovariectomy Accelerates Photoaging of Rat Skin¶ (2001)

We have previously reported the formation of wrinkles, a decrease in skin elasticity and a loss in the linearity of dermal elastic fibers in rat hind limb skin irradiated with ultraviolet radiation in wavelength ranging 290-320 nm (UVB) at a suberythemal dose for 6 weeks. Estrogens are considered effective in preventing photoaging in postmenopausal females, but the role of estrogen in the skin remains unclear. In this study we have evaluated the influence of short-term chronic UVB irradiation at a suberythemal dose on the skin of ovariectomized rats. An ovariectomy or a sham operation was performed on each 3 week-old female Sprague-Dawley rat. Starting 1 week after the operation the hind limb skin of each rat was irradiated with UVB at a suberythemal dose (130 mJ/cm2) three times a week for 3 or 6 weeks. Decreases in elasticity and wrinkle formation in the skins of ovariectomized animals were induced more quickly than in the skins of sham-operated animals following UVB irradiation. The linearity of elastic fibers in the ovariectomy group decreased significantly compared with the sham-operation group, but erythema in the ovariectomy group was induced more readily than in the sham-operation group following UVB irradiation. These findings suggest that decreases in the estrogen levels after ovariectomy accelerate photoaging in terms of the morphology and physical properties of the skin surface and the three-dimensional structure of elastic fibers.
An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae (2012)

In this study we have discovered and characterised a mutation in MTH1 enabling Pdc⁻ strains to grow on glucose as the sole carbon source. This successful example of reverse engineering not only increases the understanding of the glucose tolerance of evolved Pdc⁻ S. cerevisiae, but also allows introduction of this portable genetic element into various industrial yeast strains, thereby simplifying metabolic engineering strategies.
Making effective use of healthcare data using data-to-text technology (2018)

Healthcare organizations are in a continuous effort to improve health outcomes, reduce costs and enhance patient experience of care. Data is essential to measure and help achieving these improvements in healthcare delivery. Consequently, a data influx from various clinical, financial and operational sources is now overtaking healthcare organizations and their patients. The effective use of this data, however, is a major challenge. Clearly, text is an important medium to make data accessible. Financial reports are produced to assess healthcare organizations on some key performance indicators to steer their healthcare delivery. Similarly, at a clinical level, data on patient status is conveyed by means of textual descriptions to facilitate patient review, shift handover and care transitions. Likewise, patients are informed about data on their health status and treatments via text, in the form of reports or via ehealth platforms by their doctors. Unfortunately, such text is the outcome of a highly labour-intensive process if it is done by healthcare professionals. It is also prone to incompleteness, subjectivity and hard to scale up to different domains, wider audiences and varying communication purposes. Data-to-text is a recent breakthrough technology in artificial intelligence which automatically generates natural language in the form of text or speech from data. This chapter provides a survey of data-to-text technology, with a focus on how it can be deployed in a healthcare setting. It will (1) give an up-to-date synthesis of data-to-text approaches, (2) give a categorized overview of use cases in healthcare, (3) seek to make a strong case for evaluating and implementing data-to-text in a healthcare setting, and (4) highlight recent research challenges.
H2O2 in snow, air and open pore space in firn at Summit, Greenland (1995)

Measurements of H 2 O 2 in firn gas down to a 1.7‐m depth showed a consistent trend, with higher firn‐gas concentrations generally associated with higher concentrations in the firn at the same depth. However, firn to firn‐gas concentration ratios still exhibited a seasonal dependence, suggesting that for summer layers equilibrium has not yet been reached. The time to reach equilibrium between firn and firn gas is at least weeks. Snowfall and fog deposit several times more H 2 O 2 than the surface snow will retain at equilibrium, supporting the idea that surface snow is a temporary reservoir for H 2 O 2 . Thus from an equilibrium standpoint, the snow‐pack should be a source of atmospheric H 2 O 2 in the summer as well as fall, resulting in higher daytime concentrations than would occur based on just atmospheric photochemical reactions. But firn‐gas measurements reported here were generally near or lower than those in the atmosphere, suggesting that degassing is too slow to significantly influence atmospheric H 2 O 2 levels.
Controlled Genetic Ablation by Immunotoxin-Mediated Cell Targeting (2022)

This chapter describes the use of Immunotoxin-Mediated Cell Targeting (IMCT) to eliminate specific neurons from the brain neuronal network, shows that IMCT provides an approach to investigate the physiological and behavioral functions of specific neuronal types and creates experimental models for human neurodegerative disorders. Immunotoxins are conjugates of monoclonal antibodies and toxins that kill animal cells bearing appropriate antigens, and are potential chemotherapeutic agents for the treatment of cancer and autoimmune disorders. Immunotoxin administration to transgenic mice led to a decrease in the number of cell bodies and axon fibers in A6 neurons as well as in the immunoreactivity against tyrosine hydroxylase, the first enzyme of catecholamine biosynthetic pathway. In addition, by devising the method of the immunotoxin treatment, such as intravenous and intrauterine injection, this technique will be applicable to eliminate specific cell types in the peripheral tissues and in the embryos at various developmental stages.
The effect of top LaAlO$_{3}$ surface treatment on the q-2DEGs at the LaAlO$_{3}$/ SrTiO$_{3}$ interface (2010)

Multiple curettages in the follow-up of patients with hydatidiform mole are often performed in Sweden. Of 36 patients developing trophoblastic neoplasia after molar evacuation, 24 underwent one or more endometrial curettages. The objective was generally to verify a diagnosis of malignant disease. However, in only one patient was a histopathological proof of choriocarcinoma obtained. In 3 other patients, malignancy could not be ruled out. It is demonstrated that development of malignancy after hydatidiform mole is rarely proven by endometrial curettage.
Importance of increased ultrafiltration volume and impact on mortality: sepsis and cytokine story and the role of continuous veno-venous haemofiltration (2001)

While in end-stage renal disease dialysis dose correlates with morbidity and mortality, this correlation is less evident in acute renal failure. In spite of a poor literature in the field, a few recent papers seem to suggest that an increase in treatment dose may result in an improved outcome of critically ill patients affected by acute renal failure. This improvement appears to plateau at a certain level of dialysis dose in the general population while, in septic patients, the correlation between treatment dose and outcome continues linearly. These results suggest that, while the 'renal dose' of renal replacement therapy has a threshold beyond which further improvements cannot be expected, the 'septic dose' of renal replacement therapy is probably higher and may provide benefits beyond simple blood purification from uremic toxins. This approach is in agreement with the recently proposed 'peak concentration hypothesis', which suggests that sepsis may derive from a complete derangement of the immunological response, featuring simultaneous peaks of pro- and anti-inflammatory mediators. This would explain the systemic inflammatory syndrome and the cell hyporesponsiveness of the septic patient and, at the same time, would explain the beneficial effects of new therapies such as high volume hemofiltration, coupled plasmafiltration adsorption and dialysis with hyperpermeable membranes. These therapies could be able to reduce the peaks of the pro- and anti-inflammatory substances circulating during the syndrome, leading to a less severe degree of inflammation and immunodepression.
InGaAsP grown by He-plasma-assisted molecular beam epitaxy for 1.55 μm high speed photodetectors (1998)

Simple photoconductive optical detectors for 1.55 μm wavelength have been fabricated on InGaAsP grown by He-plasma assisted molecular beam epitaxy. Characterization of the photodetectors shows that their speed is determined by the free carrier trapping time, with a full width at half-maximum impulse response of approximately 6 ps.
3D Power Delivery for Microprocessors and High-Performance ASICs (2007)

Conventional power delivery methods for microprocessors and high-performance ASICs have fundamental limitations in meeting the power requirements of future IC technologies due to large interconnect parasitics. A new three-dimensional (3D) power delivery approach along with a cellular power supply architecture is proposed as a possible solution to the problems of conventional 2D power delivery. Different 3D integration technologies or possible power-processor integration applications are reviewed, and important 3D design partitioning considerations are discussed. A fully monolithic, two-phase interleaved buck converter design having the potential to be used as a basic building block in a cellular architecture to meet steady-state and dynamic regulation requirements of future processors is presented. Each cell of the converter is designed for 500 mA rated output current, operates at 200 MHz switching frequency, and achieves a control bandwidth of about 10 MHz. Design trade-offs, implementation methods, and prototype results including chip area, loss breakdown, efficiency, as well as dynamic responses to load step changes are presented. Scaling-up of the design through parallel operation of a large number of such standard converter cells is discussed, and the benefits of interleaved operation in drastically reducing the input and output filter size are quantified.
Molecular analysis of cardiomyocytes derived from human embryonic stem cells (2005)

During early embryogenesis, the cardiovascular system is the first system to be established and is initiated by a process involving the hypoblastic cells of the primitive endoderm. Human embryonic stem (hES) cells provide a model to investigate the early developmental stages of this system. When removed from their feeder layer, hESC create embryoid bodies (EB) which, when plated, develop areas of beating cells in 21.5% of the EB. These spontaneously contracting cells were demonstrated using histology, immunostaining and reverse transcription-polymerase chain reaction (RT-PCR), to possess morphological and molecular characteristics consistent with cardiomyocytic phenotypes. In addition, the expression pattern of specific cardiomyocytic genes in human EB (hEB) was demonstrated and analyzed for the first time. GATA-4 is the first gene to be expressed in 6-day-old EB. Alpha cardiac actin and atrial natriuretic factor are expressed in older hEB at 10 and 20 days, respectively. Light chain ventricular myosin (MLC-2V) was expressed only in EB with beating areas and its expression increased with time. Alpha heavy chain myosin (alpha-MHC) expression declined in the pulsating hEB with time, in contrast to events in EB derived from mice. We conclude that human embryonic stem cells can provide a useful tool for research on embryogenesis in general and cardiovascular development in particular.