gebhart/patrepeval huggingface dataset:
cis-4-Carboxy-6-(mercaptomethyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, a potent inhibitor of mammalian dihydroorotase (1988)

A series of cis- and trans-4-carboxy-3,4,5,6-tetrahydropyrimidin-2(1H)-ones possessing either a carboxy, hydroxymethyl, or mercaptomethyl substituent at C-6 were prepared and tested for their ability to inhibit mammalian dihydroorotase. Of these compounds, only the cis-6-mercaptomethyl compound, cis-1, was found to be a potent competitive inhibitor of the enzyme (Ki = 140 nM at pH 7.4 and 8.5) when assayed in the direction of dihydro-L-orotate hydrolysis. These results suggest that the inhibition arises from the ligation of the thiolate to the zinc atom which is thought to be located in the enzyme's active site. Although analysis of cis-1 with 2,2'-dithiobis(5-nitrobenzoic acid) revealed significant loss of the free thiol group under enzymatic assay conditions, the addition of the reducing agent, dithiothreitol, to the enzymatic reaction mixtures afforded cis-1 complete protection against this chemical decomposition, as evidenced by lowering of the inhibition constant in the presence of dithiothreitol. Compound cis-1 had no significant antiproliferative activity against B16 melanoma cells in tissue culture, possibly due to the rapid decomposition of the compound or poor permeability into cells.
Adenoviruses as Vectors for Human Gene Therapy (2002)

Human adenoviruses are well-known pathogens that cause a variety of infectious diseases. The biology of these viruses is extremely well characterized. In fact, adenoviruses have been important tools for studying the basic principles of biology including transcriptional regulation, RNA splicing, and translational control. In the early 1990s, replication-defective versions of human adenoviruses emerged as potential vectors for in vivo gene therapy. Adenoviruses have many features useful for their application as vectors including ease of production, broad tropism, and ability to transduce nondividing cells. The application of adenovirus vectors for in vivo gene therapy has taught us important paradigms, which are likely to be of broad relevance to the ﬁeld.
ChemInform Abstract: Sol‐Gel Synthesis of High‐Quality Heavy‐Metal Fluorid Glasses. (1994)

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.
ChemInform Abstract: Chemical Synthesis and Biological Studies of the Epothilones: Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug‐Resistant Cell Lines and Tumors (2002)

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.
JNJ-26481585, a novel “second-generation” oral pan-histone deacetylase (HDAC) inhibitor, shows broad-spectrum preclinical antitumoral activity against solid and hematological malignancies (2007)

A264 Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of haematological malignancies, resulting in the recent approval of Vorinostat (SAHA) for the treatment of cutaneous T-cell lymphoma. We previously have identified R306465 as highly potent class-I selective HDAC inhibitor, showing oral anti-tumor activity in human xenograft-bearing athymic nude mice. Pharmacodynamic studies revealed that, like most HDAC inhibitors in clinical development, R306465 only transiently induces histone acetylation in tumor tissue. In order to identify novel HDAC with superior pharmacodynamic properties, we developed an animal model allowing non-invasive real-time evaluation of the response to HDAC inhibitors. Human A2780 ovarian carcinoma cells were engineered to express ZsGreen fluorescent protein under control of the p21waf1, cip1 promoter. Induction of fluorescence protein in vivo was found to accurately predict long-term anti-tumor activity of HDAC inhibitors. (Belien et al., Mol. Cancer Ther., 2006). In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585, a novel “second generation” oral pan-HDAC inhibitor with broad-spectrum preclinical anti-tumoral activity. Pharmacodynamic analysis showed that once daily oral administration of JNJ-26481585 induced continuous histone H3 acetylation in human HCT116 colon tumors, resulting in complete tumor growth inhibition. Similarly, JNJ-26481585 completely inhibited tumor growth in both human ER-/PR-/Her2-negative MDA-MB-231 breast carcinoma, and also human K-ras mutant A549 non small cell lung carcinoma (NSCLC) tumor models; with observed efficacy greater than Paclitaxel. JNJ-26481585, was shown to be a potent pan-HDAC inhibitor (HDAC1, IC50 0.16 nM) and demonstrated both acetylation of HDAC1 substrates (histones) and HDAC6 substrates (Tubulin) in A2780 cells. JNJ-26481585 inhibited tumor cell proliferation (IC50 values 2 to 144 nM) and induced massive apoptosis in all tumor cell lines tested, irrespective of p53 or Ras mutational status. Patient-derived, adriamycin-resistant, breast carcinoma cells and Paclitaxel-resistant NSCLC cells were also highly sensitive to JNJ-26481585. The potent anti-tumoral activity as a single agent in preclinical models combined with its favourable pharmacodynamic profile, makes JNJ-26481585 a promising “second generation” HDAC inhibitor with potential applicability in a broad spectrum of human solid and haematological malignancies.
Photoluminescence of GaAs nanowhiskers grown on Si substrate (2004)

GaAs nanowhiskers were grown by metalorganic vapor-phase epitaxy on (111) Si substrates using the vapor-liquid-solid growth mode. The diameter of the nanowhiskers was defined by polydisperse catalytic Au nanoparticles in the range from 5 to 100 nm deposited on the Si substrate from the liquid phase. The low-temperature photoluminescence spectra exhibit a series of unresolved exciton-related transitions shifted to a shorter wavelength due to the quantization effects. Despite some structure defects, relatively high photoluminescence intensity and its linear dependence on the excitation power without saturation confirms the good material quality of fabricated GaAs nanowhiskers.
Computer-assisted structure elucidation: application of CISOC-SES to the resonance assignment and structure generation of betulinic acid (1998)

The application of a computer-assisted structure elucidation expert system, CISOC–SES, leading to the unequivocal 1H, 13C and NOE resonance assignment of betulinic acid, a biologically active triterpenoid with complicated NMR resonances, is described. The procedure consists of peak picking that is independent of background information, systematic interpretation of connectivity information from 2D NMR into bond constraints and resonance assignment based on the proposed structure. De novo structure generation based solely on the molecular formula and spectral data is also described. This application demonstrates the potential of efficient and systematic structure elucidation of natural products with modern high-resolution NMR spectroscopy combined with artificial intelligence. © 1998 John Wiley & Sons, Ltd.
Serpin α1proteinase inhibitor probed by intrinsic tryptophan fluorescence spectroscopy (1996)

Various conformational forms of the archetypal serpin human alpha 1proteinase inhibitor (alpha 1PI), including ordered polymers, active and inactive monomers, and heterogeneous aggregates, have been produced by refolding from mild denaturing conditions. These forms presumably originate by different folding pathways during renaturation, under the influence of the A and C sheets of the molecule. Because alpha 1PI contains only two Trp residues, at positions 194 and 238, it is amenable to fluorescence quenching resolved spectra and red-edge excitation measurements of the Trp environment. Thus, it is possible to define the conformation of the various forms based on the observed fluorescent properties of each of the Trp residues measured under a range of conditions. We show that denaturation in GuHCl, or thermal denaturation in Tris, followed by renaturation, leads to the formation of polymers that contain solvent-exposed Trp 238, which we interpret as ordered head-to-tail polymers (A-sheet polymers). However, thermal denaturation in citrate leads to shorter polymers where some of the Trp 238 residues are not solvent accessible, which we interpret as polymers capped by head-to-head interactions via the C sheet. The latter treatment also generates monomers thought to represent a latent form, but in which the environment of Trp 238 is occluded by ionized groups. These data indicate that the folding pathway of alpha 1PI, and presumably other serpins, is sensitive to solvent composition that affects the affinity of the reactive site loop for the A sheet or the C sheet.
Lymphocytes as cellular vehicles for gene therapy in mouse (2016)

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. We show that retroviral vectors can stably introduce genes into antigen- specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. These cells were expanded in culture and selected for expression of neomycin resistance with G418. The gene insertion, selection, and culture expansion did not alter antigen specificity or growth characteristics of the T cells in vitro. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. G418-resistant cells could be readily recovered from the spleens of recipients of transduced T cells for several months. In addition, recovered cells contin- ued to produce human adenosine deaminase. Based on these observations, we studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Exponential cultures of interleukin-2-stimulated tumor- infiltrating lymphocytes were efficiently transduced with the neomycin-resistance gene using the retroviral vector N2. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.
Ultrasound-guided tendon fenestration versus open-release surgery for the treatment of chronic lateral epicondylosis of the elbow: protocol for a prospective, randomised, single blinded study (2018)

NCT02710682.
Cardiac Microvascular Endothelial Cells in Pressure Overload–Induced Heart Disease (2021)

Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.
Nature of the chlorine-centred paramagnetic species in irradiated crystals of cytosine hydrochloride doped with thiocytosine (1996)

It has been demonstrated that the paramagnetic species formed in crystals of cytosine hydrochloride doped with thiocytosine are most likely the radicals formed by association of thiocytosine and chlorine. The unpaired electron is positively identified on the Cl atom and on at least one of the pyrimidine atoms, and the data are consistent with the formation of the 'three-electron' S-Cl sigma sigma * bonds. The spin density derived from the measured 35Cl and 14N coupling tensors compare reasonably well with the MO calculations for the 'in-plane' conformations of three hypothetical radicals formed by initial ionization of either thiocytosine or Cl- followed by their reaction. Two distinct and related centres, A and B, probably represent two different conformations of chemically the same radical in the crystal lattice of cytosine-HCL.
Formation of a C15 Laves Phase with a Giant Unit Cell in Salt-Doped A/B/AB Ternary Polymer Blends (2020)

Salt-doped A/B/AB ternary polymer blends, wherein an AB copolymer acts as a surfactant to stabilize otherwise incompatible A and B homopolymers, display a wide range of nanostructured morphologies with significant tunability. Among these structures, a bicontinuous microemulsion (BμE) has been a notable target. Here, we report the surprising appearance of a robust C15 Laves phase, at compositions near where the BμE has recently been reported, in lithium bis(trifluoromethane) sulfonimide (LiTFSI)-doped low-molar-mass poly(ethylene oxide) (PEO)/polystyrene (PS)/symmetric PS-<i>b</i>-PEO block copolymer blends. The materials were analyzed by a combination of small-angle X-ray scattering (SAXS), <sup>1</sup>H NMR spectroscopy, and impedance spectroscopy. The C15 phase emerges at a high total homopolymer volume fraction ϕ<sub>H</sub> = 0.8 with a salt composition <i>r</i> = 0.06 (Li<sup>+</sup>/[EO]) and persists as a coexisting phase across a large area of the isothermal phase diagram with high PS homopolymer compositions. Notably, the structure exhibits a huge unit cell size, <i>a</i> = 121 nm, with an unusually high micelle core volume fraction (<i>f</i><sub>core</sub> = 0.41) and an unusually low fraction of amphiphile (20%). This unit cell dimension is at least 50% larger than any previously reported C15 phase in soft matter, despite the low molar masses used, unlocking the possibility of copolymer-based photonic crystals without compromising processability. The nanostructured phase evolution from lamellar to hexagonal to C15 along the EO60 isopleth (ϕ<sub>PEO,homo-LiTFSI</sub>/ϕ<sub>H</sub> = 0.6) is rationalized as a consequence of asymmetry in the homopolymer solubility limit for each block, which leads to exclusion of PS homopolymer from the PS-<i>b</i>-PEO brush prior to exclusion of the PEO homopolymer, driving increased interfacial curvature and favoring the emergence of the C15 Laves phase.
Strategies for high-performance O-band photonic power converters (Conference Presentation) (2023)

Photonic power converters designed to operate in the telecommunications O-band were measured under non-uniform 1319 nm laser illumination. Two device architectures were studied, based on lattice-matched InGaAsP on an InP substrate and lattice-mismatched InGaAs grown on GaAs using a metamorphic buffer. The maximum measured efficiencies were 52.9% and 48.8% for the lattice-matched and -mismatched designs respectively. Both 5.4-mm2 devices were insensitive to the incident laser spot size for input powers of < 250 mW and exhibited better performance for larger spot sizes with more uniform illumination profiles at higher powers.
Subretinal gene therapy delays vision loss in a Bardet-Biedl Syndrome type 10 mouse model (2022)

Blindness in Bardet-Biedl syndrome (BBS) is caused by dysfunction and loss of photoreceptor cells in the retina. <i>BBS10</i>, mutations of which account for approximately 21% of all BBS cases, encodes a chaperonin protein indispensable for the assembly of the BBSome, a cargo adaptor important for ciliary trafficking. The loss of BBSome function in the eye causes a reduced light sensitivity of photoreceptor cells, photoreceptor ciliary malformation, dysfunctional ciliary trafficking, and photoreceptor cell death. Cone photoreceptors lacking BBS10 have congenitally low electrical function in electroretinography. In this study, we performed gene augmentation therapy by injecting a viral construct subretinally to deliver the coding sequence of the mouse <i>Bbs10</i> gene to treat retinal degeneration in a BBS10 mouse model. Long-term efficacy was assessed by measuring the electrical functions of the retina over time, imaging of the treated regions to visualize cell survival, conducting visually guided swim assays to measure functional vision, and performing retinal histology. We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their electrical function after gene augmentation. Measurement of functional vision showed that subretinal gene therapy provided a significant benefit in delaying vision loss.
Synthesis and reactivity of a stable crystalline diastereomerically pure trifluoromethanesulfinic acid derivative: (S)-(−)-1-trifluoromethylsulfinyl-(R)-4-phenyloxazolidin-2-one (2003)

Efficient synthesis of the title compound, the first diastereomerically pure trifluoromethanesulfinic acid derivative (8), has been achieved by direct trifluoromethanesulfinylation of the lithiated (4R)-(−)-4-phenyloxazolidin-2-one; in contrast to the reaction between CF3S(O)Cl and (1R,2S,5R)-(−)-menthol which occurs with low stereoselectivity (<10% de), 8 affords the O-menthyl trifluoromethanesulfinate derivative in >98% de.
A comparison of doped biopolymers using a coplanar waveguide based resonant bio-chemical sensor (2011)

This paper compares the effect of doped and un-doped biopolymers when the polymers are used as the sensing layer in a resonant chemical sensor. In addition to biopolymers, other polymers were doped as well for reference. The biopolymers used in this study were DNA-CTMA and Silk. The regular polymers used in this study were PMMA and Nafion. PMMA was doped with the metals nickel and iron. DNA-CTMA was doped with the metals manganese, nickel, and iron. Nafion and Silk were left un-doped for all of the tests. The above polymers were tested with DI water, humidity, ethanol, and isopropanol. All of the above polymers showed a resonant frequency change when subjected to the analyte of interest.
SU‐E‐T‐170: Characterization of the Location, Extent, and Proximity to Critical Structures of Target Volumes Provides Detail for Improved Outcome Predictions Among Pancreatic Cancer Patients (2015)

Purpose: In radiotherapy, size, location and proximity of the target to critical structures influence treatment decisions. It has been shown that proximity of the target predicts dosimetric sparing of critical structures. In addition to dosimetry, precise location of disease has further implications such as tumor invasion, or proximity to major arteries that inhibit surgery. Knowledge of which patients can be converted to surgical candidates by radiation may have high impact on future treat/no‐treat decisions. We propose a method to improve our characterization of the location of pancreatic cancer and treatment volume extent with respect to nearby arteries with the goal of developing features to improve clinical predictions and decisions. Methods: Oncospace is a local learning health system that systematically captures clinical outcomes and all aspects of radiotherapy treatment plans, including overlap volume histograms (OVH) – a measure of spatial relationships between two structures. Minimum and maximum distances of PTV and OARs based on OVH, PTV volume, anatomic location by ICD‐9 code, and surgical outcome were queried. Normalized distance to center from the left and right kidney was calculated to indicate tumor location and laterality. Distance to critical arteries (celiac, superior mesenteric, common hepatic) is validated by surgical status (borderline resectable, locally advanced converted to resectable). Results: There were 205 pancreas stereotactic body radiotherapy patients treated from 2009–2015 queried. Location/laterality of tumor based on kidney OVH show strong trends between location by OVH and by ICD‐9. Compared to the locally advanced group, the borderline resectable group showed larger geometrical distance from critical arteries (p=0.03). Conclusion: Our platform enabled analysis of shape/size‐location relationships. These data suggest that PTV volume and attention to distance between PTVs and surrounding OARs and major arteries may be promising for improving characterization of treatment anatomy that can refine our ability for outcome predictions and decision making. Elekta, Toshiba
Abstract P3-04-02: Protein pathway activation mapping of I-SPY 1 biopsy specimens identifies new network focused drug targets for patients with HR+/HER2− tumors (2012)

Abstract Background: Profiling protein signaling activation in cancer is critical as these proteins represent targets for new molecular therapeutics. The I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657) is a trial of neoadjuvant anthracycline- and taxane- based chemotherapy that longitudinally collected biopsy specimens and molecular and clinical/pathological characterization. Methods: Tumor epithelium was procured by Laser Capture Microdissection from 149 pretreatment frozen biopsy specimens (T1) and 102 frozen biopsy specimens (T2, 1–4 days post-chemotherapy). Reverse Phase Protein Microarray technology was used to quantitatively measure the activation of 39 and 100 key signaling proteins in the T1 and T2 biopsies, respectively, including numerous drug targets for Phase I-III and FDA-cleared therapeutics. Associations between protein activation and response to chemotherapy (RCB 0/1 vs 2/3) and relapse-free survival (RFS) were evaluated for the HR+/HER2− patient population at each time point and for changes between T1 and T2. Significance thresholds for response and RFS were as follows: Wilcoxon rank sum test p &amp;lt; 0.05; Cox proportional hazard model, likelihood ratio p &amp;lt; 0.05. Results: We focused our analysis on protein changes in patients who had poor clinical outcomes (Table 1) We observed systemic activation of HER family signaling and downstream AKT activation in tumors from patients who do not respond (RCB2/3) and/or whom recurred. Increased ERBB2 and ERBB4 levels were observed at T1 and T2, respectively, from patients who did not respond to neoadjuvant therapy. Dynamic changes in ERBB3 and AKT phosphorylation/activation were revealed between the T1 and T2 time points, which were associated with recurrence. Increased phosphorylation of MARCKS, a known PKC substrate, was seen in the T1 biopsy in the non-response cohort. Conclusions: Our analysis revealed activation/increased expression of HER family proteins along with downstream AKT activation in HR+/HER2− patients who have poor clinical response. These events, if validated, point to potential treatment options that could be rationally considered for non-responding HR+/HER2− patients with a number of investigational agents that target ERBB3 and AKT signaling in the clinic today. Increasing HER2 protein expression in a HER2− cohort may appear contradictory, however these findings may point to important subtle increases in HER2 that have important clinical considerations. Given the known clinical benefit from HER2 directed therapy in HER2− patients seen in other studies, our findings may have clinical relevance if validated. Further validation is required to explore the significance of these ongoing findings with the hope that the analysis could lead to molecularly rationalized therapies for patients with HR+/HER2− tumors. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-02.