gebhart/patrepeval huggingface dataset:
The role of oxidant injury in tumor cell sensitivity to recombinant human tumor necrosis factor in vivo. Implications for mechanisms of action. (1989)

The intracellular glutathione levels of two human tumor lines and seven murine tumor lines were determined in order to investigate the role of oxidant injury in tumor cell sensitivity to human rTNF (rhTNF). Correlations were found between high intracellular glutathione levels and in vivo tumor resistance to rhTNF, and on the other hand, low glutathione levels and rhTNF sensitivity. The transplantable murine fibrosarcoma, Meth A, a TNF-sensitive line in vivo, was less sensitive to rhTNF and host toxicity was reduced when the hosts were pretreated with uric acid, a major reactive oxygen scavenger in humans and certain other primates. Conversely, pretreatment of the tumor-bearing hosts with DL-buthionine-(S,R)-sulfoximine, an inhibitor of GSH biosynthesis, resulted in an increased sensitivity of Meth A to rhTNF. This effect was not limited to tumor-bearing mice, as rats pretreated with diethyl maleate, a compound which irreversibly binds glutathione, were more sensitive to rhTNF toxicity than control rats. On the other hand, pretreatment with N-acetyl cysteine, an oxidant scavenger, reduced the toxicity of rhTNF treatment in rats. The data are consistent with the hypothesis that tumor cell sensitivity to rhTNF in vivo is dependent on its capacity to buffer oxidative attack. In addition, host toxicity is also related to the production of reactive oxygen species. Activated effector cells such as granulocytes and macrophages are hypothesized to produce most of this damage by their respiratory burst and oxidant release, although the direct action of rhTNF may also contribute to oxidative injury in vivo.
The use of topical Healon tears in the management of refractory dry-eye syndrome. (1984)

We evaluated 28 patients with dry-eye syndrome in the setting of either primary or secondary Sjogren's syndrome, with topical Healon tears. In 26 of the 28 patients, we noted both subjective and objective improvement characterized by decreased itching, burning and foreign body sensation, decreased mucus stranding and Rose-Bengal staining of the cornea and conjunctiva, and increased corneal luster and tear break-up time.
Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. (1992)

Osteogenic protein-2, OP-2, a new member of the transforming growth factor-beta (TGF-beta) superfamily, closely related to the osteogenic/bone morphogenetic proteins, was discovered in mouse embryo and human hippocampus cDNA libraries. The TGF-beta domain of OP-2 shows 74% identity to OP-1, 75% to Vgr-1, and 76% to BMP-5, hence OP-2 may also have bone inductive activity. The genomic locus of OP-2 has seven exons, like OP-1, and spans more than 27 kilobases (kb). In the C-terminal TGF-beta domain, OP-2 has a unique additional cysteine. Mouse embryos express relatively high levels of OP-2 mRNA at 8 days, two species of 3 and 5 kb. A careful study of mRNA expression of the osteogenic proteins in specific organs revealed discrete mRNA species for BMP-3, BMP-4, BMP-5, and BMP-6/Vgr-1 in lung or liver of young and adult mice. OP-1 is expressed in kidney; however, OP-2 and BMP-2 mRNAs were not detected in any organs studied, suggesting an early developmental role.
bcl-w, a novel member of the bcl-2 family, promotes cell survival. (1996)

The prototypic mammalian regulator of cell death is bcl-2, the oncogene implicated in the development of human follicular lymphoma. Several homologues of bcl-2 are now known. Using a PCR-based strategy we cloned a novel member of this gene family, denoted bcl-w. The gene, which is highly conserved between mouse and human, resides near the T-cell antigen receptor alpha gene within the central portion of mouse chromosome 14 and on human chromosome 14 at band q11. Enforced expression of bcl-w rendered lymphoid and myeloid cells refractory to several (but not all) cytotoxic conditions. Thus, like Bcl-2 and Bcl-x, the Bcl-w protein promotes cell survival, in contrast to other close homologues, Bax and Bak, which facilitate cell death. Comparison of the expected amino acid sequence of Bcl-w with that of these relatives helps to delineate residues likely to convey survival or anti-survival function. While expression of bcl-w was uncommon in B or T lymphoid cell lines, the mRNA was observed in almost all murine myeloid cell lines analysed and in a wide range of tissues. These findings suggest that bcl-w participates in the control of apoptosis in multiple cell types. Its functional similarity to bcl-2 also makes it an attractive candidate proto-oncogene.
Therapeutic strategies in rheumatoid arthritis over a 40-year period. (2004)

Time to initiation of DMARD therapy has shortened markedly over the past 3-4 decades. These changes in management of early RA provide evidence for the translation of scientific evidence into clinical practice in rheumatology. Age and various disease characteristics are significantly associated with initiation and the number of DMARD regimens used. These should be considered as confounders when examining the effect of early DMARD treatment on disease progression and mortality.
A Comparative Effectiveness Analysis of Three Continuous Glucose Monitors (2014)

The effectiveness and safety of continuous glucose monitors (CGMs) is dependent on their accuracy and reliability. The objective of this study was to compare 3 CGMs in adult and pediatric subjects with type 1 diabetes under closed-loop blood-glucose (BG) control. Twenty-four subjects (12 adults) with type 1 diabetes each participated in one 48-hour closed-loop BG control experiment. Venous plasma glucose (PG) measurements obtained every 15 minutes (4657 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from 3 CGMs (FreeStyle Navigator, Abbott Diabetes Care; G4 Platinum, Dexcom; Enlite, Medtronic) worn simultaneously by each subject. The Navigator and G4 Platinum (G4) had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 12.3 ± 12.1% and 10.8 ± 9.9%, respectively. Both had lower MARDs of all paired points than Enlite (17.9 ± 15.8%, P < .005). Very large errors (MARD > 50%) were less common with the G4 (0.5%) than with the Enlite (4.3%, P = .0001) while the number of very large errors with the Navigator (1.4%) was intermediate between the G4 and Enlite (P = .1 and P = .06, respectively). The average MARD for experiments in adolescent subjects were lower than in adult subjects for the Navigator and G4, while there was no difference for Enlite. All 3 devices had similar reliability. A comprehensive head-to-head-to-head comparison of 3 CGMs revealed marked differences in both accuracy and precision. The Navigator and G4 were found to outperform the Enlite in these areas.
Overview (2013)

Recognizes that health and economic development are interconnected, with both macro and micro studies showing that better health status leads to more productivity, which in turn leads to increased economic growth. Over the past several decades, the growing trend of health expenditures as a share of gross domestic product (GDP) shows the health sector as an increasingly important component of the global economy, especially in high-income and emerging middle-income countries. The cyclical nature of economic performance makes economic downturns a recurring phenomenon, and while crises vary in terms of their trigger, geographic origin and scope, length, and depth, these parameters, the extent of structural preparedness, and policy reactions by governments jointly determine the severity of outcomes and the length of the impact horizon. Globally, the health sector must build systems that can effectively assess vulnerability, track system changes, and synthesize the information to improve mitigation efforts.
Gene Activation and Gene Silencing (2001)

Twenty-five years ago the field of eukaryotic gene regulation was in its infancy. Paradigms driving experiments came primarily from work with prokaryotes and the phage that infected them (12). These paradigms, pioneered by Jacob and Monod, were that genes contained promoter sequences to which RNA
A Venus Flytrap Mechanism for Activation and Desensitization of α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptors (1996)

Desensitization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptor channels is an important process shaping the time course of synaptic excitation. Upon desensitization, the receptor channel closes and the agonist affinity increases. So far, the nature of the structural rearrangements leading to these events was unknown. On the basis of the structural homology of the ligand binding domains of AMPA receptors and of the bilobated bacterial periplasmic proteins, we now show that agonist interaction with one lobe of the GluR1 subunit of homomeric AMPA receptors controls channel activation while additional interactions with the other lobe cause channel desensitization. Accordingly, we suggest that the transition of the AMPA receptor channel to the desensitized state involves the agonist-mediated stabilization of the closed lobe conformation of its binding domain and is a process akin to that used by the venus flytrap.
Superionic Conductivity in Lithium-Rich Anti-Perovskites (2012)

Lithium ion batteries have shown great promise in electrical energy storage with enhanced energy density, power capacity, charge-discharge rates, and cycling lifetimes. However common fluid electrolytes consisting of lithium salts dissolved in solvents are toxic, corrosive, or flammable. Solid electrolytes with superionic conductivity can avoid those shortcomings and work with a metallic lithium anode, thereby allowing much higher energy densities. Here we present a novel class of solid electrolytes with three-dimensional conducting pathways based on lithium-rich anti-perovskites (LiRAP) with ionic conductivity of σ > 10(-3) S/cm at room temperature and activation energy of 0.2-0.3 eV. As temperature approaches the melting point, the ionic conductivity of the anti-perovskites increases to advanced superionic conductivity of σ > 10(-2) S/cm and beyond. The new crystalline materials can be readily manipulated via chemical, electronic, and structural means to boost ionic transport and serve as high-performance solid electrolytes for superionic Li(+) conduction in electrochemistry applications.
Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor–Redirected T Cells Against Multiple Myeloma (2017)

<b>Purpose:</b> Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy.<b>Experimental Design:</b> We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide <i>in vitro</i> The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat multiple myeloma-bearing mice as combinatorial therapy.<b>Results:</b> CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion <i>in vitro</i> enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells <i>in vivo</i><b>Conclusions:</b> The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. <i>Clin Cancer Res; 24(1); 106-19. ©2017 AACR</i>.
Thermal stress cracking and the enhancement of heat extraction from fractured geothermal reservoirs (1978)

Given sufficient time, the extraction of heat from geothermal reservoirs formed by the hydraulic fracturing of competent rock will eventually result in the formation of thermal stress cracks in the reservoir. These cracks penetrate the rock in a manner such that the penetration-to-spacing ratio is approximately one. The penetration depends upon the extent of cooling and the square root of time. Initially then, the cracks are closely spaced and penetrate but little, so that a crazing pattern is apparent; but with increasing time some of these cracks, now more widely spaced, grow deeper. Eventually these larger cracks attain a critical aperture such that significant rates of water flow can be established within them and thus the newly created heat transfer area becomes useful for heat extraction. At the same time that cracks are forming within the main reservoir, thermal cracking also occurs in the wellbores that communicate with the reservoir. These cracks eventually convey water to and from the reservoir, thus leading to a decrease in the flow impedances that are often concentrated in the wellbore regions.
Critical Function for Nuclear Envelope Protein TMEM209 in Human Pulmonary Carcinogenesis (2012)

Therapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209-NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy.
The effect of pH on the initial rate kinetics of the dimeric biliverdin‐IXα reductase from the cyanobacterium Synechocystis PCC6803 (2009)

Biliverdin-IXalpha reductase from Synechocystis PCC6803 (sBVR-A) is a stable dimer and this behaviour is observed under a range of conditions. This is in contrast to all other forms of BVR-A, which have been reported to behave as monomers, and places sBVR-A in the dihydrodiol dehydrogenase/N-terminally truncated glucose-fructose oxidoreductase structural family of dimers. The cyanobacterial enzyme obeys an ordered steady-state kinetic mechanism at pH 5, with NADPH being the first to bind and NADP(+) the last to dissociate. An analysis of the effect of pH on k(cat) with NADPH as cofactor reveals a pK of 5.4 that must be protonated for effective catalysis. Analysis of the effect of pH on k(cat)/K(m)(NADPH) identifies pK values of 5.1 and 6.1 in the free enzyme. Similar pK values are identified for biliverdin binding to the enzyme-NADPH complex. The lower pK values in the free enzyme (pK 5.1) and enzyme-NADPH complex (pK 4.9) are not evident when NADH is the cofactor, suggesting that this ionizable group may interact with the 2'-phosphate of NADPH. His84 is implicated as a crucial residue for sBVR-A activity because the H84A mutant has less than 1% of the activity of the wild-type and exhibits small but significant changes in the protein CD spectrum. Binding of biliverdin to sBVR-A is conveniently monitored by following the induced CD spectrum for biliverdin. Binding of biliverdin to wild-type sBVR-A induces a P-type spectrum. The H84A mutant shows evidence for weak binding of biliverdin and appears to bind a variant of the P-configuration. Intriguingly, the Y102A mutant, which is catalytically active, binds biliverdin in the M-configuration.
The BOBYQA algorithm for bound constrained optimization without derivatives (2009)

BOBYQA is an iterative algorithm for finding a minimum of a function F(x), x2R n , subject to bounds axb on the variables, F being specified by a black box that returns the value F(x) for any feasible x. Each iteration employs a quadratic approximation Q to F that satisfies Q(y j )= F(y j ), j =1 ,2,...,m, the interpolation points y j being chosen and adjusted automatically, but m is a prescribed constant, the value m =2 n+1 being typical. These conditions leave much freedom in Q, taken up when the model is updated by the highly successful technique of minimizing the Frobenius norm of the change to the second derivative matrix of Q. Thus no first derivatives of F are required explicitly. Most changes to the variables are an approximate solution to a trust region subproblem, using the current quadratic model, with a lower bound on the trust region radius that is reduced cautiously, in order to keep the interpolation points well separated until late in the calculation, which lessens damage from computer rounding errors. Some other changes to the variables are designed to improve the model without reducing F. These techniques are described. Other topics include the starting procedure that is given an initial vector of variables, the value of m and the initial trust region radius. There is also a new device called RESCUE that tries to restore normality if severe loss of accuracy occurs in the matrix calculations of the updating of the model. Numerical results are reported and discussed for two test problems, the numbers of variables being between 10 and 320.
CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia (2015)

Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell-specific antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.
8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes (2007)

A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Enhances Radiosensitivity and Suppresses Lung Metastasis in Breast Cancer In Vitro and In Vivo (2013)

Triple-negative breast cancer (TNBC), defined by the absence of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, is associated with an early recurrence of disease and poor outcome. Furthermore, the majority of deaths in breast cancer patients are from metastases instead of from primary tumors. In this study, MCF-7 (an estrogen receptor-positive human breast cancer cell line), MDA-MB-231 (a human TNBC cell line) and 4T1 (a mouse TNBC cell line) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with suberoylanilide hydroxamic acid (SAHA, an inhibitor of histone deacetylase (HDAC)) and to determine the underlying mechanisms of these effects in vitro and in vivo. We also evaluated the ability of SAHA to inhibit the metastasis of 4T1 cells. We found that IR combined with SAHA showed increased therapeutic efficacy when compared with either treatment alone in MCF-7, MDA-MB-231 and 4T1 cells. Moreover, the combined treatment enhanced DNA damage through the inhibition of DNA repair proteins. The combined treatment was induced primarily through autophagy and ER stress. In an orthotopic breast cancer mouse model, the combination treatment showed a greater inhibition of tumor growth. In addition, SAHA inhibited the migration and invasion abilities of 4T1 cells and inhibited breast cancer cell migration by inhibiting the activity of MMP-9. In an in vivo experimental metastasis mouse model, SAHA significantly inhibited lung metastasis. SAHA not only enhances radiosensitivity but also suppresses lung metastasis in breast cancer. These novel findings suggest that SAHA alone or combined with IR could serve as a potential therapeutic strategy for breast cancer.
Transformation in Escherichia coli: cryogenic preservation of competent cells (1977)

Escherichia coli cells prepared for transformation by treatment with cold 0.1 M CaCl2 remained viable and competent after storage at -82 degrees C in 15% glycerol; thawed-cell samples yielded up to 10(6) transformants per microgram of plasmid deoxyribonucleic acid.
Targeted Modification of Atrial Electrophysiology by Homogeneous Transmural Atrial Gene Transfer (2005)

We show complete transmural atrial gene transfer by this novel painting method. Adaptation of the method could allow application to other tissue targets. Use with functional proteins in the atria could cure or even prevent diseases such as atrial fibrillation or sinus node dysfunction.
Transparent Integration of Continuous Media Support into a Multimedia DBMS (1998)

Multimedia Database Management Systems (MM-DBMS) have to efficiently provide the specific functionalities required by time-dependent multimedia data types. During presentation playout, this requires support for continuous data delivery and media-oriented optimization of presentation quality according to user requirements. In this work, we show how we integrated this type of support transparently with other MM-DBMS functions like media editing and querying. This is achieved by extending an existing data model for continuous media, in particular by means of stream abstractions for editing and presentation, and by extending the system architecture by means of supporting stream processing components, e.g., for intra-media synchronization by adaptation. This approach has been implemented as an extension of existing commercial objectrelational DBMS technology.
Entropy titration. A calorimetric method for the determination of ΔG°(K), ΔH° and ΔS° (1965)

L. D. Hansen, J. J. Christensen and R. M. Izatt, Chem. Commun. (London), 1965, 36 DOI: 10.1039/C19650000036