gebhart/patrepeval huggingface dataset:
Abstract CT236: Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results (2015)

Abstract Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibody. In vitro and in vivo preclinical data suggest that IMMU-132 is a unique ADC, being most efficacious at a high drug-antibody ratio (DAR) of 7.6, and capable of delivering up to 135-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. In vitro studies also demonstrate specific double-stranded DNA breaks by the internalizing ADC. Methods: IMMU-132 is completing a phase I/II clinical trial with phase II expansion after MTD determination (ClinicalTrials.gov.NCT01631552) in patients with advanced cancers that typically express high levels of Trop-2, at doses of 8 and 10 mg/kg on days 1 and 8 of 21-day repeated cycles. Efficacy (N = 91) and safety (N = 130) results are provided. Results: The% of grades 3/4 AEs for both dose levels are neutropenia (16/4), febrile neutropenia (4/4), anemia (4/0), diarrhea (4/0), and fatigue (4/0) (Table 1). No patient discontinued therapy due to toxicity, and no patient showed immunogenicity despite repeated therapy. Patient dose reductions were 15-16%, and dose delays after first 2 cycles were 3-4%. Conclusions: IMMU-132 shows activity in patients with diverse cancers, even when they no longer responded to a topoisomerase inhibitor. It appears to have a manageable toxicity profile, with promising efficacy at a high therapeutic index in patients with heavily-pretreated metastatic cancers, especially TNBC, SCLC, and NSCLC. Based on these results, this ADC carrying a moderately-toxic drug that is the active metabolite of a currently-used camptothecin analogue represents a novel cancer therapeutic that challenges the current dogma of requiring ultratoxic drugs conjugated at low DARs for ADC therapy. Tumor typeORR (CR+PR)Disease stabilization (CR+PR+SD)Clinical benefit (CR+PR+ SD &amp;gt; 6 moMedian TPP (mo)TNBC (N = 31)TNBC (N = 31)23%71%39%3.7+NSCLC (N = 15)27%73%42%3.3+SCLC (N = 19)26%53%29%2.8+CRC (N = 26)4%58%24%3.7 Citation Format: Alexander N. Starodub, Allyson J. Ocean, Aditya Bardia, Michael J. Guarino, Wells Messersmith, Jordan Berlin, Vincent J. Picozzi, Sajeve S. Thomas, Gregory Masters, Linda T. Vahdat, Ingrid A. Mayer, Rebecca Moroose, Jennifer S. Diamond, Scott T. Tagawa, Manish A. Shah, Francois Wilhelm, William A. Wegener, Pius Maliakal, Robert M. Sharkey, David M. Goldenberg. Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT236. doi:10.1158/1538-7445.AM2015-CT236
Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selectiveN‐methyl‐D‐aspartate receptor antagonist (2015)

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
Effects of Submental Electrical Stimulation during Sleep on Upper Airway Patency in Patients with Obstructive Sleep Apnea (1989)

We examined the effects of percutaneous electrical stimulation of the genioglossus in six patients with obstructive sleep apnea syndrome (OSAS) during sleep and investigated the possible applicability of this procedure as a treatment of OSAS. Six patients with OSAS were polysomnographically studied in the supine position during all-night sessions with and without electrical stimulation of the genioglossus. Using an apnea demand-type stimulator that we developed, electrical pulses of 0.5 ms (repetition rate, 50 Hz) and 15 to 40 V were delivered through bipolar electrodes (10 mm in diameter) attached to the skin of the submental region when apnea lasted more than 5 s, and was stopped immediately after breathing resumed or after 10 s at the longest. With submental stimulation, the apnea index, apnea time/total sleep time, longest apnea duration, and the number of times per hour that oxygen saturation dropped below 85% decreased significantly compared with those on control nights. The lowest arterial oxygen saturation and the duration of sleep stages III and IV increased significantly. The stimulation employed did not cause arousal, and it did not affect blood pressure or heart rate significantly. These findings show that submental stimulation decreases the incidence of apnea episodes and promotes deeper sleep without accompanying serious side effects, suggesting that the apnea demand-type stimulator may be a noninvasive and effective treatment for OSAS.
Primary Structure of the Saccharomyces cerevisiae GAL4 Gene (1984)

The GAL4 gene encodes a positive regulator of the galactose-inducible genes in Saccharomyces cerevisiae. Recently, GAL4 has been cloned and its 2.8-kilobase mRNA has been identified. We report here the DNA sequence of GAL4 and the mapping of the 5' and 3' ends of its transcripts. The region sequenced contains a single open reading frame, 881 codons long, which could encode a 99,350-dalton protein. The 5' ends of the GAL4 transcripts fall into two clusters. Transcripts which begin at the upstream cluster would encode the 99,350-dalton protein, whereas those starting at the downstream cluster may result in the synthesis of a shorter, 91,600-dalton protein. The putative GAL4 proteins contain an amino acid sequence near their amino termini which resembles a DNA-binding motif found in bacterial and phage repressors and gene activator proteins.
Perforin and Lymphocyte‐mediated Cytolysis (1995)

We have discussed in the previous sections the recent progress made toward elucidating the regulatory mechanism of perforin gene transcription and the domain structure of the perforin molecule. It appears that the expression of perforin is, at least partially, controlled at the transcription level through the interaction between killer cell-specific cis- and trans- acting factors. One of such cognate pairs, NF-P motif (an EBS-homologous motif) and NF-P2 (a killer cell-specific DNA-binding protein), has been described. The regulatory mechanism of gene transcription, however, is likely to involve multiple factors which act in a coordinated fashion to bring about the most efficient expression of perforin limited strictly to activated killer lymphocytes. Through studies using synthetic peptides and recombinant perforins, it has been suggested that the N-terminal region of the perforin molecule is an important, though not the only, domain responsible for the lytic activity. Further studies are warranted to elucidate the role(s) of other potential amphiphilic structures located in the central portion of the perforin molecule in the overall pore-forming activity. The molecular basis underlying the resistance of killer lymphocytes to perforin-mediated lysis still remains an open question. Preliminary results, however, suggest that the surface protein(s) restricted to killer cells may account for their self-protection against perforin. Based on recent studies using perforin-deficient mice, the involvement of perforin in lymphocyte-mediated cytolysis both in vivo and in vitro has been confirmed. Two functional roles, a direct (lytic) and an indirect (endocytosis enhancer; conduit), both of which may contribute critically to the cell-killing event can be attributed to perforin. The fact that lymphocytes may also employ perforin-independent killing mechanism(s), e.g. Fas-dependent pathway, is beyond the scope of this review. There is, nevertheless, no doubt that these alternative cytolytic mechanisms may also play important roles in immune effector and/or regulatory responses associated with killer lymphocytes. Obviously, we are still a long way from concluding on the functional relevance of each individual cytolytic mechanism seen in different physiopathological situations. Suffice it to say, however, that a wealth of information on lymphocyte-mediated killing has already emerged through the multidisciplinary efforts conducted in our and other laboratories that promise to further dissect this complicated event in the years to come.
Multifunctional Mechano-Luminescent-Optoelectronic Composites for Self-Powered Strain Sensing (2017)

Aerospace mechanical structures encounter various forms of damage throughout their operation due to mechanical stimuli. Structural health monitoring (SHM) is suggested as a way to actively check the integrity of a component by using a system of sensors. However, these conventional sensors can often require external power that is not always readily available in aerospace, thus the development of self-powered sensors could prove beneficial for SHM applications. In this study, the design of multifunctional mechano-luminescent-optoelectronic (MLO) composites strain sensor is suggested. The MLO composites sensor is composed of two transformative materials: 1) mechano-luminescent (ML) copper-doped zinc sulfide (ZnS:Cu) and 2) mechano-optoelectronic (MO) poly(3-hexylthiophene) (P3HT). ML ZnS:Cu emits light in response to mechanical stimuli. MO P3HT showed self-sensing capability by generating direct current (DC) sensor signal under light. First, ZnS:Cu ML crystals will be embedded in polydimethylsiloxane (PDMS) matrix to fabricate ZnS:Cu/PDMS elastomeric composites. ML light emission characteristics of ZnS:Cu/PDMS will be studied by subjecting the ZnS:Cu/PDMS to cyclic tensile strain loadings while videos are recorded of the light emission. The data are analyzed using a statistical factorial methodology so that a regression model to predict light emission based on loading strain and frequency can be calculated. Second, MO P3HT-based self-sensing thin films will be fabricated on glass slides using a spin-coating technique. Last, self-powered sensing capability of the MLO composites strain sensor will be validated by measuring DC voltage (DCV) in close proximity of the ZnS:Cu/PDMS subjected to cyclic tensile loadings.
Characterization of phosphoenolpyruvate carboxykinase from Corynebacterium glutamicum (1993)

Phosphoenolpyruvate (PEP) carboxykinase is present in crude extracts of Corynebacterium glutamicum grown on both glucose and lactate. Preparation of PEP carboxykinase free from interfering PEP carboxylase and oxaloacetate decarboxylase showed an absolute dependence on divalent manganese and IDP for activity in the oxaloacetate (OAA) formation. Other diphosphate nucleotides could not substitute for IDP. The enzyme activity displayed Michaelis-Menten kinetics for the substrates PEP, IDP, KHCO3, OAA and ITP with a Km of 0.7 mM, 0.4 mM, 12 mM, 1.0 mM, and 0.5 mM, respectively. At the optimum pH of 6.6, 850 nmol of OAA were formed per min per mg of protein. ATP inhibited PEP carboxykinase in the OAA forming reaction for 60% at 0.1 mM, indicating that the enzyme mainly functions in gluconeogenesis.
Silicone-Covered Expandable Metallic Stents in the Esophagus: An Experimental Study (1992)

Modified silicone-covered Gianturco expandable metallic stents were placed in the normal esophagus of six young pigs. Following endoscopic examination, the stents were placed using endoscopic and fluoroscopic control. The animals were observed for eating behavior and weight gain. Stents appeared to be tolerated well based on these parameters. Three stents remained in position for the full study period, and three stents migrated into the stomach during the study. The pigs were sacrificed at four weeks and postmortem examination performed. Esophageal wall thickening and nodular inflammation were noted at the sites where the wire skirts penetrated the mucosa. Injury was limited to the region of the wire skirts and there was no injury due to the radial force of the stent body. There was no free perforation. This preliminary study suggests that endoscopic and fluoroscopic placement of modified silicone-covered Gianturco stents in the esophagus is feasible and safe. More extensive animal studies, followed by clinical investigation for palliation of malignant strictures, are warranted.
The Effect of Long Term High Dose Heparin Treatment on the Course of Chronic Proliferative Glomerulonephritis (1971)

18 patients with biopsy proven chronic proliferative glomerulonephritis have been studied, 10 of the 18 received daily subcutaneous injections of depo-heparin until death or for a period of at least 1 year. 8 of the 10 patients so treated demonstrated significant improvement in renal function as measured by serial determination of endogenous creatinine clearance, Addis count, protein permeability index, and renal biopsy. 1 patient with severely impaired function prior to heparin therapy did not improve, but renal function remained stable during the period of treatment. 8 of the 10 control patients were followed adequately for evaluation. Of these 8, 6 demonstrated progressive diminution of renal function, 4 expired in renal failure; in addition, 1 control patient followed too sporadically to include in the study is known to have died of renal failure.
Vitamin D and chronic kidney disease (2016)

Prevalence of hypovitaminosis D is increasing in the world especially among poor countries and it has many varieties of manifestation and disease including rickets in children and osteomalacia and osteoporosis in adult. It also can affect on functional of some organ like renal and cardiovascular system and even has effect on mortality rate of some of these patients. Inadequate vitamin D in food regimen is one of reasons of hypovitaminosis D. The production of active form of this vitamin mainly is located in kidney cells, therefore end-stage renal disease (ESRD) patients or patients who have chronic kidney disease (CKD), have high chance for low serum level of the active form of this vitamin. Secondary hyperparathyroidism and renal osteodystrophy which are important side effect of CKD, be happen because of deficiency and defect in absorption of this vitamin. According to rapid increase in the prevalence of hypovitaminosis D, the aim of this review article is to summarize some of investigation about hypovitaminosis D especially among patients who have CKD.
The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle (1999)

The translationally controlled protein P23 was discovered by the early induction of its rate of synthesis after mitogenic stimulation of mouse fibroblasts. P23 is expressed in almost all mammalian tissues and it is highly conserved between animals, plants and yeast. Based on its amino acid sequence, P23 cannot be attributed to any known protein family, and its cellular function remains to be elucidated. Here, we present evidence that P23 has properties of a tubulin binding protein that associates with microtubules in a cell cycle-dependent manner. (1) P23 is a cytoplasmic protein that occurs in complexes of 100-150 kDa, and part of P23 can be immunoprecipitated from HeLa cell extracts with anti-tubulin antibodies. (2) In immunolocalisation experiments we find P23 associated with microtubules during G1, S, G2 and early M phase of the cell cycle. At metaphase, P23 is also bound to the mitotic spindle, and it is detached from the spindle during metaphase-anaphase transition. (3) A GST-P23 fusion protein interacts with alpha- and beta-tubulin, and recombinant P23 binds to taxol-stabilised microtubules in vitro. The tubulin binding domain of P23 was identified by mutational analysis; it shows similarity to part of the tubulin binding domain of the microtubule-associated protein MAP-1B. (4) Overexpression of P23 results in cell growth retardation and in alterations of cell morphology. Moreover, elevation of P23 levels leads to microtubule rearrangements and to an increase in microtubule mass and stability.
Casein kinase Iɛ in the Wnt pathway: Regulation of β-catenin function (1999)

Wnt and its intracellular effector beta-catenin regulate developmental and oncogenic processes. Using expression cloning to identify novel components of the Wnt pathway, we isolated casein kinase Iepsilon (CKIepsilon). CKIepsilon mimicked Wnt in inducing a secondary axis in Xenopus, stabilizing beta-catenin, and stimulating gene transcription in cells. Inhibition of endogenous CKIepsilon by kinase-defective CKIepsilon or CKIepsilon antisense-oligonucleotides attenuated Wnt signaling. CKIepsilon was in a complex with axin and other downstream components of the Wnt pathway, including Dishevelled. CKIepsilon appears to be a positive regulator of the pathway and a link between upstream signals and the complexes that regulate beta-catenin.
Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. (1977)

Colony-stimulating factor, which specifically stimulates mouse bone marrow cells to proliferate in vitro and generate colonies of granulocytes, or macrophages, or both, was purified 3500-fold from mouse lung-conditioned medium. Analysis by discontinuous polyacrylamide gel electrophoresis in the presence and absence of sodium dodecyl sulfate indicated that there was a single protein component. All of the colony-stimulating activity was coincident with the protein band. The molecular weight of colony-stimulating factor estimated by gel filtration was approximately 29,000 and by electrophoresis approximately 23,000. The specific activity of purified colony-stimulating factor from mouse lung-conditioned medium bound to concanavalin A-Sapharose, indicating that it is a glycoprotein. The small percentage of colony-stimulating factor in mouse lung-conditioned medium which did not bind to concanavalin A-Sepharose appeared to represent molecules which lacked the carbohydrate moieties required for binding to this lectin. It was necessary to include low concentrations (less than 0.01%, v/v) of polymers such as gelatin and polyethylene glycol, or nonionic detergents such as Triton X-100, in all of the buffers used throughout the purification scheme, otherwise colony-stimulating factor was lost from solution. At high concentrations (greater than 20 mug/ml) the factor stimulated the formation of granulocytic, macrophage, and mixed colonies from C57BL mouse bone marrow cells. As the concentration of purified colony-stimulating factor was decreased, the frequency of colonies containing granulocytes also decreased. At low concentrations of colony-stimulating factor (less than 70 pg/ml) only macrophage colonies were stimulated.
Bone Marrow Stromal Cell Transdifferentiation into Oligodendrocyte-Like Cells Using Triiodothyronine as a Inducer with Expression of Platelet-Derived Growth Factor α as a Maturity Marker (1996)

The conclusion of the study showed that BMSC can be induced to transdifferentiate into mature OLC.
Gene Expression Signatures That Predict Radiation Exposure in Mice and Humans (2007)

We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.
A genetic programming approach to designing convolutional neural network architectures (2017)

The convolutional neural network (CNN), which is one of the deep learning models, has seen much success in a variety of computer vision tasks. However, designing CNN architectures still requires expert knowledge and a lot of trial and error. In this paper, we attempt to automatically construct CNN architectures for an image classification task based on Cartesian genetic programming (CGP). In our method, we adopt highly functional modules, such as convolutional blocks and tensor concatenation, as the node functions in CGP. The CNN structure and connectivity represented by the CGP encoding method are optimized to maximize the validation accuracy. To evaluate the proposed method, we constructed a CNN architecture for the image classification task with the CIFAR-10 dataset. The experimental result shows that the proposed method can be used to automatically find the competitive CNN architecture compared with state-of-the-art models.
On IIP2 Improvement by Injecting DC Offset at the Mixer in a Wireless Receiver (2007)

We present a digital calibration technique for improving IIP2 by injecting DC offset at the mixer. Most receivers offer DC offset cancellation circuitry, and a targeted non-zero DC offset at mixer output is up-converted to RF carrier frequency due to poor reverse isolation of the mixer switch. By controlling amplitude of the injected DC, IIP2 degradation due to LO leakage at the input of RF amplifiers can be compensated. Mathematical analysis and measurement data for a quad-band GSM/GPRS receiver implemented in 90-nm digital CMOS process are presented. Calibrated IIP2 of 50 dBm is reported at LNA input.
Interferon signatures in immune disorders and disease (2012)

The interferon (IFN) family and the type-I IFNs specifically have an important and well-characterized role in antiviral defence, immune modulation and cell-cycle control and are regularly applied in the clinical context. Advances in high-content technologies have facilitated an enhanced understanding of the global IFN response capable of being induced. Recent application of these technologies is improving our understanding of the specificity and subtleties associated with this response. This review considers our current understanding of the temporal gene profile induced through IFN stimulation across a diversity of disease conditions including autoimmune diseases, bacterial and viral infections. Understanding these signatures, the disease-specific differences and the biological effects induced has the potential to facilitate IFN-driven therapeutic development.