gebhart/patrepeval huggingface dataset:
Initial results of phase I study of DCC-2618, a broad-spectrum KIT and PDGFRa inhibitor, in patients (pts) with gastrointestinal stromal tumor (GIST) by number of prior regimens (2018)

Background: DCC-2618, a kinase switch control inhibitor, broadly inhibits mutations in KIT exons 9, 11, 13, 14, 17 and 18. Based on clinical activity observed in heavily pretreated GIST pts in a Phase 1 study, DCC-2618 is being evaluated in a Phase 3 study, INVICTUS (NCT03353753), in ≥ 4th line pts. Given the breadth of inhibition of KIT mutations and favorable tolerability profile, the Phase 1 study included expansion cohorts to assess clinical benefit in 2nd and 3rd line GIST pts in advance of the expected initiation of a second Phase 3 study in 2nd line GIST pts by the end of 2018. Methods: The Phase 1 study includes a dose-escalation component testing oral DCC-2618 dosed QD or BID in 28 day cycles and an expansion phase using the RP2D of 150 mg QDin 6 cohorts, including cohorts for GIST pts based on prior regimens (2nd/3rd, 4th/>4th). RECIST response assements based on local assessment of CT scans were performed every 2 cycles. Results: At the cut off of April 18, 150 GIST pts were enrolled at dose levels of ≥ 100 mg/d with KIT (141 pts) or PDGFRa- (8 pts) -driven GIST. One pt had SDH-deficient GIST. 114 GIST pts were treated at the 150 mg QD dose, including 19, 27, and 68 pts who previously received 1, 2 or ≥ 3 prior lines of therapy, respectively. For the 114 GIST pts, ORR was 14%, 3-month DCR was 70%, mPFS was 24 weeks with 56% of the pts censored. For the 46 evaluable pts in 2nd/3rd line, ORR was 22%, 3-month DCR was 81% and mPFS was 36 weeks with 61% of the pts censored. Updated ORR, DCR and mPFS will be presented. Grade 3/4 adverse effects (regardless of attribution, in > 1 pt) for all 114 pts treated at 150 mg QD included asymptomatic lipase increase 11, anemia 4, hypertension 3, blood bilirubin increased 3, diarrhea 2, abdominal pain 2, back pain 2, hypophosphatemia 2, hyponatremia 2, hyperkalemia 2. Conclusions: DCC-2618 demonstrated encouraging clinical benefit and a favorable tolerability profile in GIST pts treated in the 2nd line or later. Clinical benefit as measured by ORR, DCR and mPFS was greater in 2nd/3rd line pts compared to more heavily pretreated pts. Preliminary data from the Phase 1 expansion supports further testing in the planned Phase 3 study in 2nd line GIST. Clinical trial identification: NCT02571036. Legal entity responsible for the study: Deciphera Pharmaceuticals, Inc. Funding: Deciphera Pharmaceuticals, Inc. Disclosure: S. George, M. Heinrich, P. Chi, M. von Mehren, M. Gordon, N. Somaiah, F. Janku: Research sponsored: Deciphera Pharmaceuticals, Inc.; Scientific advisory board: Deciphera Pharmaceuticals, Inc. A. Razak, K.N. Ganjoo, J. Wolf, J. Rodon Ahnert: Research sponsored: Deciphera Pharmaceuticals, Inc. J.C. Trent: Scientific advisory board: Deciphera Pharmaceuticals, Inc. R. Ruiz-Soto, O. Rosen: Employee: Deciphera Pharmaceuticals, Inc.
Purification and characterisation of the BIOH protein from the biotin biosynthetic pathway (2002)

Conversion of pimeloyl-coenzyme A (CoA) to biotin in Escherichia coli requires at least four enzymes encoded by genes in the bio operon. One gene, bioH, which is not present in the bioABFCD operon, is required for the synthesis of pimeloyl-CoA but its exact role in formation of this intermediate is unknown. To investigate this further, we have overexpressed and purified the bioH gene products from both E. coli (BIOH EC) and Neisseria meningitis (BIOH NM) in E. coli. When purified BIOH was incubated with excess CoA and analysed by electrospray mass spectrometry a species of mass corresponding to a BIOH:CoA complex was observed. Mutation of a conserved serine residue to alanine (BIOH EC S82A) did not prevent CoA binding. This is the first report of the purification of BIOH and the observation of a small molecule bound to the protein provides clues to its role in pimeloyl-CoA synthesis.
Mouse antibody to phosphocholine can protect mice from infection with mouse-virulent human isolates of Streptococcus pneumoniae (1992)

Previous studies have demonstrated that mouse antibodies to phosphocholine (PC) can protect mice against fatal infection caused by several, but not all, mouse-virulent laboratory strains of Streptococcus pneumoniae. Because the pneumococcal strains used in previous studies had been mouse passed and were propagated for many years outside of humans, it was not known whether antibody to PC would be able to protect mice against S. pneumoniae freshly isolated from humans. In the present study, we examined the ability of an immunoglobulin G (IgG) monoclonal antibody (MAb) to PC to protect against infections in mice caused by 14 pneumococcal strains of capsular types 3, 4, 6A, and 6B. Nine of these strains were selected as the most virulent strains for mice from a group of 69 fresh clinical isolates. Five were mouse-passed laboratory strains. Mouse IgG3 MAb to PC was able to exhibit protective effects (survival or increased time to death) against infection with virtually all of the strains injected intravenously and against infection with 70% of the strains injected intraperitoneally. The protective effects of antibody to PC appeared to be partially dependent on capsular type. MAb to PC was most effective against capsular type 3 strains and least effective against type 4 strains. With type 3 and type 4 strains, MAb to PC could frequently protect against larger numbers of CFU injected intravenously than intraperitoneally. For capsular type 6A and 6B strains the reverse was true.
Potassium Ion Transport Atpase in Insect Epithelia (1983)

K+ transport by the epithelia of midgut, salivary glands, Malpighian tubules, sensory sensilla, possibly rectum, and other organs of certain insects appears to use a unique K+ ATPase. Ouabain inhibition of transport-related events has not been demonstrated in these epithelia. The K+ pump is unlike the Na-K;ump but resembles the H;ump of phosphorylating membranes in its transport orientation, efficient thermodynamics, speculated two K+ per one MgATP2- stoichiometry, electrogenicity, and structure. Older electrochemical, tracer flux, and conductance evidence suggested that the K+ pump was on the apical plasma membrane of transporting cells in these epithelia. New X-ray microanalytical studies (XMA), reveal that the K+ concentration in all cells is more than 100 mM. Together with new microelectrode data these XMA results confirm the apical K+ pump location, resolve the K+ transport sport route, and suggest that the goblet cell cavity facilitates the generation of a large apical PD which may be used in nutrient absorption and pH regulation. K+ portasomes, which resemble F1-Fo ATPase particles, stud these K+ transporting apical membranes and are though to be the unit of active K+ transport. We have suggested a K+ transport mechanism in which two cations (2K+) are abandoned in an isolated domain of the portasomes during ATP2-hydrolysis and are repelled to the opposite membrane side via a K+ channel. Small peptides hydrolysed from the delta-endotoxin of Bacillus thuringiensis inhibit the K+ transport and may be useful as K+ pump inhibitors, apical membrane probes and insecticides. Goblet cell apical membrane fragments (GCAM) as well as fragments from columnar cell apical membrane (CCAM), lateral membrane (LM) and basal membranes (BM) were isolated as clean fractions using ultrasound, aspiration, and both differential and density gradient centrifugation; purification was monitored by electron microscopy. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS PAGE) reveals that GCAM, CCAM, LM and BM have very different protein compositions. Preliminary enzymology is consistent with the K+ ATPase being on the apical plasma membrane of the goblet cells of midgut and enveloping cells of sensilla.
Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase (1997)

The several hundred members of the eukaryotic protein kinase superfamily characterized to date share a similar catalytic domain structure, consisting of 12 conserved subdomains. Here we report the existence and wide occurrence in eukaryotes of a protein kinase with a completely different structure. We cloned and sequenced the human, mouse, rat, and Caenorhabditis elegans eukaryotic elongation factor-2 kinase (eEF-2 kinase) and found that with the exception of the ATP-binding site, they do not contain any sequence motifs characteristic of the eukaryotic protein kinase superfamily. Comparison of different eEF-2 kinase sequences reveals a highly conserved region of approximately 200 amino acids which was found to be homologous to the catalytic domain of the recently described myosin heavy chain kinase A (MHCK A) from Dictyostelium. This suggests that eEF-2 kinase and MHCK A are members of a new class of protein kinases with a novel catalytic domain structure.
Affine theorem for the Hartley transform of an image (1994)

Many well-known theorems for the two-dimensional (2D) Hartley transform are encapsulated in the affine theorem which is presented here and illustrated by example. The mode of presentation permits ready visualization of the effect on the spectral makeup when an object is subjected to a particular distortion as specified by the six disposable parameters of the affine coordinate transformation and of the effects of progressive distortion. By contrast, 2D Fourier transform pairs for images do not lend themselves to visualization in the same way. Affine transformations possess considerable flexibility and generality of a useful kind that arises from the property that a single 2D spectral component transforms into another single component. >
Epitaxially-grown Ge/Si avalanche photodiodes for 1.3 μm light detection (2008)

We designed and fabricated Ge/Si avalanche photodiodes grown on silicon substrates. The mesa-type photodiodes exhibit a responsivity at 1310 nm of 0.54 A/W, a breakdown voltage thermal coefficient of 0.05%/ degrees C, a 3 dB-bandwidth of 10 GHz. The gain-bandwidth product was measured as 153 GHz. The effective k value extracted from the excess noise factor was 0.1.
What Does the Future Hold for Irritable Bowel Syndrome and the Functional Gastrointestinal Disorders? (2005)

Our understanding of irritable bowel syndrome and the functional GI disorders has grown considerably over the last 15 years. In part this relates changes in their classification and definition from being due solely to motility disturbances, to being symptom based (eg, Rome criteria). This opened the door to the study of many other factors that contribute to the clinical expression of these disorders, including visceral hypersensitivity, sensitization, altered mucosal immunity, and dysfunction in brain-gut regulatory processes. New knowledge has been gained in areas of genetics, central nervous system and enteric nervous system neurotransmitters of motility, sensitivity and secretion, the effect of altered mucosal inflammation on cytokine and paracrine activation, and neural sensitization, postinfectious disorders, the influence of psychologic stress on gut functioning via alterations in regulatory pathways (eg, hypothalamic-pituitary adrenal axis, or pain regulatory system like the cingulate cortex), improved accuracy of diagnosis using Rome II criteria plus "red flags" the institution of behavioral treatments, and the use of new pharmacologic treatments both at the gut and brain level. Future research will improve upon this new knowledge via basic and translational studies of neuropeptide signaling with new neurotransmitters, new knowledge on the mechanisms for central nervous system-enteric nervous system communication and dysfunction, and more advanced clinical research on education, communication skills and their effects on outcome, genetics, pharmacogenetics and genetic epidemiology, better understanding as to how certain psychosocial domains (eg, catastrophizing, abuse) affect symptom behavior and outcome, newer pharmacologic treatments, and the use of combined pharmacologic and behavioral treatment packages. I am pleased to have the opportunity to provide a personal perspective on what the future will be for irritable bowel syndrome and the other functional GI disorders. Having been involved in this field for almost 30 years, I have been fortunate to witness tremendous changes. The focus of this presentation is to address the advances that have recently occurred that set the stage for proposing future research to help move the field along and ultimately to help our patients.
Cul4A Physically Associates with MDM2 and Participates in the Proteolysis of p53 (2004)

The cullin 4A (Cul4A) gene is amplified and overexpressed in breast and hepatocellular carcinomas. Cul4A functions as an E3 ligase and participates in the proteolysis of several regulatory proteins through the ubiquitin-proteasome pathway. Here, we show that Cul4A associates with MDM2 and p53. Depletion of Cul4A leads to an accumulation of p53. Moreover, expression of Cul4A increases the decay-rate of p53 and delays the accumulation of p53 in response to DNA damage. Cul4A fails to increase the decay of p53 in mouse embryonic fibroblasts lacking MDM2. In addition, the Cul4A-mediated rapid decay of p53 is blocked by p19ARF. The results provide evidence for a role of Cul4A in the MDM2-mediated proteolysis of p53.
Yellow and green luminescence in a freestanding GaN template (2001)

We have studied a broad photoluminescence band in high-mobility freestanding 200-μm-thick GaN template prepared by hydride vapor-phase epitaxy. Variable-excitation intensity and energy experiments showed two defect-related bands: a yellow luminescence (YL) band at about 2.15 eV and a green luminescence (GL) band at about 2.43 eV. In contrast to epitaxial GaN samples prepared by both vapor-phase and molecular-beam epitaxy, the YL in the sample studied is weak and can be easily saturated. However, the GL is dominant. We attribute the GL to isolated defects involving gallium vacancies and the YL to the same defect, but bound to dislocations, or possibly to structural surface defects.
Efficacy of the Simultaneous Use of Condoms and Spermicides (1991)

The topic of this paper is the demonstration of the combined effectiveness of condom and spermicide use. It is reasoned that 2 methods, which separately provide only moderate efficacy, act together independently and the probability of both failing is the product of the 2 probabilities of failure. Spermicides have a typical user failure rate of 21% and condoms 12%; combined, the 1st year probability of failure among typical users is 2.5%. Under perfect use, where there is correct use for every act of intercourse, the assumption of independence is very likely, and efficacy would be a high as steroidal implants. In addition to highly efficacious protection from pregnancy, there is protection form HIV and other sexually transmitted infections (STD). Spermicides referred to are rubber compatible, not oil based, and conform to the IPPF Agreed Test for Total Spermicidal Power. Condoms are defined as good quality which resist breakage and conform to the International Condom Standard, 1990. It is also advised that, in the event of condom breakage without spermicide, genitalia be washed immediately with soap and water to minimize risk. Also, proper douching that directs liquid sideways, not toward the cervix, should further reduce risk, It is underscored that contraceptive efficacy is not an effectiveness rate, but a failure rate. Effectiveness is the proportionate reduction in the risk of conception per cycle or infection per coitus caused by use of a method. The per cycle probability of conception is fecundability. The model described for combined use and STD use; it is based on the assumption that 1) the probability of conception and effectiveness and thus the per cycle probability of failure for the method is constant over time, and 2) there are 13 cycles per year. What is ignored is that failure rates decline among typical users with duration of use, so that life table procedures are not necessary. The annual probability of failure during perfect use of condoms and spermicides would by .00045, and if failure doubled, the probability would still be only .00186. Any lubricant also helps to reduce breakage of condoms, thereby enhancing efficacy. The probability of failure for spermicidally lubricated condoms during perfect use would be .005. If the annual probability of condom failure were doubled to 4% and spermicide effectiveness were the lowest at 73%, then the failure rate would be only 1%.
Mice Lacking Brain-Derived Neurotrophic Factor Exhibit Visceral Sensory Neuron Losses Distinct from Mice Lacking NT4 and Display a Severe Developmental Deficit in Control of Breathing (1996)

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT4) act via the TrkB receptor and support survival of primary somatic and visceral sensory neurons. The major visceral sensory population, the nodose-petrosal ganglion complex (NPG), requires BDNF and NT4 for survival of a full complement of neurons, providing a unique opportunity to compare gene dosage effects between the two TrkB ligands and to explore the possibility that one ligand can compensate for loss of the other. Analysis of newborn transgenic mice lacking BDNF or NT4, or BDNF and NT4, revealed that survival of many NPG afferents is proportional to the number of functional BDNF alleles, whereas only one functional NT4 allele is required to support survival of all NT4-dependent neurons. In addition, subpopulation analysis revealed that BDNF and NT4 can compensate for the loss of the other to support a subset of dopaminergic ganglion cells. Together, these data demonstrate that the pattern of neuronal dependencies on BDNF and NT4 in vivo is far more heterogeneous than predicted from previous studies in culture. Moreover, BDNF knockout animals lack a subset of afferents involved in ventilatory control and exhibit severe respiratory abnormalities characterized by depressed and irregular breathing and reduced chemosensory drive. BDNF is therefore required for expression of normal respiratory behavior in newborn animals.
Novel neutrophil elastase inhibitors as a treatment for neutrophil-predominant inflammatory lung diseases. (2002)

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are progressive and frequently fatal disorders, which have, at present, few effective therapeutic methods. The pathogenesis of these lung diseases is characterized by a neutrophil-predominant inflammation associated with excessive release of neutrophil proteases, including neutrophil elastase (NE), a terminal pulmonary tissue destroyer. Although precise pathogenic mechanisms have been under debate, the NE-mediated severe pulmonary tissue damage, based upon the protease-antiprotease imbalance hypothesis, may be a major pathogenic determinant of these diseases, in particular COPD. Novel aggressive therapeutic approaches to these lung disorders are required, and prevention of NE release may be considered as a promising strategy for disease outcome. This review mainly focuses upon the pathogenic contribution of NE to these neutrophil-predominant inflammatory lung diseases, and evaluates the experimental and clinical efficacies of the two-types of appropriate small molecular weight human neutrophil elastase (HNE) inhibitors: acyl-enzyme inhibitors and transition-state inhibitors. While much progress has been made in the investigation of these disorders and the contribution of HNE inhibitors, several fundamental questions remain to be answered, and so further studies are required.
Cell and tissue culture : laboratory procedures in biotechnology (1998)

The Cell: Selection and Standardization. Cell Quantification. Culture Environment. Biochemistry of Cells in Culture. Culture Processes and Scale-Up. Regulatory Issues. Concluding Remarks. Appendices. Index.
Oxidative Stress in the Pathogenesis of Diabetic Neuropathy (2004)

Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients.
Parametric projection pursuit for dimensionality reduction of hyperspectral data (2004)

This paper addresses the feasibility of utilizing parametric projection pursuit (PPP) for dimensionality reduction of hyperspectral data. With hyperspectral data, the large number of spectral bands can be both a blessing and a curse. It is known that for an accurate classification, the number of required training data increases exponentially with the number of spectral bands. When the data consists of many spectral bands, it is often not feasible to collect enough data for classification purposes, so dimensionality reduction methods, such as PPP, have been proposed for preprocessing hyperspectral data. in the past, PPP has been applied to remotely sensed hyperspectral data with the number of spectral bands being limited to /spl sim/200. In that work, it was shown that PPP can reduce the dimensionality form 100's to 10's, while maintaining class separation for target detection purposes. In this paper, the authors will build on previous research of PPP and investigate the feasibility of applying PPP to dat with 1000's of spectral bands. The data will be collected using an ASD spectroradiometer, Also, another dimensionality reduction algorithm, which is called the Best Spectral Band Combination (BSBC) using Receiver Operating Characteristics (ROC) curves, is used to examine the reliability of the PPP algorithm.