gebhart/patrepeval huggingface dataset:
PF269 FT-2102, AN IDH1 M INHIBITOR, COMBINED WITH AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS): RESULTS FROM A PHASE 1 STUDY (2019)

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7–14% of AML patients (pts) and 3% of MDS pts. FT-2102 is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors by releasing the differentiation block in IDHm leukemia models in vitro. Aims: To report safety and clinical activity data from the first-in-human phase 1 study of FT-2102 in combination with AZA in IDH1m AML/MDS pts. Methods: The Phase 1 study assessed the safety, pharmacokinetics, pharmacodynamics, and clinical activity of FT-2102 combined with AZA 75 mg/m2 x 7 days each cycle in pts with IDH1m AML or MDS (NCT02719574). Eligible pts had treatment naïve (TN) for whom AZA is considered standard treatment or relapsed/refractory (R/R) IDH1m AML/MDS and had adequate liver and renal function. Prior IDH1m inhibitors and hypomethylating agents were allowed, and there were no restrictions for concomitant non-anticancer medications. Results: As of 31 Oct 2018, 41 pts had been treated with FT-2102+AZA, with a median of 4 months on treatment (range: <1 to 18). The 41 treated pts included 35 with AML (26 R/R; 9 TN) and 6 with MDS (2 R/R; 4 TN). Six pts had received prior AZA. Doses of FT-2102 were 150 mg QD (n = 7) and 150 mg BID (n = 34). MTD was not reached and 150 mg BID was selected as the RP2D. Twenty-six pts (63%) discontinued treatment; the most common reasons were HSCT (n = 6), progressive disease (n = 5), death (n = 4), and AEs (n = 3). Severe (Grade 3/4) AEs in >10% of pts included febrile neutropenia, thrombocytopenia (29% each), neutropenia, anemia, fatigue (17% each), leukocytosis (15%), leukopenia, and hypertension (12% each). Four pts (10%) had differentiation syndrome, which resolved with temporary interruption of FT-2102 and treatment with dexamethasone, hydroxyurea, and supportive care. None led to treatment discontinuation. Two pts experienced transient QTcF prolongation associated with concomitant medications. Seven pts died on treatment or within 30 days of the last dose, none considered related to study drug. Clinical responses (Table 1) were first observed after a median of 1.9 mo (range 1 – 6) in AML pts. Clinical benefit (SD > 8 wks) in pts without an IWG-defined response and durable CR/CRh (> 6mo) were observed. Of 30 AML pts who were transfusion-dependent at baseline, 15 (50%) and 7 (23%) became transfusion-independent during 28 and 56 days on treatment, respectively in all response categories. Data on IDH1 mutation clearance and co-mutation analysis will be presented.Summary/Conclusion: The RP2D of 150 mg BID was selected for AML and MDS patients treated with FT-2102 in combination with AZA based on safety, PK and PD response. Treatment resulted in deep responses and durable disease control in a subset of pts. Although numbers were small, an ORR rate of 78% was observed among TN subjects. The Phase 2 study is ongoing.
Phase-Shifted Carrier PWM Technique for General Cascaded Inverters (2008)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> Phase-shifted carrier (PSC) pulsewidth modulation (PWM) in its conventional form is a good solution for single-phase Cascaded inverters as alternative phase opposition disposition (APOD) PWM for single-phase diode clamped inverters. PSC distributes the switching angles of APOD PWM waveform among the legs uniformly and reduces the switching frequency of each leg. This paper proposes a modified PSC technique based on partly shifted carriers for all disposition types including phase disposition (PD) which is suitable for three-phase cascaded inverters. Simulation results are also included for <formula formulatype="inline"><tex>${\hbox{PSC}}_{\hbox{PD}}$</tex> </formula> using carrier-based space-vector PWM (SVPWM). </para>
Improved regional cerebral blood flow in chronic cocaine polydrug users treated with buprenorphine. (1995)

Buprenorphine treatment, and not abstinence from drug use alone, leads to improvement in regional cerebral perfusion abnormalities in chronic cocaine- and heroin-dependent men.
A therapeutic role for cyclooxygenase‐2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis (2003)

Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.
Measurement of DNA Damage after Exposure to Electromagnetic Radiation in the Cellular Phone Communication Frequency Band (835.62 and 847.74 MHz) (1997)

Mouse C3H 10T1/2 fibroblasts and human glioblastoma U87MG cells were exposed to cellular phone communication frequency radiations to investigate whether such exposure produces DNA damage in in vitro cultures. Two types of frequency modulations were studied: frequency-modulated continuous-wave (FMCW), with a carrier frequency of 835.62 MHz, and code-division multiple-access (CDMA) centered on 847.74 MHz. Exponentially growing (U87MG and C3H 10T1/2 cells) and plateau-phase (C3H 10T1/2 cells) cultures were exposed to either FMCW or CDMA radiation for varying periods up to 24 h in specially designed radial transmission lines (RTLs) that provided relatively uniform exposure with a specific absorption rate (SAR) of 0.6 W/kg. Temperatures in the RTLs were monitored continuously and maintained at 37 +/- 0.3 degrees C. Sham exposure of cultures in an RTL (negative control) and 137Cs gamma-irradiated samples (positive control) were included with every experiment. The alkaline comet assay as described by Olive et al. (Exp. Cell Res. 198, 259-269, 1992) was used to measure DNA damage. No significant differences were observed between the test group exposed to FMCW or CDMA radiation and the sham-treated negative controls. Our results indicate that exposure of cultured mammalian cells to cellular phone communication frequencies under these conditions at an SAR of 0.6 W/kg does not cause DNA damage as measured by the alkaline comet assay.
Identification of a Novel Antimicrobial Peptide from Human Hepatitis B Virus Core Protein Arginine-Rich Domain (ARD) (2013)

The rise of multidrug-resistant (MDR) pathogens causes an increasing challenge to public health. Antimicrobial peptides are considered a possible solution to this problem. HBV core protein (HBc) contains an arginine-rich domain (ARD) at its C-terminus, which consists of 16 arginine residues separated into four clusters (ARD I to IV). In this study, we demonstrated that the peptide containing the full-length ARD I-IV (HBc147-183) has a broad-spectrum antimicrobial activity at micro-molar concentrations, including some MDR and colistin (polymyxin E)-resistant Acinetobacter baumannii. Furthermore, confocal fluorescence microscopy and SYTOX Green uptake assay indicated that this peptide killed Gram-negative and Gram-positive bacteria by membrane permeabilization or DNA binding. In addition, peptide ARD II-IV (HBc153-176) and ARD I-III (HBc147-167) were found to be necessary and sufficient for the activity against P. aeruginosa and K. peumoniae. The antimicrobial activity of HBc ARD peptides can be attenuated by the addition of LPS. HBc ARD peptide was shown to be capable of direct binding to the Lipid A of lipopolysaccharide (LPS) in several in vitro binding assays. Peptide ARD I-IV (HBc147-183) had no detectable cytotoxicity in various tissue culture systems and a mouse animal model. In the mouse model by intraperitoneal (i.p.) inoculation with Staphylococcus aureus, timely treatment by i.p. injection with ARD peptide resulted in 100-fold reduction of bacteria load in blood, liver and spleen, as well as 100% protection of inoculated animals from death. If peptide was injected when bacterial load in the blood reached its peak, the protection rate dropped to 40%. Similar results were observed in K. peumoniae using an IVIS imaging system. The finding of anti-microbial HBc ARD is discussed in the context of commensal gut microbiota, development of intrahepatic anti-viral immunity and establishment of chronic infection with HBV. Our current results suggested that HBc ARD could be a new promising antimicrobial peptide.
Rous sarcoma virus nucleic acid-binding protein p12 is necessary for viral 70S RNA dimer formation and packaging (1986)

To study the function(s) of the Rous sarcoma virus nucleic acid-binding protein p12, we constructed mutants by using two restriction sites in the p12 proviral coding sequence of the Prague C strain to insert KpnI synthetic linkers. The two restriction sites are in the same reading frame, which allowed us to construct a deletion mutant lacking the two conserved Cys-His regions and a duplication mutant containing three intact Cys-His boxes. These mutant DNAs were transfected into chicken embryo fibroblasts, and the viral particles produced in a transient assay were characterized biochemically and for infectivity. Our results indicate that the Rous sarcoma virus nucleic acid-binding protein p12 is necessary for genomic RNA packaging but not for particle assembly and is implicated in the formation of a stable 70S dimeric RNA. Moreover, the fact that one mutant was apparently able to package normal 70S RNA but was not infectious suggests a role for p12 during the infection process.
Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein–Mediated β-Cell Proliferation in Human Pancreatic Islets (2006)

High glucose concentrations have a dual effect on beta-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to beta-cell production of interleuking (IL)-1beta in human pancreatic islets. Fas, a death receptor regulated by IL-1beta, is involved in glucose-induced beta-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1beta at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1beta concentrations (0.01-0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1beta (2-5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1beta was monophasic. Low IL-1beta also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1beta. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1beta-stimulated beta-cell proliferation. Consistent with our in vitro results, IL-1beta knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1beta levels positively influence beta-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1beta concentrations.
Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines (2011)

NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors. It provides proof of concept data for clinical development of ATR inhibitors.
Exposure in wireless Ad-Hoc sensor networks (2001)

Wireless ad-hoc sensor networks will provide one of the missing connections between the Internet and the physical world. One of the fundamental problems in sensor networks is the calculation of coverage. Exposure is directly related to coverage in that it is a measure of how well an object, moving on an arbitrary path, can be observed by the sensor network over a period of time.In addition to the informal definition, we formally define exposure and study its properties. We have developed an efficient and effective algorithm for exposure calculation in sensor networks, specifically for finding minimal exposure paths. The minimal exposure path provides valuable information about the worst case exposure-based coverage in sensor networks. The algorithm works for any given distribution of sensors, sensor and intensity models, and characteristics of the network. It provides an unbounded level of accuracy as a function of run time and storage. We provide an extensive collection of experimental results and study the scaling behavior of exposure and the proposed algorithm for its calculation.
A viral suppressor of gene silencing in plants (1998)

Gene silencing is an important but little understood regulatory mechanism in plants. Here we report that a viral sequence, initially identified as a mediator of synergistic viral disease, acts to suppress the establishment of both transgene-induced and virus-induced posttranscriptional gene silencing. The viral suppressor of silencing comprises the 5'-proximal region of the tobacco etch potyviral genomic RNA encoding P1, helper component-proteinase (HC-Pro) and a small part of P3, and is termed the P1/HC-Pro sequence. A reversal of silencing assay was used to assess the effect of the P1/HC-Pro sequence on transgenic tobacco plants (line T4) that are posttranscriptionally silenced for the uidA reporter gene. Silencing was lifted in offspring of T4 crosses with four independent transgenic lines expressing P1/HC-Pro, but not in offspring of control crosses. Viral vectors were used to assess the effect of P1/HC-Pro expression on virus-induced gene silencing (VIGS). The ability of a potato virus X vector expressing green fluorescent protein to induce silencing of a green fluorescent protein transgene was eliminated or greatly reduced when P1/HC-Pro was expressed from the same vector or from coinfecting potato virus X vectors. Expression of the HC-Pro coding sequence alone was sufficient to suppress virus-induced gene silencing, and the HC-Pro protein product was required for the suppression. This discovery points to the role of gene silencing as a natural antiviral defense system in plants and offers different approaches to elucidate the molecular basis of gene silencing.
PSK self-homodyne detection using a pilot carrier for multibit/symbol transmission with inverse-RZ signal (2005)

Phase-shift-keying (PSK) self-homodyne modulation and demodulation using a polarization-multiplexed pilot-carrier with an inverse-return-to-zero (RZ) intensity modulation signal for 2-bit/symbol transmission at 20 Gb/s was demonstrated. The pilot-carrier was generated by polarization-modulation in an orthogonal polarization state with respect to a PSK signal in the transmitter, while its polarization state was rotated by 90/spl deg/ in a LiNbO/sub 3/-based hybrid module for homodyne detection in the receiver. We confirm that the proposed self-homodyne detection scheme is insensitive to cross-modulation degradation by an inverse-RZ signal with high extinction ratio, thanks to an intensity-noise reduction capability of more than 15 dB in the homodyne-balanced receiver. The proposed scheme offers robust PSK homodyne detection for multibit per symbol formats without using a complex optical phase-locked loop.
Controlled intracellular localization and enhanced antisense effect of oligonucleotides by chemical conjugation (2005)

Oligonucleotides can be covalently linked to peptides composed of any sequence of amino acids by solid phase fragment condensation. The peptides incorporated into the conjugates include nuclear localizing signals (NLS), nuclear export signals (NES), membrane fusion domain of some viral proteins and some designed peptides with amphipathic character. Evaluation of biological properties of DNA-peptide conjugates indicated that (a) the conjugates could bind to target RNA and dsDNA with increased affinity, (b) the conjugates were more resistant to cellular nuclease degradation, (c) the conjugate-RNA hybrids could activate RNase H as effectively as native oligonucleotides, (d) the conjugates with fusion peptides showed largely enhanced cellular uptake, (e) the conjugates with NLS could be predominantly delivered into the cell nucleus, (f) the conjugates with NES could be localized in the cytoplasm. As a result, antisense oligonucleotides conjugated with NLS could inhibit human telomerase in human leukemia cells much more strongly than phosphorothioate oligonucleotides.
Toll-Like Receptors (2003)

The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.
Structural basis for self‐recognition by autoimmune T‐cell receptors (2012)

T-cell receptors (TCRs) recognize peptides presented by major histocompatibility complex molecules (pMHC) to discriminate between foreign and self-antigens. Whereas T-cell recognition of foreign peptides is essential for protection against microbial pathogens, recognition of self-peptides by T cells that have escaped negative selection in the thymus can lead to autoimmune disease. Structural studies of autoimmune TCR-pMHC complexes have provided insights into the mechanisms underlying self-recognition and escape from thymic deletion. Two broad categories of self-reactive TCRs can be clearly distinguished: (i) TCRs with altered binding topologies to self-pMHC and (ii) TCRs that bind self-pMHC in the canonical diagonal orientation, but where there are structural defects or suboptimal anchors in the self-ligand. For both categories, however, the overall stability of the autoimmune TCR-pMHC complex is markedly reduced compared to anti-microbial complexes, allowing the autoreactive T cells to evade negative selection, yet retain the ability to be activated by self-antigens in target organs. Additionally, the structures provide insights into TCR cross-reactivity, which can contribute to autoimmunity by increasing the likelihood of self-pMHC recognition. Efforts are now underway to understand the impact of structural alterations in autoimmune TCR-pMHC complexes on higher order assemblies involved in TCR signaling, as well as on immunological synapse formation.
Large non-coding RNAs: missing links in cancer? (2010)

Cellular homeostasis is achieved by the proper balance of regulatory networks that if disrupted can lead to cellular transformation. These cell circuits are fine-tuned and maintained by the coordinated function of proteins and non-coding RNAs (ncRNAs). In addition to the well-characterized protein coding and microRNAs constituents, large ncRNAs are also emerging as important regulatory molecules in tumor-suppressor and oncogenic pathways. Recent studies have revealed mechanistic insight of large ncRNAs regulating key cancer pathways at a transcriptional, post-transcriptional and epigenetic level. Here we synthesize these latest advances within the context of their mechanistic roles in regulating and maintaining cellular equilibrium. We posit that similar to protein-coding genes, large ncRNAs are a newly emerging class of oncogenic and tumor-suppressor genes. Our growing knowledge of the role of large ncRNAs in cellular transformation is pointing towards their potential use as biomarkers and targets for novel therapeutic approaches in the future.
Passive leg raising predicts fluid responsiveness in the critically ill* (2006)

The changes in aortic blood flow induced by PLR predict preload responsiveness in ventilated patients, whereas with arrhythmias and spontaneous breathing activity, respiratory variations of arterial pulse pressure poorly predict preload responsiveness.
Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? (2001)

Hematopoietic stem cells from 4 different sources have been or are being used for the reconstitution of lymphohematopoietic function after myeloablative, near-myeloablative, or nonmyeloablative treatment. Bone marrow (BM)-derived stem cells, introduced by E. D. Thomas in 1963, are considered the classical stem cell source. Fetal liver stem cell transplantation has been performed on a limited number of patients with aplastic anemia or acute leukemia, but only transient engraftment has been demonstrated. Peripheral blood as a stem cell source was introduced in 1981, and cord blood was introduced as a source in 1988. The various stem cell sources differ in their reconstitutive and immunogenic characteristics, which are based on the proportion of early pluripotent and self-renewing stem cells to lineage-committed late progenitor cells and on the number and characteristics of accompanying "accessory cells" contained in stem cell allografts.
Oncogenic activation in prostate cancer progression and metastasis: Molecular insights and future challenges (2012)

Prostate cancer is a leading cause of death among men in the United States, and currently early diagnosis and appropriate treatment remain key approaches for patient care. Molecularly prostate cancer cells carry multiple perturbations that generate malignant phenotype capable of uncontrolled growth, survival, and invasion-metastasis to other organs. These alterations are acquired both by genetic and epigenetic changes in tumor cells resulting in the activation of growth factor receptors, signaling proteins, kinases, transcription factors and coregulators, and multiple proteases required for the progression of the disease. Recent advances provide novel insights into the molecular functions of these oncogenic activators, implicating potential therapeutic targeting opportunities for the treatment of prostate cancer.