gebhart/patrepeval huggingface dataset:
Oxygen consumption and energy metabolism of the early mouse embryo (1996)

Oxygen consumption of preimplantation and early postimplantation mouse embryos has been measured using a novel noninvasive ultramicrofluorescence technique, based on an oil-soluble, nontoxic quaternary benzoid compound pyrene, whose fluorescence is quenched in the presence of oxygen. Pyruvate and glucose consumption, lactate production, and glycogen formation from glucose were also measured. Preimplantation mouse embryos of the strain CBA/Ca x C57BL/6 were cultured in groups of 10-30 in 2 microliters of modified M2 medium containing 1 mmol l-1 glucose, 0 mmol l-1 lactate, and 0.33 mmol l-1 pyruvate, for between 4-6 hr. Day 6.5 and 7.5 embryos were cultured singly in 40 microliters M2 medium for between 2-3 hr. Oxygen consumption was detected at all stages of development, including, for the first time, in the early postimplantation embryo. Consumption remained relatively constant from zygote to morula stages before increasing in the blastocyst and day 6.5-7.5 stages. When expressed as QO2 (microliters/mg dry weight/hr), oxygen consumption was relatively constant from the one-cell to morula stages before increasing sharply at the blastocyst stage and declining to preblastocyst levels on days 6.5 and 7.5. Pyruvate was consumed during preimplantation stages, with glucose uptake undetectable until the blastocyst stage. Glucose was the main substrate consumed by the 6.5 and 7.5 day embryo. The proportions of glucose accounted for by lactate appearance were 81%, 86%, and 119% at blastocyst, day 6.5, and day 7.5 stages, respectively. The equivalent figures for glucose incorporated into glycogen were 10.36%, 0.21%, and 0.19%, respectively. The data are consistent with a switch from a metabolism dependent on aerobic respiration during early preimplantation stages to one dependent on both oxidative phosphorylation and aerobic glycolysis at the blastocyst stage, a pattern which is maintained on days 6.5 and 7.5. Our technique for measuring oxygen consumption may have diagnostic potential for selecting viable embryos for transfer following assisted conception techniques in man and domestic animals.
Mini‐review The role of interleukin‐12 in human infectious diseases: only a faint signature (2003)

IL-12 is the signature IFN-gamma-inducing cytokine and, as such, is thought to be crucial for protective immunity against intracellular microorganisms. This concept is supported by results from experimental infections of knockout mice lacking IL-12 or the IL-12 receptor. The description of human patients with inherited IL-12 or IL-12-receptor deficiency challenges this view. Indeed, in natural conditions of infection and immunity - the hallmark of the human model - IL-12 was found to be redundant in defense against intracellular microorganisms other than Mycobacteria and Salmonella. More surprisingly, IL-12 was recently found to be redundant even in defense against primary intection by Mycobacteria and Salmonella in many patients, and against secondary infection by Mycobacteria but not Salmonella in most patients.
Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study. (2016)

5515 Background: Median survival is limited to only ~7 months in patients (pts) with metastatic or recurrent cervical cancer despite current treatments. Upregulation of the PD-1/PD-L1 pathway on tumor or infiltrating immune cells may negatively regulate immunity and contribute to disease progression. Pembrolizumab, an anti–PD-1 antibody, blocks the interaction between PD-1 and its ligands, PD-L1/PD-L2. Results from the cervical cancer cohort of KEYNOTE-028 (NCT02054806), a phase 1b study to evaluate the safety and efficacy of pembrolizumab in pts with advanced solid tumors, are presented. Methods: Key eligibility criteria included advanced cervical squamous cell cancer, failure of prior systemic therapy, ECOG PS 0-1, and PD-L1 expression in ≥1% of tumor or stroma cells by IHC. Pembrolizumab 10 mg/kg was given every 2 wk for up to 24 mo or until confirmed progression, intolerable toxicity, death, or withdrawal of consent. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator assessment. Results: 24 pts with advanced cervical cancer were enrolled; median age was 41.5 y, 75.0% had an ECOG PS of 1, and 62.5% had received ≥2 prior therapies for metastatic disease. As of Dec 10, 2015, median follow-up duration was 48.9 wk (range, 5.6-90 wk). 18 (75.0%) pts experienced a treatment-related adverse event (TRAE), with pyrexia (n =4) and rash (n = 3) occurring in ≥10% of pts. 5 (20.8%) pts had grade 3 TRAEs, 2 of whom discontinued pembrolizumab (colitis, Guillain-Barre syndrome). No grade 4 or 5 TRAEs occurred. ORR (confirmed) was 12.5% (3/24; 95% CI, 2.7%-32.4%; all were PRs); the median duration of response was 19.3 wk (range, 17.7-52.0 wk). The stable disease (SD) rate was 12.5% (3/24; 95% CI, 2.7%-32.4%); the median duration of SD was 19.6 wk (range, 16.3-29.7+ wk). The 6-mo PFS rate was 13.0%; the 6-mo OS rate was 66.7%. Conclusions: Pembrolizumab was well tolerated and showed promising antitumor activity in pts with PD-L1+ advanced cervical squamous cell cancer. The clinical benefit of pembrolizumab in advanced cervical cancer will be further investigated in the phase 2 KEYNOTE-158 trial (NCT02628067). Clinical trial information: NCT02054806.
Melatonin Phase-Shifts Human Circadian Rhythms with No Evidence of Changes in the Duration of Endogenous Melatonin Secretion or the 24-Hour Production of Reproductive Hormones (2003)

The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive hormones in humans. Eight healthy men took part in this double-blind, crossover study. Surge/sustained release melatonin (1.5 mg) or placebo was administered for 8 d at the beginning of a 16-h sleep opportunity (1600 h to 0800 h) in dim light. Compared with placebo, melatonin administration advanced the timing of endogenous melatonin and cortisol rhythms. Activity was reduced in the first half and increased in the second half of the sleep opportunity with melatonin; however, total activity during the sleep opportunities and wake episodes was not affected. Melatonin treatment did not affect the endogenous melatonin profile duration, pituitary/gonadal hormone levels (24-h), or sleepiness and mood levels on the subsequent day. In the short term, suitably timed sustained-release melatonin phase-shifts circadian rhythms and redistributes activity during a 16-h sleep opportunity, with no evidence of changes in the duration of endogenous melatonin secretion or pituitary/gonadal hormones.
Benzylpiperazine derivatives. II. Syntheses and cerebral vasodilating activities of 1-((3-alkyl-3-hydroxy-3-phenyl)propyl)-4-benzylpiperazine derivatives. (1987)

Analogs of 1-[ (3-alkyl-3-hydroxy-3-phenyl) propyl]-4- (2, 3, 4-trimethoxybenzyl) piperazine (1) were prepared and tested for cerebral vasodilating activity. It was found that the potency depends positively on the number of methoxyl groups on the benzyl moiety, and the homopiperazine analogs seem to be equipotent to the corresponding piperazines.From the standpoints of potency and ease of synthesis, 8k was selected for further study. Further analogs, which have various substituents in place of the benzyl moiety of 8k, were prepared and tested for cerebral vasodilating activity. These analogs were less potent than 8k. It was suggested that the benzyl moiety of 8k plays an important role in the high cerebral vasodilating activity.
Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast (2003)

Inactivation of the budding yeast telomere binding protein Cdc13 results in abnormal telomeres (exposed long G-strands) and activation of the DNA damage checkpoint. In the current study, we show that inactivation of Cdc13p induces apoptotic signals in yeast, as evidenced by caspase activation, increased reactive oxygen species production, and flipping of phosphatidylserine in the cytoplasmic membrane. These apoptotic signals were suppressed in a mitochondrial (rho(o)) mutant. Moreover, mitochondrial proteins (e.g. MTCO3) were identified as multicopy suppressors of cdc13-1, suggesting the involvement of mitochondrial functions in telomere-initiated apoptotic signaling. These telomere-initiated apoptotic signals were also shown to depend on MEC1, but not TEL1, and were antagonized by MRE11. Our results are consistent with a model in which single-stranded G-tails in the cdc13-1 mutant trigger MEC1-dependent apoptotic signaling in yeast.
Free-Drifting Icebergs: Hot Spots of Chemical and Biological Enrichment in the Weddell Sea (2007)

The proliferation of icebergs from Antarctica over the past decade has raised questions about their potential impact on the surrounding pelagic ecosystem. Two free-drifting icebergs, 0.1 and 30.8 square kilometers in aerial surface area, and the surrounding waters were sampled in the northwest Weddell Sea during austral spring 2005. There was substantial enrichment of terrigenous material, and there were high concentrations of chlorophyll, krill, and seabirds surrounding each iceberg, extending out to a radial distance of approximately 3.7 kilometers. Extrapolating these results to all icebergs in the same size range, with the use of iceberg population estimates from satellite surveys, indicates that they similarly affect 39% of the surface ocean in this region. These results suggest that free-drifting icebergs can substantially affect the pelagic ecosystem of the Southern Ocean and can serve as areas of enhanced production and sequestration of organic carbon to the deep sea.
The Mouse p (pink‐eyed dilution) and Human P Genes, Oculocutaneous Albinism Type 2 (OCA2), and Melanosomal pH (2001)

Recessive mutations of the mouse p (pink-eyed dilution) gene lead to hypopigmentation of the eyes, skin, and fur. Mice lacking a functional p protein have pink eyes and light gray fur (if non-agouti) or cream-colored fur (if agouti). The human orthologue is the P protein. Humans lacking a functional P protein have oculocutaneous albinism type 2 (OCA2). Melanocytes from p-deficient mice or OCA2 individuals contain small, minimally pigmented melanosomes. The mouse and human proteins are predicted to have 12 membrane spanning domains and possess significant sequence homology to a number of membrane transport proteins, some of which are involved in the transport of anions. The p protein has been localized to the melanosome membrane. Recently, it has been shown that melanosomes from p protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from p protein-deficient mice are non-acidic. Melanosomes and related endosome-derived organelles (i.e., lysosomes) are thought to have an adenosine triphosphate (ATP)-driven proton pump that helps to generate an acidic lumen. To compensate for the charge of these protons, anions must also be transported to the lumen of the melanosome. In light of these observations, a model of p protein function is presented in which the p protein, together with the ATP-driven proton pump, regulates the pH of the melanosome.
Protective Immunity to Vaccinia Virus Induced by Vaccination with Multiple Recombinant Outer Membrane Proteins of Intracellular and Extracellular Virions (2004)

Infectious intracellular and extracellular forms of vaccinia virus have different outer membrane proteins, presenting multiple targets to the immune system. We investigated the immunogenicity of soluble forms of L1, an outer membrane protein of the intracellular mature virus, and of A33 and B5, outer membrane proteins of the extracellular enveloped virus. The recombinant proteins, in 10-microg amounts mixed with a Ribi- or saponin-type adjuvant, were administered subcutaneously to mice. Antibody titers to each protein rose sharply after the first and second boosts, reaching levels that surpassed those induced by percutaneous immunization with live vaccinia virus. Immunoglobulin G1 (IgG1) antibody predominated after the protein immunizations, indicative of a T-helper cell type 2 response, whereas live vaccinia virus induced mainly IgG2a, indicative of a T-helper cell type 1 response. Mice immunized with any one of the recombinant proteins survived an intranasal challenge with 5 times the 50% lethal dose of the pathogenic WR strain of vaccinia virus. Measurements of weight loss indicated that the A33 immunization most effectively prevented disease. The superiority of protein combinations was demonstrated when the challenge virus dose was increased 20-fold. The best protection was obtained with a vaccine made by combining recombinant proteins of the outer membranes of intracellular and extracellular virus. Indeed, mice immunized with A33 plus B5 plus L1 or with A33 plus L1 were better protected than mice immunized with live vaccinia virus. Three immunizations with the three-protein combination were necessary and sufficient for complete protection. These studies suggest the feasibility of a multiprotein smallpox vaccine.
Polyomavirus Large T Antigen Binds Symmetrical Repeats at the Viral Origin in an Asymmetrical Manner (2013)

Polyomaviruses have repeating sequences at their origins of replication that bind the origin-binding domain of virus-encoded large T antigen. In murine polyomavirus, the central region of the origin contains four copies (P1 to P4) of the sequence G(A/G)GGC. They are arranged as a pair of inverted repeats with a 2-bp overlap between the repeats at the center. In contrast to simian virus 40 (SV40), where the repeats are nonoverlapping and all four repeats can be simultaneously occupied, the crystal structure of the four central murine polyomavirus sequence repeats in complex with the polyomavirus origin-binding domain reveals that only three of the four repeats (P1, P2, and P4) are occupied. Isothermal titration calorimetry confirms that the stoichiometry is the same in solution as in the crystal structure. Consistent with these results, mutation of the third repeat has little effect on DNA replication in vivo. Thus, the apparent 2-fold symmetry within the DNA repeats is not carried over to the protein-DNA complex. Flanking sequences, such as the AT-rich region, are known to be important for DNA replication. When the orientation of the central region was reversed with respect to these flanking regions, the origin was still able to replicate and the P3 sequence (now located at the P2 position with respect to the flanking regions) was again dispensable. This highlights the critical importance of the precise sequence of the region containing the pentamers in replication.
Peptide Receptors as Molecular Targets for Cancer Diagnosis and Therapy (2003)

During the past decade, proof of the principle that peptide receptors can be used successfully for in vivo targeting of human cancers has been provided. The molecular basis for targeting rests on the in vitro observation that peptide receptors can be expressed in large quantities in certain tumors. The clinical impact is at the diagnostic level: in vivo receptor scintigraphy uses radiolabeled peptides for the localization of tumors and their metastases. It is also at the therapeutic level: peptide receptor radiotherapy of tumors emerges as a serious treatment option. Peptides linked to cytotoxic agents are also considered for therapeutic applications. The use of nonradiolabeled, noncytotoxic peptide analogs for long-term antiproliferative treatment of tumors appears promising for only a few tumor types, whereas the symptomatic treatment of neuroendocrine tumors by somatostatin analogs is clearly successful. The present review summarizes and critically evaluates the in vitro data on peptide and peptide receptor expression in human cancers. These data are considered to be the molecular basis for peptide receptor targeting of tumors. The paradigmatic peptide somatostatin and its receptors are extensively reviewed in the light of in vivo targeting of neuroendocrine tumors. The role of the more recently described targeting peptides vasoactive intestinal peptide, gastrin-releasing peptide, and cholecystokinin/gastrin is discussed. Other emerging and promising peptides and their respective receptors, including neurotensin, substance P, and neuropeptide Y, are introduced. This information relates to established and potential clinical applications in oncology.
Access emulation and buffering techniques for streaming of non-stream format video files (2001)

Videos recorded in a non-stream format are widely used in the Internet. However, they are not directly utilized in video streaming. For streaming without download a time consuming format conversion is usually required. For the direct utilisation of such videos in video-on-demand systems, we have developed a new service model and implementation techniques. We describe the techniques in detail along with a prototype movie-on-demand system. With a low-end Linux server, the system successfully supports over 30 clients connected at the same time.
Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants (1999)

Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.
Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients (2006)

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m 2 . Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in &lt;5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]
Distributing layered encoded video through caches (2002)

The efficient distribution of stored information has become a major concern in the Internet which has increasingly become a vehicle for the transport of stored video. Because of the highly heterogeneous access to the Internet, researchers and engineers have argued for layered encoded video. We investigate delivering layered encoded video using caches. Based on a stochastic knapsack model we develop a model for the layered video caching problem. We propose heuristics to determine which videos and which layers in the videos should be cached. We evaluate the performance of our heuristics through extensive numerical experiments. We also consider two intuitive extensions to the initial problem.
Synergy between immunotoxins prepared with native ricin A chains and chemically-modified ricin B chains. (1986)

Ricin B chains treated with chloramine-T in the presence or absence of NaI show a 100-fold to 200-fold reduction in their ability to bind to the galactose-containing protein asialofetuin. Such treated B chains do not form covalently associated homodimers with treated B chains or heterodimers with native ricin A chains. Furthermore, they cannot enhance the toxicity of a ricin A chain-containing rabbit anti-human immunoglobulin (RAHIg-A) for Daudi cells. However, when such B chains are coupled to goat anti-rabbit Ig (GARIg), they potentiate the killing of RAHIg-A-treated Daudi cells only slightly less effectively than GARIg coupled to native B chains. Furthermore, if GARIg-B chain conjugates are treated with chloramine-T after coupling, they fail to bind to asialofetuin but enhance the killing of Daudi cells treated with RAHIg-A. These results demonstrate that the ability of ricin B chains to bind to galactose and to enhance the toxicity of ricin A chains (in the form of an antibody-A chain) can be operationally separated. Thus, the two functions of the B chain may reside on separate domains of the molecule.
Cell growth regulation in epithelial ovarian cancer (1993)

Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.