gebhart/patrepeval huggingface dataset:
Free Polymerized Hemoglobin Versus Hydroxyethyl Starch in Resuscitation of Hypovolemic Dogs (1992)

Polymerized bovine hemoglobin (PBH) was compared with hydroxyethyl starch (HES) in a hypovolemic shock model. Eighteen dogs were subjected to hemorrhage; systolic arterial blood pressure was maintained at 40 mm Hg for 30 min (mean blood pressure 37.8 +/- 4.7 [SD] mm Hg). Resuscitation was conducted by infusing their own shed blood (control group) or 6% HES (mol wt 200,000) in 0.9% NaCl (HES group) or PBH (PBH group), both in an equal amount to the shed blood. Directly after infusion, oxygen delivery and consumption returned to prehemorrhage levels in all three groups. In the HES group, the lowered arterial oxygen content was compensated by a 158% increase in cardiac output, in contrast to an increase of 31% and 9%, respectively, in the control and PBH groups. Early recovery from hypovolemic shock with regard to oxygen transport and delivery in the PBH group seemed to be comparable to the control group, without the increase in cardiac output seen with HES infusion.
Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). (2001)

Mesothelin is a new marker for pancreatic adenocarcinoma identified by gene expression analysis. Mesothelin overexpression in pancreatic adenocarcinoma has potential diagnostic, imaging, and therapeutic implications.
[Inhibition of protein kinase C by stilbenoids]. (1994)

The effect of 15 stilbenoids on protein kinase C (PKC) was studied in order to search for naturally occurring PKC inhibitors. All these compounds were isolated from Chinese medicines. Three oligomeric stilbenes from Caragana sinica, alpha-viniferin, kobophenol A and miyabenol C, were shown to intensely inhibit the activity of partially purified rat brain PKC with IC50 values of 62.5, 52.0, and 27.5 mumol.L-1, respectively. Kinetic analyses revealed that that inhibition was noncompetitive. The other compounds also showed the effect. Monomer stilbenes exhibited PKC inhibitory activity at higher mumol.L-1 concentrations than oligomeric stilbenes. Whenever they are methylated or acetylated perfectly, the inhibition weakens or disappears.
Sperm Autoantigens and Fertilization: II. Effects of Anti-Guinea Pig Sperm Autoantibodies on Sperm-Ovum Interactions (1981)

Bivalent (IgG) and monovalent (Fab) antibodies isolated from antisperm autoantiserum of the guinea pig were tested for their effects on 1) the penetration of guinea pig anna pellucida by acrosome-reacted guinea pig spermatozoa and 2) the fusion of acrosome-reacted guinea pig spermatozoa with plasma membranes of guinea pig and hamster ova. In the presence of antiserum IgG, acrosome-reacted spermatozoa appeared as single, highly motile cells. They were completely prevented from interacting with guinea pig anna and from fusing with zona-free hamster ova, while their fusion with zona-free guinea pig ova was markedly inhibited. These cellular interactions were blocked, to a lesser degree, by monovalent (Fab) antibodies isolated from the same antisperm antiserum. IgG or Fab from normal guinea pig sera had no effect on these cellular interactions. Pretreatment of ova with antisperm IgG or Fab did not interfere with the interaction of ova with untreated acrosome-reacted spermatozoa. This study provides the first evidence that autoantigenic molecules on the surface and/or an intracellular membrane (e.g., the inner acrosomal membrane) of spermatozoa may be involved in the recognition of complementary ligands on the ova during the process of sperm-zona and sperm-vitellus interaction. It follows that blockage of these cellular events in fertilization by antireceptor antibodies is a potential mechanism whereby immune responses to sperm-specific antigens can render females infertile.
Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer (2008)

PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
New drug approved for pulmonary arterial hypertension (2007)

Journal Article New drug approved for pulmonary arterial hypertension Get access Donna Young Donna Young Search for other works by this author on: Oxford Academic Google Scholar American Journal of Health-System Pharmacy, Volume 64, Issue 15, 1 August 2007, Page 1562, https://doi.org/10.2146/news070068 Published: 01 August 2007
Metabotropic Transmitter Actions in Auditory Thalamus (2000)

Neurons in the ventral partition of the medial geniculate body (MGBv), the primary auditory thalamus, receive afferent input from the inferior colliculus via excitatory glutamate-ergic and inhibitory GABA-ergic input fibres. The feedback from the auditory cortex to the thalamic relay also is mediated via neuron systems using glutamate and GABA as transmitters. We studied effects on excitability mediated by these transmitters via G-protein coupled metabotropic receptors. In a slice preparation of rat thalamus we investigated the membrane responses of MGBv neurons using the whole cell recording technique. Application of a metabotropic glutamate receptor (mGluR) agonist, ACPD (5-100 microM), depolarized MGBv neurons. As a result, the burst mode of firing, which characterizes states of sleep at hyperpolarized potentials was replaced by the tonic mode, which is compatible with sound signal transmission during alertness. The depolarization was caused by an inward current (I(ACPD)) that persisted during blockade of Na+ channels with tetrodotoxin (TTX) and of Ca2+ channels with Cd2+. The I(ACPD) depended, however, on extracellular Na+, which could be replaced with Li+, excluding a major contribution of the Na+/Ca2+ exchange current. ACPD application also inhibited an inwardly rectifying K+ current at hyperpolarized potentials and activated an outward current in the depolarized range. Application of the GABA(B) agonist, baclofen (10 microM), hyperpolarized MGBv neurons by activation of an inwardly rectifying K+ current. The corresponding membrane conductance acted as a powerful shunt that reduced voltage responses and inhibited firing in both the tonic and burst modes. Thus, the effects of GABA(B) receptor activation would suppress auditory signal transfer, whereas mGluR activation enhances excitability, possibly accounting for the alerting effects of certain auditory stimuli.
Secure Bit: Transparent, Hardware Buffer-Overflow Protection (2006)

We propose a minimalist, architectural approach, Secure Bit (patent pending), to protect against buffer overflow attacks on control data (return-address and function-pointer attacks in particular). Secure Bit provides a hardware bit to protect the integrity of addresses for the purpose of preventing such buffer-overflow attacks. Secure Bit is transparent to user software: it provides backward compatibility with legacy user code. It can detect and prevent all address-corrupting buffer-overflow attacks with little runtime performance penalty. Addresses passed in buffers between processes are marked insecure, and control instructions using those addresses as targets will raise an exception. An important differentiating aspect of our protocol is that, once an address has been marked as insecure, there is no instruction to remark it as secure. Robustness and transparency are demonstrated by emulating the hardware, booting Linux on the emulator, running application software on that Linux, and performing known attacks
CRP as a Mediator of Disease (2004)

Of the various hypotheses offered to explain atherosclerosis, inflammation now appears to provide a key to this pathological process. Inflammation has been shown to play a major role in precipitating a cascade of events from formation of the atheromatous lesion in response to vascular injury through lipid ingestion by macrophages, to subsequent rupture of the lesion, and myocardial infarction. Atherosclerosis shares many inflammatory features with rheumatoid arthritis (RA), an autoimmune disease, and drugs that block the inflammatory cytokine pathway now provide effective treatment for RA. In animal models, blockers of the inflammatory cytokine pathway appear to block mononuclear cell binding to arterial plaque. C-reactive protein (CRP), an inflammatory marker, may also play a proinflammatory role in activating monocyte chemotactic protein. Antiatherosclerotic drugs may be exerting some of their beneficial effects by inhibiting the harmful effects of CRP.
Microcurrent stimulation in the treatment of dry and wet macular degeneration (2015)

The substantial changes observed over this period, combined with continued improvement for patients who continued treatment once a month, are encouraging for future studies. The changes observed indicate the potential efficacy of microcurrent to delay degeneration and possibly improve age-related macular degeneration, both wet and dry. However, this study has no control arm, so results should be treated with caution. Randomized double-blind controlled studies are needed to determine long-term effects.
Serializable isolation for snapshot databases (2008)

Many popular database management systems offer snapshot isolation rather than full serializability. There are well-known anomalies permitted by snapshot isolation that can lead to violations of data consistency by interleaving transactions that individually maintain consistency. Until now, the only way to prevent these anomalies was to modify the applications by introducing artificial locking or update conflicts, following careful analysis of conflicts between all pairs of transactions.
Distinguishing the Specificities of Closely Related Proteases (1997)

Elucidating subtle specificity differences between closely related enzymes is a fundamental challenge for both enzymology and drug design. We have addressed this issue for two intimately related serine proteases, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), by modifying the technique of substrate phage display to create substrate subtraction libraries. Characterization of individual members of the substrate subtraction library accomplished the rapid, direct identification of small, highly selective substrates for t-PA. Comparison of the amino acid sequences of these selective substrates with the consensus sequence for optimal substrates for t-PA, derived using standard substrate phage display protocols, suggested that the P3 and P4 residues are the primary determinants of the ability of a substrate to discriminate between t-PA and u-PA. Mutagenesis of the P3 and P4 residues of plasminogen activator inhibitor type 1, the primary physiological inhibitor of both t-PA and u-PA, confirmed this prediction and indicated a predominant role for the P3 residue. Appropriate replacement of both the P3 and P4 residues enhanced the t-PA specificity of plasminogen activator inhibitor type 1 by a factor of 600, and mutation of the P3 residue alone increased this selectivity by a factor of 170. These results demonstrate that the combination of substrate phage display and substrate subtraction methods can be used to discover specificity differences between very closely related enzymes and that this information can be utilized to create highly selective inhibitors.
Management of the metabolic syndrome. (2004)

The metabolic syndrome (MetS) is strongly associated with insulin resistance and consists of a constellation of factors that raise the risk for cardiovascular diseases and diabetes mellitus. Therefore, the primary goals of treating MetS are prevention of type 2 diabetes and cardiovascular events. Three levels of intervention may be considered for individuals with MetS : 1) management of underlying risk conditions by controlling weight excess, enhancing regular physical exercise and promoting healthy diet; 2) management of individual risk factors such as dyslipidaemia, hypertension, hyperglycaemia and prothrombotic state; and 3) targeting insulin resistance by using specific insulin sensitizers such as thiazolidinediones. The most important therapeutic intervention effective in subjects with MetS should focus on modest weight reduction and regular leisure-time physical activities. Although lifestyle modification is the first-line therapy, drug therapy may be necessary in many patients to achieve recommended goals regarding lipid profile, blood pressure and blood glucose control. Rather than to use a magic bullet that might fully reverse the underlying cause of the syndrome, one appealing alternative would be to use a so-called "polypill" targeting each of the components of MetS. However, such a polypill should ideally contain numerous molecules that all have shown a potential interest for the management of MetS such as metformin, acarbose, a thiazolidinedione, a statin, a fibrate, an inhibitor of the renin-angiotensin system, aspirin. The growing prevalence and high-risk nature of MetS highlights the need to identify individuals with this condition and to treat them with an aggressive multitargeted approach.
N-Glycan Structures from the Major Glycoproteins of Pigeon Egg White (2001)

N-Glycans from major glycoproteins of pigeon egg white (ovotransferrin, ovomucoid, and ovalbumins) were enzymatically released and were reductively aminated with 2-aminopyridine, separated, and structurally characterized by mass spectrometry and a three-dimensional mapping technique using three different columns of high performance liquid chromatography (HPLC) (Takahashi, N., Nakagawa, H., Fujikawa, K., Kawamura, Y., and Tomiya, N. (1995) Anal. Biochem. 226, 139-146). Twenty-five major N-glycan structures, all of them hitherto unknown, were identified as pyridylamino derivatives. Of these, 13 were neutral, 10 were monosialyl, and 2 were disialyl oligosaccharides. All N-glycans contain from one to four Galalpha(1,4)Galbeta(1,4) sequences at the nonreducing terminal positions and are devoid of fucose residues. N-Acetylneuraminic acids were alpha(2,6)-linked only to beta-galactose. The HPLC profiles of the N-glycans from four different glycoproteins were qualitatively very similar to each other, but not identical in the peak distributions. Monosialyl glycans were most abundant in all four glycoproteins, followed by neutral glycans. Disialyl glycans were lowest in ovotransferrin, and highest in ovomucoid. Triantennary structures with bisecting GlcNAc were predominant in ovotransferrin, and tetra-antennary (with and without bisecting GlcNAc-containing) structures were predominant in other glycoproteins. Penta-antennary structures (with a sialic acid and without bisecting GlcNAc residue) were also found in small quantities in all four glycoproteins. In contrast to the chicken egg white counterparts, which contain mostly high mannose and hybrid types, all N-glycan structures in the major pigeon egg white glycoproteins are complex type.
The p110δ Isoform of Phosphatidylinositol 3-Kinase Controls the Quality of Secondary Anti- Leishmania Immunity by Regulating Expansion and Effector Function of Memory T Cell Subsets (2010)

We showed previously that mice with an inactivating knockin mutation in the p110delta isoform of PI3K (referred to as p110delta(D910A) mice) displayed enhanced primary resistance to Leishmania major despite mounting paradoxically impaired T cell responses. In this study, we show that p110delta(D910A) mice are impaired in their secondary (memory) anti-Leishmania responses in vitro and in vivo. Following secondary L. major challenge, p110delta(D910A) mice exhibited reduced delayed-type hypersensitivity response and weaker parasite control compared to wild-type mice. Using adoptive transfer experiments, we show that immune T cells from healed p110delta(D910A) mice were impaired in their proliferation and effector cytokine (IFN-gamma) responses upon L. major challenge. Interestingly, Leishmania-reactive T cells from healed p110delta(D910A) mice contain severalfold lower numbers of CD62L(lo) and CD62(hi) T cells than those from healed wild-type mice. The reduction in numbers of CD62L(lo) T cells in p110delta(D910A) mice is due to failure of their CD62L(hi) T cells to downregulate CD62L expression in response to L. major. Furthermore, although CD62L(lo) cells from p110delta(D910A) mice could home efficiently to lymphoid organs, their ability to exit these tissues and emigrate to cutaneous sites of infection was greatly impaired. Collectively, our data identify PI3K signaling as important events that control memory T cell subset differentiation, generation, effector function, and recruitment to cutaneous tissues and suggest that manipulating this pathway could provide means of enhancing desired memory T cell subset, response during vaccination, or both.
A mechanism of migration inhibition in delayed-type hypersensitivity reactions. II. Lymphokines promote procoagulant activity of macrophages in vitro. (1981)

Abstract Although lymphokine supernatants had no procoagulant activity per se, guinea pig peritoneal exudate cells (PEC), incubated with lymphokine supernatants or with a lymphokine fraction of 35,000 to 50,000 daltons decreased the recalcification time of platelet-poor plasma. PEC from animals immunized with BCG or with ovalbumin and incubated with the corresponding antigen had increased procoagulant activity. Similar effects were observed with PEC incubated with endotoxin. The induction of procoagulant activity by the cells was accompanied by a concomitant decrease in their ability to respond to chemotactic agents and to migrate from capillary tubes. Separation of exudate cells by sedimentation velocity indicated that large macrophages had the highest degree of procoagulant activity after incubation with lymphokines. The clotting time of Factor IX-deficient plasma was decreased by lymphokine-treated macrophages, indicating that the extrinsic clotting sequence may be activated as a result of increased tissue factor on the treated cells. Heparin abolished the ability of lymphokines to inhibit macrophage migration.
Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis (2016)

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×10<sup>9</sup>/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.
A Permutation Network (1968)

In this paper the construction of a switching network capable of n !-permutation of its n input terminals to its n output terminals is described. The building blocks for this network are binary cells capable of permuting their two input terminals to their two output terminals. The number of cells used by the network is 〈 n · log 2 n - n + 1〉 = Σ n k =1 〈log 2 k 〉. It could be argued that for such a network this number of cells is a lower bound, by noting that binary decision trees in the network can resolve individual terminal assignments only and not the partitioning of the permutation set itself which requires only 〈log 2 n !〉 = 〈Σ n k =1 log 2 k 〉 binary decisions. An algorithm is also given for the setting of the binary cells in the network according to any specified permutation.
1.1 W CW, diffraction-limited operation of a monolithically integrated flared-amplifier master oscillator power amplifier (1992)

Monolithically integrated flared-amplifier master oscillator power amplifiers (MFA-MOPA) have been fabricated that operate to greater than 1.1 W CW in a single diffraction-limited output beam. The device operates in a single spatial and spectral mode throughout its operating range. The farfield radiation pattern is a single diffraction-limited output beam which does not exhibit any steering as a result of changes in injection current.
Eliminating Positively Charged Lysine ε-NH3+ Groups on the Surface of Carbonic Anhydrase Has No Significant Influence on Its Folding from Sodium Dodecyl Sulfate (2005)

This study compares the folding of two polypeptides--bovine carbonic anhydrase (BCA) and peracetylated BCA (BCA-Ac(18))--having the same sequence of amino acids but differing by 18 formal units of charge, from a solution containing denaturing concentrations of sodium dodecyl sulfate (SDS). Acetylation of BCA with acetic anhydride converts all 18 lysine-epsilon-NH(3)(+) groups to lysine-epsilon-NHCOCH(3) groups and generates BCA-Ac(18). Both BCA and BCA-Ac(18) are catalytically active, and circular dichroism spectroscopy (CD) suggests that they have similar secondary and tertiary structures. SDS at concentrations above approximately 10 mM denatured both proteins. When the SDS was removed by dialysis, both proteins were regenerated in native form. This study suggests that large differences in the net charge of the polypeptide have no significant influence on the structure, the ability to refold, or the rate of refolding of this protein from solutions containing SDS. This study reinforces the idea that charged residues on the surface of BCA do not guide protein folding and raises the broader question of why proteins have charged residues on their surface, outside of the region of the active site.