gebhart/patrepeval huggingface dataset:
Subcutaneous daratumumab (DARA) in patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Part 2 update of the open-label, multicenter, dose escalation phase 1b study (PAVO). (2018)

8013 Background: Intravenous (IV) administration of DARA 16 mg/kg is approved as monotherapy and in combination with standard of care regimens for RRMM. The phase 1b PAVO study (NCT02519452) demonstrated that delivery of DARA with recombinant human hyaluronidase enzyme (rHuPH20) by subcutaneous (SC) infusion through a syringe pump (Part 1) or by manual SC injection (Part 2) was well tolerated with an efficacy profile consistent with IV DARA (Chari A, et al. ASH 2017; abstract 838). We present updated data from Part 2. Methods: Eligible pts received ≥2 prior lines of therapy (LOTs) including a proteasome inhibitor and an immunomodulatory drug. In Part 2, pts received a concentrated co-formulation of DARA (DARA SC; 1,800 mg in 15 mL) and rHuPH20 (30,000 U) dose in a single, pre-mixed vial, which was administered in 3 to 5 minutes by manual SC injection. Primary endpoints were Ctrough of DARA at the end of weekly dosing on Cycle 3 Day 1 (C3D1) and safety. Secondary endpoints included overall response rate (ORR), rate of complete response, time to response, and duration of response. Results: Pts in Part 2 (n = 25) had a median age of 68 years and received a median of 3 prior LOTs. At a median follow-up of 4.6 months, none discontinued due to treatment-emergent adverse events (TEAEs). Pharmacokinetic analyses indicated that DARA SC had a Tmax of approximately 72 h and achieved similar or greater Ctrough on C3D1 compared to what has been observed with DARA IV. Most common Grade 3/4 TEAEs ( > 1 pt) were lymphopenia (16%), thrombocytopenia (8%), and neutropenia (8%). IRRs were reported in 3 (12%) pts, all occurring ≤6 h of the first injection. No grade 4 IRRs or discontinuations due to IRRs occurred. DARA SC injections in the periumbilical area were well tolerated with reversible erythema observed in 20% of pts. DARA SC achieved an ORR of 44%, including 28% ≥very good partial response. Conclusions: DARA SC, which enables dosing in 3-5 minutes, was well tolerated with low IRR rates, had an acceptable PK profile, and demonstrated clinical response rates similar to DARA-IV. Updated data based on longer follow-up will be presented at the meeting. Clinical trial information: NCT02519452.
Evaluation of the proximal adductor canal block injectate spread: a cadaveric study (2019)

This anatomical study provides some insights into the mechanism of analgesia to the knee following a proximal adductor canal injection and its motor sparing properties. Further clinical investigation is required to confirm cadaveric findings.
Lactate Boosts TLR4 Signaling and NF-κB Pathway-Mediated Gene Transcription in Macrophages via Monocarboxylate Transporters and MD-2 Up-Regulation (2009)

It has been shown that lactate induces insulin resistance. However, the underlying mechanisms have not been well understood. Based on our observation that lactate augments LPS-stimulated inflammatory gene expression, we proposed that lactate may enhance TLR4 signaling in macrophages, which has been shown to play an important role in insulin resistance in adipocytes. In this study, we demonstrated that lactate stimulated MD-2, a coreceptor for TLR4 signaling activation, NF-kappaB transcriptional activity, and the expression of inflammatory genes in human U937 histiocytes (resident macrophages). Similar enhancement of the inflammatory gene expression by lactate was also observed in human monocyte-derived macrophages. The essential role of MD-2 in lactate-augmented TLR4 signaling was confirmed by observation that the suppression of MD-2 expression by small interfering RNA led to significant inhibition of inflammatory gene expression. To further elucidate how lactate treatment enhances TLR4 activation, we showed that the augmentation of inflammatory gene expression by lactate was abrogated by antioxidant treatment, suggesting a critical role of reactive oxygen species in the enhancement of TLR4 activation by lactate. Finally, we showed that alpha-cyano-4-hydroxycinnamic acid, a classic inhibitor for monocarboxylate transporters, blocked lactate-augmented inflammatory gene expression and nuclear NF-kappaB activity, indicating that lactate transport through monocarboxylate transporters is required for lactate-enhanced TLR4 activation. Collectively, this study documents that lactate boosts TLR4 activation and NF-kappaB-dependent inflammatory gene expression via monocarboxylate transporters and MD-2 up-regulation.
Cloning and Characterization of an Alternatively Spliced Form of SR Protein Kinase 1 That Interacts Specifically with Scaffold Attachment Factor-B (2001)

Serine/arginine protein kinases have been conserved throughout evolution and are thought to play important roles in the regulation of mRNA processing, nuclear import, germline development, polyamine transport, and ion homeostasis. Human SRPK1, which was first identified as a kinase specific for the SR family of splicing factors, is located on chromosome 6p21.2-p21.3. We report here the cloning and characterization of SRPK1a, which is encoded by an alternatively processed transcript derived from the SRPK1 gene. SRPK1a contains an insertion of 171 amino acids at its NH(2)-terminal domain and is similar to SRPK1 in substrate specificity and subcellular localization. Moreover, both isoforms can induce alternative splicing of human tau exon 10 in transfected cells. Using the yeast two-hybrid assay, we found that the extended NH(2)-terminal domain of SRPK1a interacts with Scaffold Attachment Factor-B, a nuclear scaffold-associated protein. Confirmation of this interaction was provided by in vitro binding assays, as well as by co-immunoprecipitation from 293T cells doubly transfected with SRPK1a and SAF-B. Our studies suggest that different SRPK family members are uniquely regulated and targeted and thus the multiple SRPK kinases present in higher eukaryotes may perform specialized and differentiable functions.
Is Salicylic Acid a Translocated Signal of Systemic Acquired Resistance in Tobacco? (1995)

Salicylic acid (SA) is a likely endogenous signal in the development of systemic acquired resistance (SAR) in some dicotyledonous plants. In tobacco mosaic virus (TMV)-resistant Xanthi-nc tobacco, SA levels increase systemically following the inoculation of a single leaf with TMV. To determine the extent to which systemic increases in SA result from SA export from the inoculated leaf, SA produced in TMV-inoculated or healthy leaves was noninvasively labeled with 18O2. Spatial and temporal distribution of 18O-SA indicated that most of the SA detected in the healthy tissues was synthesized in the inoculated leaf. No significant increase in the activity of benzoic acid 2-hydroxylase, the last enzyme involved in SA biosynthesis, was detected in upper uninoculated leaves, although the basal level of enzyme activity was relatively high. No increases in SA level, pathogenesis-related PR-1 gene expression, or TMV resistance in the upper uninoculated leaf were observed if the TMV-inoculated leaf was detached up to 60 hr after inoculation. Apart from the inoculated tissues, the highest increase in SA was observed in the leaf located directly above the inoculated leaf. The systemic SA increase observed during SAR may be explained by phloem transport of SA from the inoculation sites.
Multilayer add-drop multiplexers in a self-healing WDM ring network (1995)

Each optical add-drop multiplexer (OADM) includes two Fabry-Perot multilayer filters including 32 alternate high- and low-index layers. One filter is used for the drop function, and the other is used for the add function; so there is no spectral-bandwidth narrowing along the ring. Channel spacing is 10 nm. Figure 1 shows the measured spectral transmission of the add port and the output port of a 1560-nm OADM. The mean insertion loss is 1.5 dB for the drop-and-add port and 1 dB for the output port, whereas the near-end channel cross talk is 20 dB. The add or drop port has 5.4 nm FWHM, and the rejection level is about 22 dB. Isolation between drop and add ports is better than 50 dB.
Continual Low-Level Activation of the Classical Complement Pathway (2001)

There is evidence that the classical complement pathway may be activated via a "C1-tickover" mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.
Construction of a Novel Bovine Papillomavirus Vector Without Detectable Transforming Activity Suitable for Gene Transfer (1995)

Bovine papillomavirus type 1 (BPV-1)-derived vectors may be useful for gene therapy because of their episomal maintenance at intermediate to high copy number and stable, high-level expression of gene products. To increase the safety of BPV-1 for human trials, the transforming early genes E5, E6, and E7 were deleted and a new vector, B45-Neo, was established and its transforming potential, episomal maintenance, and cDNA expression determined. Deletion of E5, E6, and E7, caused a decrease of the copy number to 80 in 3T3 fibroblasts when B45-Neo was compared to the parent vector that supported more than 1,000 copies per cell. No significant difference in the copy number, which ranged between 13 and 30 per cell, was detected in other cell lines of murine or human origin. The episomal maintenance of B45 and its ability to express cDNA was retained. B45-Neo, in contrast to BMG-Neo, however, was unable to transform NIH-3T3 and C1271 cells in soft agar colony assays. Unlike BMG-Neo, B45-Neo did not cause morphological changes in 3T3 and C1271 cells characteristic for transformation. It is concluded that B45-Neo is an efficient expression vector without detectable transforming activity and may be useful and safe for human gene therapy trials.
Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. (1984)

Activation of peripheral blood lymphocytes (PBL) from a melanoma patient either in secondary MLC in which EBV-transformed B cells from the cell line JY were used as stimulator cells, or by co-cultivation with the autologous melanoma cells in a mixed leukocyte tumor cell culture (MLTC) resulted in the generation of cytotoxic activity against the autologous melanoma (O-mel) cells. From these activated bulk cultures four cloned cytotoxic T lymphocyte (CTL) lines were isolated. The CTL clone O-1 (T3+, T4+, T8-, OKM-1-, HNK-, and HLA-DR+), and O-36 (T3+, T4-, T8+, OKM-, HNK-, and HLA-DR+) were obtained from MLC, whereas the CTLC clones O-C7 (T3+, T4+, T8-, OKM-1-, HNK-, and HLA-DR+) and O-D5 (T3+, T4-, T8+, OKM-1-, HNK, and HLA-DR+) were isolated from autologous MLTC. All four CTL clones were strongly cytotoxic for O-mel cells but failed to lyse autologous fibroblasts and autologous T lymphoblasts. Moreover, the CTL clones lacked NK activity as measured against K562 and Daudi cells. Panel studies indicated that the CTL clones also killed approximately 50% of the allogeneic melanoma cells preferentially, whereas the corresponding T lymphoblasts were not lysed. Monoclonal antibodies against class I (W6/32) and class II (279) MHC antigens failed to block the reactivity of the CTL clones against O-mel and allogeneic melanoma cells, indicating that a proportion of human melanoma cells share determinants that are different from HLA antigens and that are recognized by CTL clones. In contrast to the CTL clones isolated from MLTC, the clones obtained from MLC also lysed JY cells, which initially were used as stimulator cells. The reactivity of O-36 against JY could be inhibited with W6/32, demonstrating that this reactivity was directed against class I MHC antigens. These results suggest that the lysis of O-mel and JY cells by O-36 has to be attributed to two independent specificities of this CTL clone. The specificity of the other cross-reactive CTL clone (O-1) could not be determined. The notion that individual CTL clones can have two specificities was supported by the following observations. The cytotoxic reactivity of both O-1 (T4+) and O-36 (T8+) against JY was blocked by monoclonal antibodies directed against T3 and human LFA-1, and against T3, T8, and human LFA-1, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
Enzymatically Inactive Macrophage Migration Inhibitory Factor Inhibits Monocyte Chemotaxis and Random Migration (1999)

Macrophage migration inhibitory factor (MIF) is a cytokine that was first described as an inhibitor of the random migration of monocytes and macrophages and has since been proposed to have a number of immune and catalytic functions. One of the functions assigned to MIF is that of a tautomerase that interconverts the enol and keto forms of phenylpyruvate and (p-hydroxyphenyl)pyruvate and converts D-dopachrome, a stereoisomer of naturally occurring L-dopachrome, to 5,6-dihydroxyindole-2-carboxylic acid. The physiological significance of the MIF enzymatic activity is unclear. The three-dimensional structure of MIF is strikingly similar to that of two microbial enzymes (4-oxalocrotonate tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase) that otherwise share little sequence identity with MIF. MIF and these two enzymes have an invariant N-terminal proline that serves as a catalytic base. Here we report a new biological function for MIF, as an inhibitor of monocyte chemoattractant protein 1- (MCP-1-) induced chemotaxis of human peripheral blood monocytes. We find that MIF inhibition of chemotaxis does not occur at the level of the CC chemokine receptor for MCP-1, CCR2, since MIF does not alter the binding of (125)I-MCP-1 to monocytes. The role of MIF enzymatic activity in inhibition of monocyte chemotaxis and random migration was studied with two MIF mutants in which the N-terminal proline was replaced with either a serine or a phenylalanine. Both mutants remain capable of inhibiting monocyte chemotaxis and random migration despite significantly reduced or no phenylpyruvate tautomerase activity. These data suggest that this enzymatic activity of MIF does not play a role in its migration inhibiting properties.
Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma (1991)

To test the possibility that interleukin-9 (IL-9), the human homologue of the mouse T-cell growth factor P40, may be involved in the pathogenesis of human lymphomas, we examined IL-9 expression in a variety of tumors both by Northern blot analysis and by in situ hybridization. Of 18 B-cell non-Hodgkin's lymphomas and 11 peripheral T-cell lymphomas, none expressed IL-9 message. By contrast, IL-9 message was found in two of six cases of large cell anaplastic lymphoma (LCAL) and in 6 of 13 cases of Hodgkin's disease (HD). In HD the strongest signals were observed in Hodgkin (H) and Sternberg-Reed (SR) cells, but IL-9 mRNA was also detected in small lymphocytic cells. A search for IL-9 message in a panel of 20 cell lines derived both from hematopoietic and nonhematopoietic tumors confirmed the unique association of IL-9 expression with HD and LCAL in as much as the only two cell lines with IL-9 message were derived from cases of HD and LCAL. These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas, but that it may play a role in HD and LCAL.
A possible role for PAF in allergen-induced late responses: modification by a selective antagonist (1989)

We determined whether platelet-activating factor (PAF) plays a role in allergen-induced airway responses by studying the effects of a selective PAF antagonist WEB-2086 on antigen-induced early and late airway responses in allergic sheep. In seven sheep, inhaled Ascaris suum produced significant early (282%) and late (176%) increases in specific lung resistance (sRL). WEB-2086 (1 mg/kg iv) given 20 min before antigen challenge did not affect the early response, but the peak late increase in sRL was only 37% over base line (P less than 0.05 vs. control). To study the mechanism by which PAF contributes to antigen-induced responses, we evaluated the effects of pharmacological probes on PAF-induced bronchoconstriction. Inhaled PAF (dose range 75-700 micrograms) caused reproducible (r = 0.781, P less than 0.05) increases in sRL in eight sheep. The PAF-induced bronchoconstriction was blocked by WEB-2086 (1 mg/kg iv) and by the leukotriene antagonist FPL-55712 (30 mg by aerosol); however, neither the cyclooxygenase blocker indomethacin (2 mg/kg iv) nor the histamine H1-antagonist chlorpheniramine (2 mg/kg iv) blocked the PAF response. WEB-2086, however, did not block bronchoconstriction induced by aerosol leukotriene D4, indicating that PAF acts indirectly through leukotrienes. Finally, we determined whether PAF could induce late airway responses. Inhaled PAF produced an immediate increase in sRL in all seven sheep tested, but late airway responses were observed in only three of the seven sheep.(ABSTRACT TRUNCATED AT 250 WORDS)
Poly(L-lysine) Aggregates as Templates for the Formation of Hollow Silica Spheres (2001)

A novel and facile method for the fabrication of hollow spherical silica is presented. Mixing poly(L-lysine) together with lipophilic amine additives in water results in the formation of large aggregates, which can be transcribed into their spherical silica analogues by the addition of tetraethylorthosilicate (TEOS). By varying the additives it has been established that the amino moieties of the additive, rather than those of the poly(L-lysine), play a crucial role in the transcription process.
High Power and High External Efficiency m-Plane InGaN Light Emitting Diodes (2007)

High power and high efficiency nonpolar m-plane (1100) nitride light emitting diodes (LEDs) have been fabricated on low extended defect bulk m-plane GaN substrates. The LEDs were grown by metal organic chemical vapor deposition (MOCVD) using conditions similar to that of c-plane device growth. The output power and external quantum efficiency (EQE) of the packaged 300 ×300 µm2 was 23.7 mW and 38.9%, respectively, at 20 mA. The peak wavelength was 407 nm and <1 nm redshift was observed with change in drive current from 1–20 mA. The EQE shows a minimal drop off at higher currents.
Modulation of Blood Pressure by Central Melanocortinergic Pathways (2008)

Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.
A human monoclonal autoantibody recognizes a neoantigen on glycoprotein IIIa expressed on stored and activated platelets (1987)

We prepared a heterohybrid cell line that secretes a human IgM monoclonal autoantibody that recognizes an antigen found on thrombin- activated or stored platelets. The surface expression of the epitope recognized by this autoantibody, 5E5, increases with time as platelets age in vitro, suggesting that it may represent a senescence or activation-specific antigen. 5E5 binds to the purified platelet membrane glycoprotein (GP) IIb-IIIa complex in an enzyme-linked immunosorbent assay (ELISA). In an immunoblot technique, 5E5 binds to a protein with an apparent mol wt of 95,000, which is identical to that of GPIIIa under nonreduced conditions. In crossed immunoelectrophoresis (CIE), the predominant antigen recognized by 5E5 is contained in the GPIIb-IIIa precipitin arc. An additional precipitin arc recognized by 5E5 is often observed only on gels derived from lysates of platelets stored under blood bank conditions for greater than 3 days. These findings illustrate the usefulness of human monoclonal antibodies for the identification of membrane neoantigens expressed as a result of platelet activation or revealed as platelets age in vitro.
Comprehensive and Neuropsychologic Evaluations (1996)

This article reviews longitudinal data collected from patients with Alzheimer's disease (AD) that are relevant to the design and interpretation of clinical treatment trials. Longitudinal data from patients tested with the Alzheimer's Disease Assessment Scale demonstrate that cognitive symptoms, including memory loss, dysphasia, and dyspraxia, worsen relentlessly over time with the rate of change depending upon baseline dementia severity. Noncognitive symptoms, such as agitation, depressed mood, and psychosis, are episodic, do not necessarily worsen over time, and tend not to be highly correlated with one another. The reliability of cognitive change measures increases with follow-up duration so that the likelihood of detecting drug effects on the rate of cognitive deterioration is greater with longer treatment trials. Functional measures of activities of daily living are difficult to standardize for AD patients but are important for determining the overall clinical and economic impact of AD treatments.
Distributed Maximum Likelihood Sensor Network Localization (2014)

We propose a class of convex relaxations to solve the sensor network localization problem, based on a maximum likelihood (ML) formulation. This class, as well as the tightness of the relaxations, depends on the noise probability density function (PDF) of the collected measurements. We derive a computational efficient edge-based version of this ML convex relaxation class and we design a distributed algorithm that enables the sensor nodes to solve these edge-based convex programs locally by communicating only with their close neighbors. This algorithm relies on the alternating direction method of multipliers (ADMM), it converges to the centralized solution, it can run asynchronously, and it is computation error-resilient. Finally, we compare our proposed distributed scheme with other available methods, both analytically and numerically, and we argue the added value of ADMM, especially for large-scale networks.