gebhart/patrepeval huggingface dataset:
A phase 2, multicenter, open-label study of the safety and efficacy of luspatercept in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis and anemia with or without RBC transfusion dependence. (2018)

TPS7083 Background: Anemia is an important complication of MPN-associated myelofibrosis. There are few effective therapies other than RBC transfusions, and responses to other therapies are typically brief. Anemia and RBC transfusion dependence are independent adverse prognostic and predictive variables for survival. Luspatercept is a fusion protein consisting of a modified type IIB activin receptor linked to the Fc domain of human IgG1. Luspatercept acts as an erythroid maturation agent by binding specific TGFβ superfamily ligands such as GDF11, blocking their inhibitory effect and leading to increased RBC production. Luspatercept ameliorated anemia in preclinical models and preliminary data have shown it is effective and well tolerated in subjects with lower-risk myelodysplastic syndromes and anemia, with or without RBC transfusion dependence. Methods: Eligible subjects have MPN-associated myelofibrosis, are aged ≥18 y, and have anemia (hemoglobin < 9.5 g/dL) or RBC transfusion dependence (defined as receiving 2–4 U RBC/28 d averaged over 84 d). There are 3 cohorts: (1) cohort 1: 20 subjects with anemia only, no ruxolitinib received in the past 112 d; (2) cohort 2: 20 subjects with RBC transfusion dependence, no ruxolitinib; and (3) cohort 3: 30 subjects with anemia or RBC transfusion dependence receiving a stable ruxolitinib dose. Luspatercept is given subcutaneously at a starting dose level of 1.0 mg/kg every 3 w for 8 cycles. The primary endpoint is anemia response, defined as a hemoglobin increase of ≥1.5 g/dL from baseline or RBC transfusion independence for ≥84 d. Responders can continue therapy in an extension phase. Secondary endpoints include time to response, response duration, health-related quality of life, and safety. Response rates with 95% confidence interval will be calculated. The statistical analyses are descriptive. Enrollment began November 2017. Clinical trial information: NCT03194542.
Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation (2004)

Signal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPalpha binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPbeta1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPbeta2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.
Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons (2011)

Bacterial diversity among environmental samples is commonly assessed with PCR-amplified 16S rRNA gene (16S) sequences. Perceived diversity, however, can be influenced by sample preparation, primer selection, and formation of chimeric 16S amplification products. Chimeras are hybrid products between multiple parent sequences that can be falsely interpreted as novel organisms, thus inflating apparent diversity. We developed a new chimera detection tool called Chimera Slayer (CS). CS detects chimeras with greater sensitivity than previous methods, performs well on short sequences such as those produced by the 454 Life Sciences (Roche) Genome Sequencer, and can scale to large data sets. By benchmarking CS performance against sequences derived from a controlled DNA mixture of known organisms and a simulated chimera set, we provide insights into the factors that affect chimera formation such as sequence abundance, the extent of similarity between 16S genes, and PCR conditions. Chimeras were found to reproducibly form among independent amplifications and contributed to false perceptions of sample diversity and the false identification of novel taxa, with less-abundant species exhibiting chimera rates exceeding 70%. Shotgun metagenomic sequences of our mock community appear to be devoid of 16S chimeras, supporting a role for shotgun metagenomics in validating novel organisms discovered in targeted sequence surveys.
Impaired primary T cell responses in L-selectin-deficient mice. (1996)

L-selectin is a homing receptor that mediates the selective attachment of leukocytes to specialized high endothelial venules. To study the potential role of L-selectin in immune responses in intact mice, we generated L-selectin-deficient mice by gene targeting. L-selectin-deficient mice are defective in cutaneous delayed-type hypersensitivity (DTH) responses when tested after conventional intervals of immunization (4 d). Primary T cell proliferative responses and cytokine production (interleukin [IL] 2, IL-4, and interferon gamma) were also compromised when tested after 5 d of immunization, indicating that L-selectin is important for the immune response to antigens. In contrast, after more prolonged immunization protocols (9 d), normal responses were observed, suggesting that L-selectin-independent compensatory mechanisms exist. Interestingly, humoral responses of L-selectin-deficient mice to keyhole limpet hemocyanin are indistinguishable from wild-type control mice, implying that L-selectin plays no rate-limiting role in T cell help of B cell function. Thus, our results suggest that L-selectin plays an important role in the generation of primary T cell responses but may not be essential for humoral and memory T cell responses. L-selectin does not appear to be rate limiting for the events leading to antigen-driven neutrophil recruitment, since normal DTH responses are obtained at late time points after immunization.
ChemInform Abstract: The Role of Magnetic Nanoparticles (MNP) as Reducing Agents in an MNP‐Supported Pd—Catalyst for the Reductive Homocoupling of Aryl Halides. (2012)

Abstract The catalyst exhibits good activity in the synthesis of compounds (II).
Assertion Checkers in Verification, Silicon Debug and In-Field Diagnosis (2007)

Assertion based design, and more specifically, assertion based verification (ABV) is quickly gaining wide acceptance in the design community. Assertions are mainly targeted at functional verification during the design and verification phases. In this paper, we concentrate on the use of assertions in post-fabrication silicon debug. We develop tools that efficiently generate the checkers from assertions, for their inclusion in the debug phase. We also detail how a checker generator can be used as a means of circuit design for certain portions of self test circuits, and more generally the design of monitoring circuits. Efficient subset partitioning of checkers for a dedicated fixed-size reprogrammable logic area is developed for efficient use of dedicated debug hardware
CREB AND MEMORY (1998)

The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.
Isolation and Characterization of Broad-Spectrum Disease-Resistant Arabidopsis Mutants (2002)

Abstract To identify Arabidopsis mutants that constitutively express systemic acquired resistance (SAR), we constructed reporter lines expressing the firefly luciferase gene under the control of the SAR-inducible PR-1 promoter (PR-1/luc). After EMS mutagenesis of a well-characterized transgenic line, we screened 250,000 M2 plants for constitutive expression of the reporter gene in vivo. From a mutant collection containing several hundred putative mutants, we concentrated on 16 mutants lacking spontaneous hypersensitive response (HR) cell death. We mapped 4 of these constitutive immunity (cim) mutants to chromosome arms. Constitutive expression of disease resistance was established by analyzing responses to virulent Peronospora parasitica and Pseudomonas syringae strains, by RNA blot analysis for endogenous marker genes, and by determination of salicylic acid levels in the mutants. The variety of the cim phenotypes allowed us to define distinct steps in both the canonical SAR signaling pathway and a separate pathway for resistance to Erysiphe cichoracearum, active in only a subset of the mutants.
Recombinant Respiratory Syncytial Virus That Does Not Express the NS1 or M2-2 Protein Is Highly Attenuated and Immunogenic in Chimpanzees (2000)

Mutant recombinant respiratory syncytial viruses (RSV) which cannot express the NS1 and M2-2 proteins, designated rA2DeltaNS1 and rA2DeltaM2-2, respectively, were evaluated as live-attenuated RSV vaccines. The rA2DeltaNS1 virus contains a large deletion that should have the advantageous property of genetic stability during replication in vitro and in vivo. In vitro, rA2DeltaNS1 replicated approximately 10-fold less well than wild-type recombinant RSV (rA2), while rA2DeltaM2-2 had delayed growth kinetics but reached a final titer similar to that of rA2. Each virus was administered to the respiratory tracts of RSV-seronegative chimpanzees to assess replication, immunogenicity, and protective efficacy. The rA2DeltaNS1 and rA2DeltaM2-2 viruses were 2,200- to 55,000-fold restricted in replication in the upper and lower respiratory tracts but induced a level of RSV-neutralizing antibody in serum that was only slightly reduced compared to the level induced by wild-type RSV. The replication of wild-type RSV in immunized chimpanzees after challenge was reduced more than 10,000-fold at each site. Importantly, rA2DeltaNS1 and rA2DeltaM2-2 were 10-fold more restricted in replication in the upper respiratory tract than was the cpts248/404 virus, a vaccine candidate that retained mild reactogenicity in the upper respiratory tracts of 1-month-old infants. Thus, either rA2DeltaNS1 or rA2DeltaM2-2 might be appropriately attenuated for this age group, which is the major target population for an RSV vaccine. In addition, these results show that neither NS1 nor M2-2 is essential for RSV replication in vivo, although each is important for efficient replication.
Hardware acceleration for lock-free data structures and software-transactional memory (2008)

In this paper, we report on a new CPU-architecture extension proposal, named Advanced Synchronization Facility (ASF), which is geared toward accelerating and easing lock-free programming and software transactional memory (STM). We present an initial performance simulation and usability study of ASF’s application to a lock-free data structure (a singly linked list) and to accelerating a state-of-the-art STM system, TinySTM. Our results indicate that ASF can significantly increase the throughput and scaling behavior of these workloads: Single-thread performance increased by up to 15 %, and the factor of scaling to eight CPUs increased by up to 20 %.
Catalytic Activities of Thermally Prepared Poly-α-Amino Acids: Effect of Aging (1970)

Thermally prepared poly-alpha-amino acids were tested after being stored in the dry state for 5 to 10 years. Polymers effective in catalyzing the hydrolysis of p-nitrophenyl acetate showed the same levels of activity as observed 10 years earlier. Polymers effective in catalyzing the decarboxylation of oxaloacetic acid had in 5 years become insoluble in assay medium; their activity, however, had increased by 32 to 145 percent. The results suggest that particular primitive enzyme molecules could have been stable enough to have contributed to evolutionary processes long after they had been produced.
Highly conductive PEDOT:PSS electrode by simple film treatment with methanol for ITO-free polymer solar cells (2012)

We proposed a simple yet robust film treatment method with methanol having only one hydroxyl group to enhance the conductivity of poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) by four orders of magnitude. Different methods of film treatment: immersing PEDOT:PSS film in the methanol solution; dropping methanol on the film; and a combination of these are employed and the results are compared. The conductivity of PEDOT:PSS films was enhanced from 0.3 S cm−1 to 1362 S cm−1 after film treatment with methanol. Other alcohols like ethanol and propanol were also used to treat the PEDOT:PSS film and showed inferior conductivity enhancement compared to methanol. The conductivity enhancement was greatly affected by the hydrophilicity and dielectric constant of the alcohols used. The mechanism of conductivity enhancement was investigated through various characterization techniques including FTIR, XPS and AFM. Removal of the insulator PSS from the film, and morphology and conformational changes are the mechanisms for the conductivity enhancement. The treated films also showed high transmittance and low sheet resistance desirable for a standalone electrode. ITO-free polymer solar cells were fabricated using PEDOT:PSS electrodes treated with methanol and showed almost equal performance to ITO electrodes.
The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock (2011)

Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤ 28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and school-age (≥ 6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.
Mechanisms of Tolerance (1998)

Accumulating evidence indicates that many neurons or neuronal systems adapt to chronic receptor activation by the expression of compensating mechanisms. These compensating mechanisms can take the form of a reduced sensitivity of the receptor through which the agonist acts (homologous desensitization), a reduced sensitivity of co-expressed receptors that serve similar functional roles (heterologous desensitization), and a change in the functions of effector systems to compensate for the persistent activation of one class of receptors. Each of these mechanisms has been observed in some circumstances following chronic exposure of cells or whole animals to morphine and other opiate drugs. All these processes may play a role in opiate drug tolerance, but their relative contributions will probably vary in different situations. Furthermore, the physiologic environment in which opiate drugs act may vary with time in ways that will influence the sensitivity of the system to opiates.
Ein newer allgemeiner Zugang zu α-trifluormethyl-substituierten aromatischen und heteroaromatischen α-Aminosäuren (1989)

A New General Access to α-Trifluoromethyl-Substituted Aromatic and Heteroaromatic α-Amino Acids Syntheses of α-trifluoromethyl substituted heteroarylglycine and phenylalanine derivatives 7 bzw. 12a from 5-fluoro-2-phenyl-4-trifluoromethyloxazole (2) are described. The key step of the new method is a 1,3-benzyl shift from oxygen to carbon. The isolation of mixed products in "cross experiments"in the phenylalanine series supports the notion that the 1,3-benzyl shift is not a 1,3-sigmatropic process.
Down‐regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer (2009)

To identify novel biomarkers of metastasis of colorectal cancer (CRC), we developed an orthotopic implantation model of murine CRC and selected in vivo M5, a subclone of the SW480 CRC cell line with enhanced potential for metastasis to the liver. We compared the differences in the gene expression profiles between M5 and SW480 cells using gene expression profiling. We found that expression of special AT-rich sequence-binding protein 2 (SATB2) was down-regulated in M5 cells. Immunohistochemical analysis of 146 colorectal tumour samples showed that underexpression of SATB2 was strongly correlated with poor prognosis, tumour invasion, lymph node metastasis, distant metastasis, and Dukes' classification for CRC. Univariate and multivariate survival analyses further showed that SATB2 expression was a potential favourable prognostic factor for CRC. These results demonstrated not only that SATB2 is a potential novel prognostic factor for CRC, but also that selection of a highly metastatic clone of SW480 in vivo coupled with gene expression profiling is a powerful approach to identifying prognostic markers for CRC.
Expression of maspin is up‐regulated during the progression of mammary ductal carcinoma (2003)

These results and our previous investigation in which 27.4% of IDC were positive for maspin suggest that the expression of maspin in epithelial cells could be up-regulated during the progression of ductal carcinoma, and that it could be correlated with the acquisition of an aggressive phenotype.
Myocardial Gene Expression in Dilated Cardiomyopathy Treated with Beta-Blocking Agents (2002)

In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.
Properties and distribution of a lectin-like hemagglutinin differentially expressed by murine stromal tissue macrophages. (1986)

We describe a novel hemagglutinin which is differentially expressed on murine stromal tissue macrophages. Resident bone marrow macrophages (RBMM), which are physically associated with immature, proliferating hematopoietic cells in vivo, formed striking rosettes with unopsonized sheep erythrocytes (E) in vitro, unlike resident peritoneal macrophages (RPM). Binding of E was macrophage (M phi) specific, not accompanied by ingestion and independent of temperature (0-37 degrees C), divalent cations, and the metabolic inhibitors azide and iodoacetate. Pretreatment of RBMM with trypsin prevented rosette formation, but neuraminidase enhanced it. Conversely, binding was virtually abrogated if E were pretreated with neuraminidase, whereas trypsin pretreatment of the ligand resulted in a slight enhancement. The lectin-like nature of the E receptor (SER), with specificity for sialylated glycoconjugates, was consistent with the inhibition of binding we saw with neuraminyllactose or the ganglioside GD1a (50% inhibition at 5-10 mM and 11 microM, respectively). Expression of SER on freshly isolated RBMM was heterogeneous and exhibited a striking inverse correlation with expression of Ia antigens. During cultivation in 10% FCS, levels of SER on RBMM declined with a half-life of approximately 24 h. Other cell surface changes induced by cultivation included a transient increase in expression of Ia antigen and acquisition of Mac-1. To determine whether SER was expressed on other stromal M phi populations, adherent cells were isolated from various tissues by collagenase digestion or lavage. Binding of E was highest on RBMM and lymph node stromal M phi, at intermediate levels on Kupffer cells and splenic stromal M phi, but was low or undetectable on blood monocytes and thymic, peritoneal, pleural, and bronchoalveolar M phi. SER therefore appeared to be expressed on certain M phi populations embedded in solid tissues but was largely absent from M phi recoverable by lavage. Its absence from monocytes implies that SER is acquired by M phi after entering tissues where it may perform adhesive functions. In bone marrow, SER on RBMM could interact with an appropriate sialylated ligand on murine hematopoietic cells, and could influence their rate of growth and differentiation.
Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro. (1993)

The adoptive immunotherapy of human malignancy requires reliable methods to sensitize and expand patients' T-cells reactive to autologous tumors. In animal studies, we have generated therapeutic effector cells against a poorly immunogenic tumor by a two-step procedure: vaccination of the host followed by the secondary stimulation of vaccine-primed lymph node (LN) cells by in vitro sensitization (IVS) with tumor in the presence of interleukin 2 (IL-2). Based on these observations, we performed a clinical trial in patients with advanced cancer to evaluate the antitumor efficacy of vaccine-primed LN cells which were similarly activated in vitro. Patients were vaccinated with irradiated autologous tumor admixed with Bacillus Calmette-Guérin and had draining LN excised 10 days later for IVS culture. During IVS culture, LN cells expanded up to 14-fold (average of 8.4-fold). A mean of 6.7 x 10(9) cells was infused in ten patients (seven melanoma, three renal cell cancer) along with the concomitant i.v. administration of IL-2 (180,000 IU/kg every 8 h for 5 days). Phenotype analysis of IVS-LN cells revealed 78 +/- 4% CD3+ T-cells which were predominantly CD4+ (67 +/- 5%) with expression of HLA-DR and IL-2 receptor. IVS-LN cells displayed relative specificity of autologous tumor lysis in four of ten cases compared to zero of seven IVS-peripheral blood lymphocytes derived from the same patients as measured by the 51Cr release assay. One mo after therapy, seven of nine patients treated with IVS-LN cells and IL-2 developed delayed-type hypersensitivity reactivity to autologous tumor compared to zero of nine patients treated with tumor vaccination and IL-2 only (P < 0.002). These observations suggest that antitumor reactivity was passively transferred with the IVS-LN cells. Major toxic side effects including fever, hepatic dysfunction, and weight gain associated with the capillary leak syndrome were associated with exogenous IL-2 administration. Tumor vaccination and cell transfer were well tolerated without significant complications. Of the ten patients treated with IVS-LN cells and IL-2, there were one partial and one minor response, and one patient has had stable disease for 27+ mo. There was no evidence of tumor response in ten patients treated with tumor vaccination and IL-2 only. Further clinical studies evaluating the antitumor reactivity of vaccine-primed LN cells are warranted.