gebhart/patrepeval huggingface dataset:
Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells (2005)

The immunosuppressive drugs rapamycin and cyclosporin A (CsA) are widely used to prevent allograft rejection. Moreover, they were shown to be instrumental in experimental models of tolerance induction. However, it remains to be elucidated whether these drugs have an effect on the CD4+ CD25+ regulatory T-cell (T(REG)) population, which plays an important role in allograft tolerance. Recently, we reported that alloantigen-driven expansion of human CD4+ CD25+ T(REG)s gives rise to a distinct highly suppressive CD27+ T(REG) subset next to a moderately suppressive CD27- T(REG) subset. In the current study we found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4+ CD25+ T cells. However, in contrast to CsA, rapamycin preserved the dominance of the potent CD27+ T(REG) subset over the CD27- T(REG) subset after alloantigen-driven expansion of CD4+ CD25+ T(REG)s in vitro. Accordingly, CD4+ CD25+ T(REG)s cultured in the presence of rapamycin displayed much stronger suppressive capacity than CD4+ CD25+ T(REG)s cultured in the presence of CsA. In addition, CD4+ CD25+ T(REG) cells cultured in the presence of rapamycin, but not CsA, were able to suppress ongoing alloimmune responses. This differential effect of rapamycin and CsA on the CD27+ T(REG) subset dominance may favor the use of rapamycin in tolerance-inducing strategies.
Plinabulin, a novel small molecule clinical stage IO agent with anti-cancer activity, to prevent chemo-induced neutropenia and immune related AEs. (2018)

126 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects by targeting Dendritic Cells (DCs). In preclinical studies, Plin induces DC maturation and the production of MHCII, CD40, CD80 and CD86 and related antigen-specific T-cell activation. Plin had synergistic anticancer efficacy with PD1+CTLA4inhibitors in animal models. In addition, Plin increases expression of IL-1β, IL-6, IL-12 in DC cell, which cytokines protect neutrophils against apoptosis. In a Phase 2 (Ph2) trial, the addition of Plin to Docetaxel (Plin+Doc; n = 38) in NSCLC patients (pts) with a measurable lesion, improved mOS with 4.6 mo vs Doc alone (n = 38). DOR (a marker of immune effect) was ~1 yr longer (P &lt; 0.05) with Plin+Doc vs Doc alone. Plin exerted immune-enhancing effects (DOR), without increasing Immune-Related AEs (IR-AEs). This may suggest that Plin exerts immune-enhancing and anti-inflammatory effects. Methods: Prospective, randomized Ph2 clinical trial (NCT00630110) and non-clinical studies. Results: In-vitro screens showed that Plin is a PDE4-inhibitor, and clinical evidence (p &lt; 0.03; n = 90) of PDE4-inhibition with Plin was observed in Ph2. PDE4-inhibitors have steroid-like effects and are approved for the treatment of Inflammatory disorders, and thus have the potential to prevent IR-AEs. In addition, Plin prevented chemo-induced Neutropenia (CIN), through a mechanism, different from G-CSF, in non-clinical (with various chemotherapies) and Ph2. In Ph2, Gr 4 Neutropenia occurred in 5% with Plin+Doc vs 33 % off pts with Doc (p &lt; 0.0003) in Cycle 1, day 8. Plin is given 30 min after chemo (on the same day of chemo), and does not cause bone pain. G-CSF is given 24 hr after chemo, and causes bone pain in most pts. Conclusions: Plin exerts anticancer immune-enhancing effects, combined with anti-inflammatory effects, due to PDE4-inhibition. Plin holds the promise of an agent with anti-cancer efficacy, while also mitigating IR-AEs and CIN. Therefore, Plin is an attractive candidate for combination therapy with PD1-inhibitors (or PD-L1 inhibitors), PD1+CTLA-inhibitor, or PD1-inhibitor/chemotherapy.
Value of the Fern Test to Confirm or Reject the Diagnosis of Ruptured Membranes is Modest in Nonlaboring Women Presenting with Nonspecific Vaginal Fluid Loss (1994)

The strength of the fern test to differentiate between amniotic and nonamniotic fluid in vaginal discharge was determined in 51 term women in labor with ruptured membranes and compared with that in a group of 120 nonlaboring subjects, presenting with nonspecific vaginal fluid loss. Sensitivity and specificity in the laboring group were 98.0 and 88.2%, respectively, in agreement with previous reports. In contrast, in the non-laboring group sensitivity and specificity were only 51.4 and 70.8%, respectively. The result of the fern test predicted the actual state of the membranes correctly in 63% and incorrectly in 29% of these patients. In 16 or 39 subjects with ruptured membranes (approximately 40%), the outcome of the fern test was negative. The modest diagnostic strength of the fern test in the present study compared with previously reported data is at least in part due to differences in study population (laboring versus nonlaboring) and to the fact that observers were deprived of relevant clinical information. It is concluded that the fern test should be granted supportive rather than conclusive value in diagnosing ruptured membranes in nonlaboring women presenting with nonspecific vaginal fluid loss.
Vascular microRNAs (2010)

MicroRNAs are endogenously expressed small non-coding RNAs that regulate gene expression on the posttranscriptional level. During the last years microRNAs have emerged as key regulators of several physiological and pathophysiological processes in the vascular wall. Endothelial cell functions and angiogenesis are critically regulated by microRNAs such as miR-126 and the miR-17-92 cluster in vitro and in vivo. Tumor angiogenesis is additionally controlled by miR-296 and miR-378. MicroRNAs also regulate smooth muscle cell phenotypes and control neointima formation and atherosclerosis. In this respect, miR-143 and miR-145 have been shown to play a crucial role. In this review, we summarize the role of microRNAs and their target genes in endothelial and smooth muscle cells and discuss their applicability as drug targets.
Cholera toxin adjuvant greatly promotes antigen priming of T cells (1993)

Cholera toxin (CT) given perorally is a powerful mucosal immunogen and adjuvant. Information that explains the adjuvant effect of CT may be used for the development of more effective oral vaccines and might also contribute to our understanding of the mechanisms involved in regulating mucosal immunity. The present study was undertaken to investigate if CT administered together with keyhole limpet hemocyanin (KLH) would act to promote or inhibit priming of KLH-specific T cells and whether the adjuvant effect of CT is restricted to mucosal immune responses or is a generalized phenomenon due to direct immunomodulating effects of CT. We found that CT adjuvant greatly augmented the effectiveness of a single oral priming immunization with KLH: re-challenge with KLH in vitro 1 week following immunization gave several-fold stronger proliferation in KLH-specific spleen, mesenteric lymph node, Peyer's patch and gut lamina propria T cells from KLH + CT adjuvant as opposed to KLH only-treated mice. Moreover, several-fold stronger cytokine production, i.e. interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10 and interferon-gamma accompanied the enhanced proliferative response of T cells from CT adjuvant-treated mice. The adjuvant effect of CT was not restricted to mucosal immune responses but was evident also following a single parenteral immunization with KLH + CT. Limiting dilution analysis revealed that CT adjuvant promoted a 20- to 40-fold increase in the frequency of primed KLH-specific T cells. Phenotypic and functional analyses clearly demonstrated that CT adjuvant primarily enhanced priming of CD4+ rather than CD8+ T cells and the pattern of lymphokine secretion disclosed that CT most probably promoted antigen priming of both Th1 and Th2 type of CD4+ T precursor cells.
Paulínia, São Paulo, Brasil: situação da cárie dentária com relação às metas OMS 2000 e 2010 (2004)

An epidemiological survey was conducted in Paulínia, São Paulo State, Brazil, in 2000, aimed at verifying the prevalence of principal oral health problems, using the DMFT index and WHO diagnostic criteria. The sample (1,151) was randomly selected. The dmft was 1.90 in 5-year-olds, with 54.2% caries-free. DMFT was 1.00 in 12-year-olds, with 46.4% caries-free in the permanent dentition. Fluorosis prevalence in 7 to 12-year-olds was 30.5%, mostly the very mild form (22.9%). Prevalence of opacities and hypoplasias was 9.1%. In adults, the dental care index was 55.4% and an average of 21.30 teeth presented caries experience. In the elderly, DMFT was 29.50, consisting predominantly of extracted teeth (93.0%).
Hydrogen gas production for electronic-grade polycrystalline silicon growth (2004)

The production of polycrystalline silicon (polysilicon) requires several main feedstocks. Polysilicon is produced by the reaction of trichlorosilane, SiHCl/sub 3/ (TCS) with hydrogen, H/sub 2/. Trichlorosilane is produced in the TCS plant while hydrogen is produced in H/sub 2/ plant. Hydrogen and oxygen can be produced from water using electricity through the process of electrolysis. The purification or rectification of the H/sub 2/ gas is typically done by passing an impure H/sub 2/ stream over a heated palladium (Pd) alloy. The purity of H/sub 2/ is then tested using a laboratory-constructed hydrogen gas purity test method which has been found to be at 99.9%.
Immunotherapy and allergic inflammation (1991)

A double-blind placebo-controlled trial of allergen injection immunotherapy in adult patients with severe summer hayfever. We used a partially purified biologically standardised grass pollen depot preparation (Alutard SQ, ALK Denmark Ltd.). Immunotherapy was extremely effective in reducing symptoms and medication requirements. Clinical improvement was accompanied by a decrease in both a target organ (conjunctival) and skin sensitivity. The injections were well-tolerated with minimal side effects. The results suggest that 30 minutes rather than 2 hours is an acceptable post-injection observation period. Successful immunotherapy was accompanied by suppression of the late cutaneous response to allergen. Specific immunostaining of skin biopsies revealed inhibition of the characteristic CD4+ T cell and EG2+ activated eosinophil cellular infiltrate during the late response. There was a significant relationship between CD4+ T cell and eosinophil counts after immunotherapy, i.e. the lower the number of infiltrating CD4+ cells, the lower the eosinophil counts. An unexpected finding was a prominent CD25+ (interleukin-2 receptor positive) cellular infiltrate which was only observed following Alutard SQ. Further studies involving double immunostaining methods should identify the phenotype of these activated, IL-2R+ cells. Based on murine studies Mosmann and colleagues have classified T cell responses into two types according to their profile of lymphokine production [11]. TH1 cells produce predominantly the IL-4 family of cytokines (IL-3, IL-4, IL-5) whereas TH2 cells produce predominantly interleukin-2 and interferon gamma. Insofar as the Mosmann classification may possibly be relevant to human T cell responses, the above findings would support a switch from a "TH2-" to a "TH1-" lymphocyte response following immunotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
L‐arginine infusion has no effect on systemic haemodynamics in normal volunteers, or systemic and pulmonary haemodynamics in patients with elevated pulmonary vascular resistance. (1993)

1. The evidence that the infusion of L-arginine, the precursor of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO), may reduce systemic blood pressure, via the generation of intracellular cyclic guanosine-3,5-monophosphate(cGMP), in normotensive volunteers is controversial. In the first part of the study we investigated the effect of an L-arginine infusion on systemic blood pressure and plasma cGMP in healthy volunteers. 2. Patients with systemic sclerosis have widespread endothelial damage which, by reducing the release of NO, could contribute to the raised pulmonary vascular resistance (PVR) often found in this condition. We hypothesised that if there were a failure of NO synthesis this might be overcome by infusing L-arginine into the pulmonary artery, thereby lowering PVR. In the second part of the study we investigated the effect of L-arginine infusion on systemic and pulmonary haemodynamics, and on plasma cGMP levels in patients with pulmonary hypertension and systemic sclerosis. 3. L-arginine (500 mg kg-1) was infused over 30 min into five normotensive volunteers and five patients with systemic sclerosis and pulmonary hypertension. Blood pressure, heart rate and skin temperature were measured non-invasively in the volunteers and systemic and pulmonary haemodynamics recorded via radial artery cannulae and balloon-tipped, flow directed, pulmonary artery catheters in the patients with systemic sclerosis. 4. L-arginine had no significant effect on blood pressure, heart rate or skin temperature in the normotensive volunteers nor on systemic or pulmonary haemodynamics in the systemic sclerotic group. Cyclic-GMP levels did not significantly change in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
Sample preparation: a challenge in the development of point-of-care nucleic acid-based assays for resource-limited settings (2007)

Currently available nucleic acid testing (NAT)-based assays are complex and time-consuming, and they require expensive instrumentation and dedicated laboratory spaces for sample preparation as well as for amplification and detection of the nucleic acid target. Reagents required for these tests are also expensive and must be transported and stored refrigerated or frozen. These characteristics have limited the use of such assays for point-of-care (POC) testing, especially in resource-poor settings. Efforts to develop simple and rapid NAT-based assays have focused predominantly on the amplification and detection steps, with sample preparation and nucleic acid extraction remaining the bottleneck in the development of NAT systems suitable for POC applications or resource-limited settings. A review of NAT platforms and technologies currently under development and validation for rapid field testing revealed that, in addition to requiring expensive and complex instrumentation, many of these systems also require off-line sample preparation and reagent handling. In their current format, they are therefore not appropriate for POC testing in resource-limited settings. We evaluated several commercially available technologies and procedures for the isolation of nucleic acid with the extraction of HIV-1 RNA from human plasma as a model system. Our results indicate that solid-phase extraction with silica or glass in the presence of a chaotropic salt provides the highest extraction efficiency. However, none of the existing methods and technologies is readily adaptable to a POC system. The integration of sample preparation procedures well suited to NAT-based assays in resource-limited settings therefore remains a challenge.
Bimodal Correlation between the Circulating Insulin Level and the Production Rate of Dehydroepiandrosterone: Positive Correlation in Controls and Negative Correlation in the Polycystic Ovary Syndrome with Acanthosis Nigricans* (1990)

The objective of this study was to define the relationship among the circulating insulin level (IRI), the MCR of dehydroepiandrosterone (MCR-D), and the production rate of DHEA (PR-D) in 10 women with the polycystic ovary syndrome and acanthosis nigricans (PCOS-AN). Seven normal weight and 10 obese women served as controls. Measurement of the MCR-D and PR-D was accomplished by iv saline infusion (0.9% NaCl solution) on day 1 as a control and a 4-h iv dehydroepiandrosterone (unlabeled) infusion (1 mg/h) was performed on day 2. Mean MCR-D was more than 2-fold higher in the obese controls compared to the normal weight controls. However, the plasma concentration of DHEA(PC-D) was not significantly different in the normal and obese control women, since the PR-D was increased proportionately to the MCR-D. The MCR-D and the PR-D were coupled through insulin in the control women, and their correlation coefficients with IRI were positive and identical (0.77 and 0.73, respectively). In contrast, IRI was negatively correlated with PR-D in the PCOS-AN women. Also, unlike the control women, there was minimal or no change in the MCR-D across a broad range of IRI in the PCOS-AN women. Thus, the MCR-D and PR-D were not coupled in these women.
On the Preferred Orientation and Microstructural Manipulation of Molecular Sieve Films Prepared by Secondary Growth (1998)

MFI-supported films were prepared using secondary growth of precursor layers. The precursor layers were prepared free of additives and no calcination step was used before secondary growth. Combined microstructural control over film thickness, orientation, continuity, and surface roughness was achieved. Hydrothermal conditions were identified, such as film growth proceeds predominantly by direct growth of the particles of the precursor layer. The prepared polycrystalline films have a columnar microstructure. The out-of-plane grain orientation can be manipulated by secondary growth conditions, and is such that the c-axes of the grains range from perpendicular to the substrate to an angle of ∼34° from the direction normal to the substrate, whereas the in-plane grain orientation is random. Initial film growth rates were sustained at a constant value for extended periods of time with an activation energy of 70 kJ/mol. The degree of out-of-plane orientation increases with film thickness up to a point where changes in concentrations in the secondary growth solution lead to surface roughening and change in the preferred growth direction. Sustained growth preserving film orientation and columnar microstructure is achieved during repeated secondary growth, allowing for control of the film thickness without compromising the deposit orientation and surface smoothness. As a result of their microstructure exhibiting well-intergrown columnar texture with small surface roughness, oriented films with thickness well exceeding the wavelength of visible light are optically transparent.
The Calpain Small Subunit Gene Is Essential: Its Inactivation Results in Embryonic Lethality (2000)

Creation of transgenic (knockout) mice deficient in calpain small (30 kDa) subunit gene was undertaken to clarify the proposed role of the small subunit for calpain proteolytic activity and to gain insight into the importance of the gene in the whole animal. The gene was targeted and disrupted in embryonic stem cells by homologous recombination, and chimeric mice were generated. Heterozygous F1 generation mice were crossed to obtain F2 generation. Among F2 generation mice, we found only wild-type and heterozygous animals in the 80 pups genotyped to date; no homozygous mice have been found, although 20 were expected. The heterozygotes had no apparent phenotypic abnormalities. Analysis of their tissues revealed no significant difference in mRNA expression, protein content, or proteolytic activity in comparison with their wild-type littermates. Genotyping of fetuses at different stages of development also revealed only wild-type and normal heterozygous fetuses. No moribund embryos or resorption sites were observed in the uterine cavity. The results indicate that at least one normal allele is essential for postnatal survival. Disruption of both alleles appears to be lethal in very early fetal development.
Antisense Oligonucleotides as Therapeutic Agents—Is the Bullet Really Magical? (1993)

Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.
26.2 An Ultra-Low-Power receiver using transmitted-reference and shifted limiters for in-band interference resilience (2016)

The coexistence of more and more wireless standards in the ISM bands increases the design difficulty of interference-robust receivers (RX), especially for Wireless Sensor Nodes because of their Ultra-Low-Power (ULP) budget.
A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease (2013)

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.