gebhart/patrepeval huggingface dataset:
Signalling pathways leading to IFN‐α production in human plasmacytoid dendritic cell and the possible use of agonists or antagonists of TLR7 and TLR9 in clinical indications (2008)

Plasmacytoid dendritic cells (PDC) are highly specialized immune cells capable of producing large amounts of type I and III IFN in response to viral infection. This response is mediated through TLR7 and TLR9 signalling pathways. In addition, PDC can differentiate into fully mature dendritic cells able to efficiently crosspresent viral antigens, thus playing an important role in adaptive immunity. This dual property of PDC is being used in clinical settings where synthetic TLR7 and TLR9 ligands are currently evaluated in clinical trials for the treatment of viral infections, allergies and cancers. Interestingly, there is evidence suggesting that chronic activation of PDC by endogenous RNA and DNA containing immune complexes maybe an important mechanism of driving autoimmunity and significant efforts to develop bi-functional antagonists of TLR7 and TLR9 are currently underway.
Pituitary adenylate cyclase activating polypeptide and migraine (2014)

Pituitary adenylate cyclase activating peptide (PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus (SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache (n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg (n = 11), and further reduced interictally (n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics.
Abstract B22: A chimeric antigen receptor (CARs) based upon a killer immunoglobulin-like receptor (KIR) triggers robust cytotoxic activity in solid tumors (2015)

Abstract Chimeric antigen receptors (CARs) based upon a single chimeric molecule bearing an antigen binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors CD28 or 4-1BB provide a potent method for engineering T cell cytotoxicity towards tumors. We describe a simple chimeric multichain receptor based upon a killer immunoglobulin-like receptors (KIRs) normally expressed by natural killer (NK) cells and T cells. Constructed by fusing a single chain variable fragment (scFv) to the transmembrane and cytoplasmic domain of a KIR, we show that a KIR-based CAR targeting mesothelin (SS1-KIR) triggers antigen-specific cytotoxic activity and cytokine production that is comparable to CD3ζ-based CARs with antigen-induced proliferation that is independent of additional costimulation. Using a xenograft model of mesothelioma resistant to T cell immunotherapy, we further demonstrate that a KIR-based CAR targeting mesothelin exhibits more potent anti-tumor activity compared with T cells bearing mesothelin-specific CD3ζ-based CARs with costimulation despite in vivo persistence of the latter CAR-modified T cells. Evaluation of tumor infiltrating lymphocytes demonstrate that KIR-based CAR+ T cells show resistance to acquired hypofunction within the tumor microenivornment compared with CD3ζ-based CARs with costimulatory receptor domains. The ability of a KIR-based CAR to induce regression of a tumor in which second generation CD3ζ-based CARs show limited activity supports the future clinical evaluation of a KIR-based CAR in mesothelioma and other tumors. Citation Format: Enxiu Wang, Liang-Chuan Wang, Ching-Yi Tsai, Vijay Bhoj, Steven Albelda, Edmund Moon, Michael C. Milone. A chimeric antigen receptor (CARs) based upon a killer immunoglobulin-like receptor (KIR) triggers robust cytotoxic activity in solid tumors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B22.
Variational Anatomy of the Human Cochlea (2008)

The human cochlea exhibits extensive anatomic variations. These variations will influence the location of cochlear implant arrays and affect the potential of hearing preservation surgery. Our results may explain the surgeon's difficulties sometimes to insert electrode arrays even in so-called "normal" cochleae.
DNA synthesis and topoisomerase inhibitors increase transduction by adeno-associated virus vectors. (1995)

Viral vectors based on adeno-associated virus (AAV) preferentially transduce cells in S phase of the cell cycle. We recently found that DNA-damaging agents increased the transduction of nondividing cells. However, the optimal concentrations were toxic to cells. Here we show that the transduction of normal human fibroblasts by AAV vectors is increased by prior exposure to DNA synthesis inhibitors, such as aphidicolin or hydroxyurea, and topoisomerase inhibitors, such as etoposide or camptothecin. Transduction efficiencies could be increased > 300-fold in stationary cultures at concentrations that did not affect cell viability or proliferative potential. Both S-phase and non-S-phase cells were affected, suggesting that cellular functions other than replicative DNA synthesis may be involved. Applying these methods to gene transfer protocols should improve prospects for gene therapy by AAV vectors.
Chondroitinase ABC enhances axonal regrowth through Schwann cell‐seeded guidance channels after spinal cord injury (2003)

Grafting of Schwann cell-seeded channels into hemisected adult rat thoracic spinal cords has been tested as a strategy to bridge the injured cord. Despite success in guiding axonal growth into the graft, regeneration across the distal graft-host interface into the host spinal cord was limited. We hypothesized that chondroitin sulfate (CS) glycoforms deposited at the gliotic front of the interface constitute a molecular barrier to axonal growth into the host cord. Because CS glycoforms deposited by purified astrocytes in vitro were removable by digestion with chondroitinase ABC, we attempted to achieve likewise by infusion of the enzyme to the host side of the interface. By 1 month post-treatment, significant numbers of regenerating axons crossed an interface that was subdued in macrophage/microglia reaction and decreased in CS-immunopositivity. The axons extended as far into the caudal cord as 5 mm, in contrast to nil in vehicle-infused controls. Fascicular organizations of axon-Schwann cell units within the regenerated tissue cable were better-preserved in enzyme-treated cords than in vehicle-infused controls. We conclude that CS glycoforms deposited during gliosis at the distal graft-host interface could be cleared by the in vivo action of chondroitinase ABC to improve prospects of axonal regeneration into the host spinal cord.
A cDNA specifying the human amyloid β precursor protein (ABPP) encodes a 95-kDa polypeptide (1988)

It has come to our attention that a small 5′ region of the cDNA encoding ABPP derived from λHAP2 contains an unusual cloning artifact that is almost certainly not present in the ABPP mature mRNA. The DNA sequence of the ABPP chromosomal gene published recently [ et al. (1988) EMBO J., 7, 2807] agrees completely with our sequence in the region downstream of nt 76; however, the λHAP2 cDNA sequence from at 1-nt 75 is not represented in the ABPP genomic sequence. Analysis of this region showed that nucleotides 14–82 in the λHAP2 cDNA form a perfect inverted repeat with a 69-nt region within the body of the authentic ABPP cDNA. This inverted region was most likely incorporated into the cDNA during library construction.
Microalbuminuria in sickle cell disease. (1990)

The kidney is involved in virtually all individuals who inherit the sickle cell form of hemoglobin. Though asymptomatic and relatively common, proteinuria in patients with sickle cell anemia (SS) over 40 years old is associated with reduced creatinine clearance. The subclinical increase in urinary albumin is termed microalbuminuria and is a marker of preclinical glomerular damage. The aim of the present study was to determine the presence of microalbuminuria measured by radioimmunoassay in patients with sickle cell disease. The study included 41 patients with SS, 11 patients with hemoglobin SC disease, 4 subjects with S beta-thalassemia and 10 normal controls. All subjects were teenagers or adults. Sixteen SS patients (40%) and 1 SC (9%) and 1 S beta (25%) patient presented mean urinary albumin excretion (UAE) above normal values (30 mg/l. No correlation was observed between UAE and age, creatinine clearance, hemoglobin level or %HbF. These parameters, as well as the presence of leg ulcers, were not significantly different between SS patients with and without UAE above 30 mg/dl. The high prevalence of microalbuminuria in patients with sickle cell anemia indicates that glomerular damage is common. The connection between microalbuminuria and clinical nephropathy has been demonstrated in diabetes and may indicate a sign of early disease rather than a marker for susceptibility. Thus, microalbuminuria may be an early indicator of glomerular damage for patients with sickle cell disease.
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq (2017)

Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations (2012)

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter '523', based on the number of 'T'-residues: 'Short' (S, T≤19), 'Long' (L, 20≤T≤29) and 'Very Long' (VL, T≥30). Homopolymers, particularly long homopolymers like '523', are difficult to genotype because 'slippage' occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new '523' genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the '523' allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-'523' and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the '523'S-APOEε4 haplotype. These data may be used as references for '523' allele and '523'-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.
Animal Models of Depression: Utility for Transgenic Research (2000)

The utility of available animal models of depression for transgenic research is reviewed. Criteria for usefulness are non-dependence on a mechanism of action, pharmacological validity, existence of genetic determinants, availability of a mouse version, procedural simplicity, and reproducibility. The following models are reviewed: behavioral despair, tail suspension, learned helplessness, chronic mild stress, olfactory bulbectomy, DRL behavior and conditioned place preference. It is concluded that the behavioral despair and tail suspension models satisfy the criteria most closely. On the other hand, despite its procedural complexity and poor reproducibility, the chronic mild stress model shows high promise for the future.
Molecular Mechanism of the Activation-Induced Cell Death Inhibition Mediated by a p70 Inhibitory Killer Cell Ig-Like Receptor in Jurkat T Cells (2002)

In this study we investigated the molecular mechanism of the activation-induced cell death (AICD) inhibition mediated by a p70 inhibitory killer cell Ig-like receptor (KIR3DL1, also called NKB1) in Jurkat T cells. Using stable Jurkat transfectants that express KIR or CD8-KIR fusion proteins we have shown for the first time that KIR inhibits, in a ligation-independent manner, the AICD induced by PHA, PMA/ionomycin, or anti-CD3 Ab. The AICD inhibition mediated by KIR appears to result from the blockade of Fas ligand induction upon activation of the Jurkat transfectants. Moreover, the membrane-proximal 20 aa of the KIR cytoplasmic tail were determined to play a crucial role in this process. Since the membrane-proximal portion of the KIR cytoplasmic tail contains a putative protein kinase C (PKC) substrate site, we investigated the molecular interaction between KIR and PKC. Immunoprecipitation analysis demonstrated that KIR constitutively bound both to PKCalpha, a conventional Ca(2+)-dependent PKC, and to PKCtheta, a novel Ca(2+)-independent PKC. Furthermore, an in vitro kinase assay revealed that PKC activation was blocked after PHA stimulation in Jurkat transfectants expressing KIR. These observations were supported by the finding that a recombinant KIR cytoplasmic tail also appeared to inhibit PKCalpha activation in vitro. Taken together these data strongly suggest that KIR inhibits the AICD of T cells by blocking Fas ligand induction upon stimulation, in a process that seems to be accomplished by PKC recruitment to the membrane-proximal PKC binding site and subsequent inhibition of PKC activation against the activating stimuli.
Immunomodulatory Function of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Type 1 Diabetes (2009)

Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
Red Cell Deformability and its Relevance to Blood Flow (1987)

The resistance to blood flow is a function of the rheological properties of blood as well as the geometric features of blood vessels. While circulatory investigations generally aim at studying the functions of the heart and blood vessels, there is an increasing realization that blood rheology can also play a significant role in circulatory regulation in health and disease (10, 11). The principal factors determining blood viscosity are hematocrit, plasma viscos­ ity, cell aggregation, and cell deformability (8). This review focuses on the role of the deformability of the red blood cell (RBC) in circulatory regulation under physiological and pathophysiological conditions. 1 Deformability is a relatively general term that describes the ability of a body (RBCs in this case) to change its shape in response to a deforming force. RBC deformation (or strain) can involve a change in cell curvature, a uniaxial deformation, or area expansion (3, 33). The deforming stress (force per unit area) is usually applied from outside the cell, e.g. by fluid shear stress or local membrane aspiration, but it can also originate from within the cell, e.g. RBC swelling in hypotonic medium or fiber formation in deoxygenated sickle cells. The extent, rate, and mode of deformation depend on the magnitude, rate, and direction of the stress. Therefore, the stress-strain (and stress-strain rate) relationships are complex and cannot be described by a single deformability parameter.
Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients (2006)

The anterior gradient protein-2 (AGR2) is inducible by oestrogen and itself can induce metastasis in a rat model for breast cancer. Here, a rabbit antibody to recombinant human AGR2 was used to assess its prognostic significance in a retrospective cohort of 351 breast cancer patients treated by adjuvant hormonal therapy. The antibody stains 66% of breast carcinomas to varying degrees. The percentage of positive carcinoma cells in tumours directly correlates with the level of AGR2 mRNA (Spearman's rank correlation, P = 0.0007) and protein (linear regression analysis r2 = 0.95, P = 0.0002). There is a significant association of staining of carcinomas for AGR2 with oestrogen receptor alpha (ERalpha) staining and with low histological grade (both Fisher's Exact test P<0.0001). In the ERalpha-positive cases, but not the ERalpha-negative cases, when subdivided into the separate staining classes for AGR2, there is a significantly progressive decrease in patient survival with increased staining (log rank test, P = 0.006). The significant association of staining for AGR2 with patient death over a 10-year period (log rank test P = 0.007, hazard ratio = 3) only becomes significant at 6 years of follow-up. This may be due to the cessation of adjuvant hormonal therapy at an earlier time, resulting in adverse re-expression of the metastasis-inducing protein AGR2.
Thoracic splanchnic nerves: implications for splanchnic denervation (2001)

Splanchnic neurectomy is of value in the management of chronic abdominal pain. It is postulated that the inconsistent results of splanchnicectomies may be due to anatomical variations in the pattern of splanchnic nerves. The advent of minimally invasive and video-assisted surgery has rekindled interest in the frequency of variations of the splanchnic nerves. The aims of this study were to investigate the incidence, origin and pattern of the splanchnic nerves in order to establish a predictable pattern of splanchnic neural anatomy that may be of surgical relevance. Six adult and 14 fetal cadavers were dissected (n = 38). The origin of the splanchnic nerve was bilaterally asymmetrical in all cases. The greater splanchnic nerve (GSN) was always present, whereas the lesser splanchnic nerve (LSN) and least splanchnic nerve (ISN) were inconsistent (LSN, 35 of 38 sides (92%); LSN, 21 of 38 sides (55%). The splanchnic nerves were observed most frequently over the following ranges: GSN, T6-9: 28 of 38 sides (73%); LSN, when present, T10-11: (10 of 35 sides (29%); and ISN, T11-12: 3 of 21 sides (14%). The number of ganglionic roots of the GSN varied between 3 and 10 (widest T4-11; narrowest, T5-7). Intermediate splanchnic ganglia, when present, were observed only on the GSN main trunk with an incidence of 6 of 10 sides (60%) in the adult and 11 of 28 sides (39%) in the fetus. The higher incidence of the origin of GSN above T5 has clinical implications, given the widely discussed technique of undertaking splanchnicectomy from the T5 ganglion distally. This approach overlooks important nerve contributions and thereby may compromise clinical outcome. In the light of these variations, a reappraisal of current surgical techniques used in thoracoscopic splanchnicectomy is warranted.
Sorting Nexin 6, a Novel SNX, Interacts with the Transforming Growth Factor-β Family of Receptor Serine-Threonine Kinases (2001)

Sorting nexins (SNX) comprise a family of proteins with homology to several yeast proteins, including Vps5p and Mvp1p, that are required for the sorting of proteins to the yeast vacuole. Human SNX1, -2, and -4 have been proposed to play a role in receptor trafficking and have been shown to bind to several receptor tyrosine kinases, including receptors for epidermal growth factor, platelet-derived growth factor, and insulin as well as the long form of the leptin receptor, a glycoprotein 130-associated receptor. We now describe a novel member of this family, SNX6, which interacts with members of the transforming growth factor-beta family of receptor serine-threonine kinases. These receptors belong to two classes: type II receptors that bind ligand, and type I receptors that are subsequently recruited to transduce the signal. Of the type II receptors, SNX6 was found to interact strongly with ActRIIB and more moderately with wild type and kinase-defective mutants of TbetaRII. Of the type I receptors, SNX6 was found to interact only with inactivated TbetaRI. SNXs 1-4 also interacted with the transforming growth factor-beta receptor family, showing different receptor preferences. Conversely, SNX6 behaved similarly to the other SNX proteins in its interactions with receptor tyrosine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivo of oligomeric complexes. These findings are the first evidence for the association of the SNX family of molecules with receptor serine-threonine kinases.
SMD-type 42 GHz waveguide filter (2003)

A novel concept for the transition between a microstrip line and a rectangular waveguide is presented and applied to a 42 GHz waveguide filter. Measurement results are presented which are in very good agreement to simulations. The waveguide is formed by soldering a U-shaped metallic filter part onto a RF-PCB (printed circuit board) using the board metalization as the last remaining waveguide wall. This technology is potentially enabling a fully automated SMD-assembly (surface mounted device) of waveguide components integrated into planar circuits.