gebhart/patrepeval huggingface dataset:
Intralesional Immunotherapy for Metastatic Melanoma: The Oldest and Newest Treatment in Oncology (2016)

The last few years have yielded exciting developments in immunotherapy for cancer. The promise of cancer immunotherapy has been well known for many years, but had generally produced limited or inconsistent benefit to patients. Intralesional therapies, which are in fact one of the oldest forms of immunotherapy, are also demonstrating benefits in the modern age. This review discusses the origins of intralesional immunotherapy and its underlying rationale. It also discusses the reemergence of this mode of therapy into the modern era, which is where Donald L. Morton, subject of this edition of the journal, plays a major role. The review also discusses current areas of investigation. Given the intuitive advantages of this strategy and the demonstrated, expanding areas of clinical responses, it is likely that intralesional immunotherapy will remain a useful component of cancer treatment into the future.
The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1 (2009)

The Wnt coreceptor LRP6 is required for canonical Wnt signaling. To understand the molecular regulation of LRP6 function, we generated a series of monoclonal antibodies against the extra cellular domain (ECD) of LRP6 and selected a high-affinity mAb (mAb135) that recognizes cell surface expression of endogenous LRP6. mAb135 enhanced Wnt dependent TCF reporter activation and antagonized DKK1 dependent inhibition of Wnt3A signaling, suggesting a role in modulation of LRP6 function. Detailed analysis of LRP6 domain mutants identified Ser 243 in the first propeller domain of LRP6 as a critical residue for mAb135 binding, implicating this domain in regulating the sensitivity of LRP6 to DKK1. In agreement with this notion, mAb135 directly disrupted the interaction of DKK1 with recombinant ECD LRP6 and a truncated form of the LRP6 ECD containing only repeats 1 and 2. Finally, we found that mAb135 completely protected LRP6 from DKK1 dependent internalization. Together, these results identify the first propeller domain as a novel regulatory domain for DKK1 binding to LRP6 and show that mAb against the first propeller domain of LRP6 can be used to modulate this interaction.
Early expression of the myogenic regulatory gene, myf-5, in precursor cells of skeletal muscle in the mouse embryo (1991)

We have analysed by in situ hybridization the expression of myf-5, the murine homologue of the human myogenic regulatory sequence myf5, during embryogenesis in the mouse. myf-5 sequences were first detected in the earliest somites (from about 8 days p.c.) in the dermomyotome, before formation of the dermatome, myotome and sclerotome. The dermomyotome is classically considered to give rise to the precursor muscle cells of body and limb skeletal muscle. myf-5-positive cells were also detected early in the visceral arches and limb buds. In this case, as in somites, myf-5 expression precedes that of the two related myogenic regulatory sequences, myogenin and MyoD1, and indeed any other skeletal muscle marker examined to date. myf-5 is not detected at any stage in developing cardiac muscle. From 11.5 days p.c., the level of myf-5 transcripts begins to decrease to become undetectable (by in situ hybridization) from 14 days p.c. Both the appearance and disappearance of myf-5 follow the anteroposterior gradient of somite formation and maturation in the embryo. The time and place of myf-5 expression are consistent with a role in the early events of myogenic differentiation, possibly during determination of the myogenic lineage.
CDCP1 Identifies a Broad Spectrum of Normal and Malignant Stem/Progenitor Cell Subsets of Hematopoietic and Nonhematopoietic Origin (2004)

CUB-domain-containing protein 1 (CDCP1) is a novel transmembrane molecule that is expressed in metastatic colon and breast tumors as well as on the surface of hematopoietic stem cells. In this study, we used multiparameter flow cytometry and antibodies against CDCP1 to analyze the expression of CDCP1 on defined hematopoietic cell subsets of different sources. In addition, CDCP1 expression on leukemic blasts and on cells with nonhematopoietic stem/progenitor cell phenotypes was determined. Here we demonstrate that a subset of bone marrow (BM), cord blood (CB), and mobilized peripheral blood (PB) CD34+ cells expressed this marker and that CDCP1 was detected on CD34(+)CD38- BM stem/progenitor cells but not on mature PB cells. Analysis of leukemic blasts from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia in blast crisis revealed that CDCP1 is predominantly expressed on CD34(+)CD133+ myeloid leukemic blasts. However, CDCP1 was not strictly correlated with CD34 and/or CD133 expression, suggesting that CDCP1 is a novel marker for leukemia diagnosis. Stimulation of CD34+ BM cells with CDCP1-reactive monoclonal antibody CUB1 resulted in an increased (approximately twofold) formation of erythroid colony-forming units, indicating that CDCP1 plays an important role in early hematopoiesis. Finally, we show that CDCP1 is also expressed on cells phenotypically identical to mesenchymal stem/progenitor cells (MSCs) and neural progenitor cells (NPCs). In conclusion, CDCP1 is not only a novel marker for immature hematopoietic progenitor cell subsets but also unique in its property to recognize cells with phenotypes reminiscent of MSC and NPC.
A specific subdomain in φ29 DNA polymerase confers both processivity and strand-displacement capacity (2005)

Recent crystallographic studies of phi29 DNA polymerase have provided structural insights into its strand displacement and processivity. A specific insertion named terminal protein region 2 (TPR2), present only in protein-primed DNA polymerases, together with the exonuclease, thumb, and palm subdomains, forms two tori capable of interacting with DNA. To analyze the functional role of this insertion, we constructed a phi29 DNA polymerase deletion mutant lacking TPR2 amino acid residues Asp-398 to Glu-420. Biochemical analysis of the mutant DNA polymerase indicates that its DNA-binding capacity is diminished, drastically decreasing its processivity. In addition, removal of the TPR2 insertion abolishes the intrinsic capacity of phi29 DNA polymerase to perform strand displacement coupled to DNA synthesis. Therefore, the biochemical results described here directly demonstrate that TPR2 plays a critical role in strand displacement and processivity.
Localization of ribophorin II to the endoplasmic reticulum involves both its transmembrane and cytoplasmic domains (2000)

Proteins that are concentrated in specific compartments of the endomembrane system in order to exert their organelle-specific function must possess specific localization signals that prevent their transport to distal regions of the exocytic pathway. Some resident proteins of the endoplasmic reticulum (ER) that are known to escape with low efficiency from this organelle to a post ER compartment are recognized by a recycling receptor and brought back to their site of residence. Other ER proteins, however, appear to be retained in the ER by mechanisms that operate in the organelle itself. The mammalian oligosaccharyltransferase (OST) is a protein complex that effects the cotranslational N-glycosylation of newly synthesized polypeptides, and is composed of at least four rough ER-specific membrane proteins: ribophorins I and II (RI and RII), OST48, and Dadl. The mechanism(s) by which the subunits of this complex are retained in the ER are not well understood. In an effort to identify the domains within RII responsible for its ER localization we have studied the fate of chimeric proteins in which one or more RII domains were replaced by the corresponding ones of the Tac antigen, the latter being a well characterized plasma membrane protein that lacks intrinsic ER retention signals and serves to provide a neutral framework for the identification of retention signals in other proteins. We found that the luminal domain of RII by itself does not contain retention information, while the cytoplasmic and transmembrane domains contain independent ER localization signals. We also show that the retention function of the transmembrane domain is strengthened by the presence of a flanking luminal region consisting of 15 amino acids.
Properties of gallium arsenide (1996)

It was in 1986 that INSPEC (The Information Division of the Institution of Electrical Engineers) published the book Properties of Gallium Arsenide. Since then, major developments have taken place. This third edition is comprised of 150 specially commissioned articles contributed by experts from the USA, Europe and Japan. Gallium arsenide is revolutionizing the semiconductor industry. It is a major competitor to silicon in the push for faster, higher frequency and greater bandwidth circuits. GaAs has a much higher electron mobility, has greater thermal stability and provides higher resistivity IC (integrated circuit) substrates than silicon. Moreover, it is a key material in some areas where silicon is of only minor significance; namely, the burgeoning field of heterostructures which permit combinations of digital, microwave, millimetre wave and optical circuits. Gallium arsenide is also widely used in LEDs (light emitting diodes) and solar cells.
Sacral Neuromodulation for the Treatment of Fecal Incontinence: Analysis of Cost-Effectiveness (2010)

Our data show SNM to be an efficient investment with an acceptable incremental cost-effectiveness ratio and a limited impact on the total allocated budget for fecal incontinence.
Routing in a linear lightwave network (1995)

Dynamic routing of point-to-point connections in a waveband selective linear lightwave network is addressed. Linear lightwave networks are all optical networks in which only linear operations are performed on signals in a waveband selective manner. Special constraints arise because of the linearity in the linear lightwave network. The overall problem of finding a path satisfying all the routing constraints for point-to-point connections is shown to be very complex. Owing to the complexity, the overall routing problem is decomposed into several subproblems. In particular, given a request for a point-to-point connection a waveband is first chosen for the call. Two heuristics, MAXBAND which allocates the most used band to a call and another MINBAND (least used band) are studied. Then, the problem of routing in a given waveband is further divided into smaller subproblems of finding a path in the waveband, checking for feasibility of the path in the chosen waveband and channel allocation (within the waveband). For finding paths in a waveband, K-SP, BLOW-UP and MIN-INT algorithms are proposed. A recursive algorithm checks for feasibility of the path on the waveband. Two channel allocation schemes (within a single waveband) MIN and MAX are presented. Simulations show that using MAXBAND (waveband), MIN-INT (path on waveband) and MIN (channel within waveband) policies resulted in the best performance (least blocking).< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution (2020)

The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed "thymic involution." A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.
Macrophages: Master Regulators of Inflammation and Fibrosis (2010)

Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-beta1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the master "regulators" of fibrosis.
Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology (2017)

This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, <i>KRAS/NRAS</i> mutational status, and patient comorbidities and preferences. Location of the primary tumor, the <i>BRAF</i> mutation status, and tumor microsatellite stability should also be considered in treatment decisions.
Preparation and investigation on properties of lysozyme chemically bonded to single-walled carbon nanotubes (2010)

The purpose of this research is the preparation of a lysozyme-single-walled carbon nanotube (SWCNT) conjugate and investigation of the effect of conjugation on the structure and function of lysozyme. At first, SWCNTs were functionalised by oxygen and lysozyme was coupled to the SWCNTs by carbodiimide method. The high chemical stability of conjugation was purposed for the SWCNTs conjugated enzyme as approved by Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM) images, agarose gel electrophoresis and X-ray diffraction (XRD) patterns. The degree of conjugation was determined by thermogravimetric analysis (TGA) process. The results showed no significant differences between the XRD patterns of the native lysozyme and conjugated lysozyme–SWCNTs and these indicated excellent capacity of the SWCNTs to conjugated enzyme. The gel electrophoresis studies and TEM image confirmed the covalent attachment of the enzyme to the functionalised SWCNTs. These results revealed that the enzyme retain a high fraction of their native structure and activity upon attachment to SWCNTs. Therefore, this conjugated protein represents novel preparations that make it an attractive choice as a natural antimicrobial agent.
Changing Epidemiology ofClostridium difficile-Associated Disease in Children (2007)

This study revealed a steady increase in the number of patients seen in the emergency department with community-acquired CDAD. Findings from this study suggest that the characteristics of CDAD in children--a population that has not been considered to be at high risk for this disease in the past--are changing. Further investigations are warranted to explore deviations from the established burdens of the disease and patient risk factors.
Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment (2013)

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-α (HIF1α) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation.
MPEG-4 multimedia for our time (1999)

The MPEG-4 standard explores every possibility of the digital environment. Recorded images and sounds co-exist with their computer-generated counterparts, a new language for sound promises compact-disk quality at extremely low data rates; and the multimedia content could even adjust itself to suit the transmission rate and quality. Possibly the greatest of the advances made by MPEG-4 is that viewers and listeners need no longer be passive. The height of "interactivity" in audiovisual systems today is the users ability merely to stop or start a video in progress. MPEG-4 is completely different: it allows the user to interact with objects within the scene, whether they derive from so-called real sources, such as moving video, or from synthetic sources, such as computer-aided design output or computer-generated cartoons. Authors of content can give users the power to modify scenes by deleting, adding, or repositioning objects, or to alter the behavior of the objects. Perhaps the most immediate need for MPEG-4 is defensive. It supplies tools with which to create uniform (and top-quality) audio and video encoders and decoders on the Internet, preempting what may become an unmanageable tangle of proprietary formats. In addition to the Internet, the standard is also designed for low bit-rate communications devices, which are usually wireless.
Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty (1993)

Familial male-limited precocious puberty is a male-limited autosomal dominant condition. It is characterized by increased testosterone synthesis in the absence of testicular stimulation by luteinizing hormone (LH). We hypothesised that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in this condition. To test this hypothesis, we screened for mutations in a part of the LH receptor gene that is important for G protein binding. DNA sequence variation was detected in 2 out of 5 families with male-limited precocious puberty by the single strand conformation polymorphism technique. Direct sequencing demonstrated different single nucleotide substitutions in the sixth transmembrane region of the LH receptor gene. The mutations cosegregated with the disorder in both families (lod score 5.76 without recombination). Both mutations cause an amino acid substitution in the sixth transmembrane domain, close to the C-terminal portion of the third cytoplasmatic loop, a region which is important for the binding of G proteins. We conclude that familial male-limited precocious puberty cosegregates with missense mutations in the LH receptor gene. These findings support the hypothesis that increased activity of the LH receptor is the pathogenetic mechanism that causes the abnormal pubertal development in this condition.
Clinical Gram-positive sepsis (1999)

Results of antimediator therapies in clinical trials in septic shock are inconclusive but suggest that the response may differ, depending on the type of microbic pathogen. The immune-mediated pathophysiologic mechanisms that underlie gram-positive sepsis and the potential interactions between the infecting microorganism and efficacy of anticytokine therapies require further investigation. Treatment strategies that explain the causative organism may be necessary for optimal use of immunoadjuvants in the future.
Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment (2019)

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2⁻0.4 mg/day pemafibrate was administered for 52 weeks to 189 patients with hypertriglyceridemia and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m² on statin or regardless of eGFR when statin was not administered. Post-hoc analyses were performed on subgroups stratified by baseline eGFR. Triglyceride levels decreased by 45.9% at week 52 (last-observation-carried-forward). These reductions were not correlated with baseline eGFR. The eGFR < 30 mL/min/1.73 m² subgroup showed the greatest reduction in chylomicron, very low-density lipoprotein, small low-density lipoprotein cholesterol levels, and an increase in high-density lipoprotein cholesterol levels. The incidences of adverse events and adverse drug reactions were 82.0% and 31.7%, respectively, and these were not associated with baseline eGFR. In CKD patients, pemafibrate blood concentrations were not elevated. Pemafibrate showed a good safety profile and efficacy in correcting lipid abnormalities in a broad range of patients, including those with CKD.
Olefin Cross‐Metathesis: A Powerful Tool for Constructing Vaccines Composed of Multimeric Antigens (2005)

The preparation of biologically pertinent glycosylamino acids from O‐pentenyl glycosides is described. The procedure involves sequential cross‐metathesis reactions followed by hydrogenation. The generality and value of this procedure have been demonstrated by the preparation of peracetylated Gb3, GM2, and fucosyl GM1 glycosylamino acids, which are of potentially large value in the preparation of future anticancer vaccines.
Expression pattern of tumor endothelial marker 8 protein in gallbladder carcinomas. (2011)

Tumor endothelial marker 8 protein (TEM8) is highly specific to tumor angiogenesis and is not required for normal adult angiogenesis and hence might prove to be a target for anti-angiogenic therapies in the future. We here evaluated protein and gene expression patterns in human endothelial cells of benign gallbladder - gallstone diseases (GSDs) and gallbladder carcinomas (GBCs) using immunostaining, immunofluorescence and western blotting techniques. Subjects comprised 175 GBC patients, 38 males and 137 females, aged 30-85 years (mean age 50.3 ± 13.4 years) and twenty with GSDs, aged 30-75 years, (51.4 ± 10.0 years) for comparison (male 4/20 and females 16/20). TEM8 protein expression increased significantly (p < 0.0001) with increasing stage of GBC and was mostly limited to endothelial cells, although there was no significant change with the grade. Interestingly, only 80-85 kDa and 60 kDa isoforms of TEM8 increased significantly whereas 45 kDa isoform was absent in GBCs. Conclusions- These results suggest that TEM8 plays an unknown important biological role to promote tumor angiogenesis in GBC.