gebhart/patrepeval huggingface dataset:
The program of androgen-responsive genes in neoplastic prostate epithelium (2002)

The human prostate gland is an important target organ of androgenic hormones. Testosterone and dihydrotestosterone interact with the androgen receptor to regulate vital aspects of prostate growth and function including cellular proliferation, differentiation, apoptosis, metabolism, and secretory activity. Our objective in this study was to characterize the temporal program of transcription that reflects the cellular response to androgens and to identify specific androgen-regulated genes (ARGs) or gene networks that participate in these responses. We used cDNA microarrays representing about 20,000 distinct human genes to profile androgen-responsive transcripts in the LNCaP adenocarcinoma cell line and identified 146 genes with transcript alterations more than 3-fold. Of these, 103 encode proteins with described functional roles, and 43 represent transcripts that have yet to be characterized. Temporal gene expression profiles grouped the ARGs into four distinct cohorts. Five uncharacterized ARGs demonstrated exclusive or high expression levels in the prostate relative to other tissues studied. A search of available DNA sequence upstream of 28 ARGs identified 25 with homology to the androgen response-element consensus-binding motif. These results identify previously uncharacterized and unsuspected genes whose expression levels are directly or indirectly regulated by androgens; further, they provide a comprehensive temporal view of the transcriptional program of human androgen-responsive cells.
Nicotine Up-Regulates Expression of Orexin and Its Receptors in Rat Brain* (2000)

Orexins are two recently discovered neuropeptides that can stimulate food intake. As the chronic use of tobacco typically leads to a reduction in body weight, it is of interest to determine whether nicotine, the major biologically active tobacco ingredient, has an effect on orexin metabolism in the brain. Using a semiquantitative RT-PCR technique, the levels of messenger RNA (mRNA) for prepro-orexin, orexin A (OX1-R) and orexin B (OX2-R) receptors were 20-50% higher in rats receiving nicotine for 14 days at the level of 2-4 mg/kg day compared with rats receiving saline solvent alone. In animals treated with nicotine at 4 mg/kg x day, the expression levels of mRNA for prepro-orexin, OX1-R, and OX2-R were significantly higher compared with those in either the free-feeding control or pair-fed saline control rats. RIA data indicated that both orexin A and orexin B peptide levels were significantly elevated (45-54%; P < 0.01) in the dorsomedial nucleus (DMH) of the nicotine-treated rats compared with either solvent-only or pair-fed controls. Additionally, orexin B was significantly elevated (83%; P < 0.01), over levels in both types of the control animals, in the paraventricular nucleus (PVN) region. In summary, we demonstrated that an inverse association between nicotine and food intake as well as body weight held with doses comparable to those consumed by average human smokers. Moreover, our data indicated that chronic exposure to nicotine can induce a long-term increase in the expression levels of prepro-orexin and their receptor mRNA in the rat hypothalamus and in the levels of orexin A in the DMH and orexin B in the DMH and PVN among the six hypothalamic regions that we examined.
Ubiquitin-metallothionein fusion protein expression in yeast. A genetic approach for analysis of ubiquitin functions. (1988)

We have established a Saccharomyces cerevisiae genetic system that expresses the fusion protein ubiquitin-metallothionein. We have evaluated the effects of amino-terminal ubiquitination of metallothionein on the stability and function of metallothionein. The fusion protein of wild type ubiquitin and metallothionein was rapidly processed in vivo to release free ubiquitin and metallothionein. Site-directed mutants of ubiquitin-metallothionein expressed in yeast were used to study the specificity of the (alpha-NH2-ubiquitin) protein endopeptidases. The data suggest that amino-terminal ubiquitination is not a signal for the proteolysis of yeast metallothionein in yeast. We have also discovered that expression of selected ubiquitin mutants blocked the growth of yeast. The data suggest that in addition to its function as a proteolytic signal, ubiquitination of proteins plays multiple roles in the cell.
Low Levels of Circulating Invariant Natural Killer T Cells Predict Poor Clinical Outcome in Patients With Head and Neck Squamous Cell Carcinoma (2007)

A severe circulating iNKT cell deficiency was related to poor clinical outcome in HNSCC patients, suggesting their critical contribution to antitumor immune responses. Furthermore, screening for iNKT cell levels may be useful for determining which patients can benefit from immunotherapeutic adjuvant therapies aimed at reconstitution of the circulating iNKT cell pool.
Novel thioester reagents afford efficient and specific S‐acylation of unprotected peptides under mild conditions in aqueous solution (2005)

S-acylated peptides have many potential uses for elucidating the biophysical, structural and other properties of the numerous S-acylated proteins of mammalian cells. However, with the currently available reagents, preparation of specifically S-acylated derivatives of peptides is generally laborious or simply unfeasible. We here show that novel, easily preparable aryl and alkyl thioester derivatives of palmitic acid can mediate S-acylation of peptides corresponding to physiologically S-acylated sequences from the proteins p56(lck) and H-ras and the Po glycoprotein of peripheral myelin, with high selectivity for cysteine over other amino acid functional groups (including hydroxyl and both alpha- and epsilon-amino residues), and with much greater efficiency than is obtained using acyl-coenzyme A derivatives. Efficient and selective S-acylation can be accomplished under very mild conditions in aqueous systems containing lipid vesicles or detergent micelles, or in homogenous aqueous/acetonitrile mixtures. Using these novel thioesterifying reagents, we confirm previous suggestions that the N-terminal cysteine residue of Hedgehog proteins can exhibit rapid, uncatalyzed S-to-N acyl transfer following S-acylation to produce the N-palmitoylated amino terminus found in the mature protein. By contrast, we demonstrate that spontaneous S-to-N acyl transfer from the cysteine to the terminal glycine residue in the amino-terminal peptide of G(alphas) is far less rapid and is likely too slow to explain the physiological N-palmitoylation of the amino terminus of this protein.
Transcriptional co-operativity between distant retinoic acid response elements in regulation ofCyp26A1inducibility (2005)

Cyp26A1 encodes an RA (retinoic acid)-catabolizing CYP (cytochrome P450) protein that plays a critical role in regulating RA distribution in vivo. Cyp26A1 expression is inducible by RA, and the locus has previously been shown to contain a RARE (RA response element), R1, within the minimal promoter [Loudig, Babichuk, White, Abu-Abed, Mueller and Petkovich (2000) Mol. Endocrinol. 14, 1483-1497]. In the present study, we report the identification of a second functional RARE (R2) located 2.0 kb upstream of the Cyp26A1 transcriptional start site. Constructs containing murine sequences encompassing both R1 and R2 showed that these elements work together to generate higher transcriptional activity upon treatment with RA than those containing R1 alone. Inclusion of R2 also dramatically enhanced the sensitivity of reporter constructs to RA, as even treatment with 10(-8) M RA resulted in a 5-fold induction of reporter activity. Mutational analysis identified R2 as the functional element responsible for the increased RA inducibility of promoter constructs. The element was shown to bind RARgamma (RA receptor gamma)/RXRalpha (retinoid X receptor alpha) heterodimers in vitro, and inclusion of nuclear receptors in transfections boosted the transcriptional response. A construct containing both R1 and R2 was used to generate a stable luciferase reporter cell line that can be used as a tool to identify factors regulating Cyp26A1 expression. The analysis of R1 and R2 has led to the proposal that the two elements work synergistically to provide a maximal response to RA and that R2 is an upstream enhancer.
Vaccination of Advanced Hepatocellular Carcinoma Patients with Tumor Lysate-Pulsed Dendritic Cells (2005)

Hepatocellular carcinoma (HCC) is a common and rapidly progressing malignancy. Current treatment options for advanced HCC are limited. This clinical study of dendritic cell (DC)-based immunotherapy for HCC enrolled 31 patients with advanced HCC. DCs, propagated from peripheral blood monocytes, were pulsed with autologous tumor lysates to treat HCC. The first 14 patients underwent pulsed therapy with five courses of DC vaccination intravenously at weekly intervals. The other 17 patients underwent monthly boost vaccinations after the initial pulsed therapy. Among the 31 patients, 4 (12.9%) exhibited partial response to DC vaccination. Seventeen patients (54.8%) had stable disease. Ten patients (32.3%) had progressive disease. The overall 1-year survival rate of all 31 patients was 40.1 +/- 9.1%. The patients treated with pulsed and boosted therapy had better 1-year survival rates than those treated by pulsed therapy alone (63.3 +/- 12.0% vs. 10.7 +/- 9.4%; P < 0.001). In this trial, DC vaccinations for advanced HCC were safe. Liver function tests showed no difference before and after DC vaccinations. The results of this clinical trial indicate that DC vaccination is a safe treatment for HCC. Pulsed DC vaccination followed by boosters can provide better clinical survival for advanced HCC patients than pulsed DC vaccination only. Further studies are needed to increase the efficacy of this therapeutic approach.
APG350 Induces Superior Clustering of TRAIL Receptors and Shows Therapeutic Antitumor Efficacy Independent of Cross-Linking via Fcγ Receptors (2013)

Cancer cells can be specifically driven into apoptosis by activating Death-receptor-4 (DR4; TRAIL-R1) and/or Death-receptor-5 (DR5; TRAIL-R2). Albeit showing promising preclinical efficacy, first-generation protein therapeutics addressing this pathway, especially agonistic anti-DR4/DR5-monoclonal antibodies, have not been clinically successful to date. Due to their bivalent binding mode, effective apoptosis induction by agonistic TRAIL-R antibodies is achieved only upon additional events leading to antibody-multimer formation. The binding of these multimers to their target subsequently leads to effective receptor-clustering on cancer cells. The research results presented here report on a new class of TRAIL-receptor agonists overcoming this intrinsic limitation observed for antibodies in general. The main feature of these agonists is a TRAIL-mimic consisting of three TRAIL-protomer subsequences combined in one polypeptide chain, termed the single-chain TRAIL-receptor-binding domain (scTRAIL-RBD). In the active compounds, two scTRAIL-RBDs with three receptor binding sites each are brought molecularly in close proximity resulting in a fusion protein with a hexavalent binding mode. In the case of APG350-the prototype of this engineering concept-this is achieved by fusing the Fc-part of a human immunoglobulin G1 (IgG1)-mutein C-terminally to the scTRAIL-RBD polypeptide, thereby creating six receptor binding sites per drug molecule. In vitro, APG350 is a potent inducer of apoptosis on human tumor cell lines and primary tumor cells. In vivo, treatment of mice bearing Colo205-xenograft tumors with APG350 showed a dose-dependent antitumor efficacy. By dedicated muteins, we confirmed that the observed in vivo efficacy of the hexavalent scTRAIL-RBD fusion proteins is-in contrast to agonistic antibodies-independent of FcγR-based cross-linking events.
Nyctohemeral Growth Hormone Profiles in Young and Aged Men: Correlation with Somatomedin-C Levels* (1987)

The effects of aging on GH secretion and somatomedin-C (SM-C) levels were studied in 10 young (22-45 yr) and 10 elderly (65-85 yr) men. Plasma GH levels were measured in samples obtained at 20-min intervals for 1300 min. Plasma SM-C levels were measured in samples obtained at 0600, 1100, 1600, 2100, and 0200 h. In the elderly men the mean basal plasma GH level was similar to that in the young men, but the total GH peak area as well as the amplitude of the peaks were significantly (p less than 0.01) lower than those in young men during both the day and the night. Plasma SM-C levels were significantly lower in the elderly men and were correlated with the total integrated GH levels and total GH peak areas, but not with basal plasma GH levels, suggesting that the GH peaks determine SM-C levels and that the decreased GH secretion in elderly men has biological significance.
Process development for production of recombinant human interferon-? expressed in Escherichia coli (2004)

A simple fed-batch process was carried out using constant and variable specific growth rates for high-cell-density cultivation of Escherichia coli BL21 (DE3) expressing human interferon-gamma(hIFN-gamma). The feeding rate was adjusted to achieve an appropriate specific growth rate. The dissolved oxygen level was maintained at 20-30% of air saturation by control of airflow and stirrer speed and, where necessary, by enrichment of inlet air with pure oxygen. Glucose was the sole source of carbon and energy and was provided by following a simple exponential feeding rate. The final cell density in the fed-batch fermentation with constant and variable specific growth rate feeding strategies was ~100 g dry cell wt l(-1) after 36 and 20 h, respectively. The final specific yield and overall productivity of recombinant hIFN-gamma in the variable specific growth rate strategy were 0.35 g rHu-IFN-gamma g(-1) dry cell wt and 0.9 g rHu-IFN-gamma l(-1) h(-1), respectively. A new chromatographic purification procedure involving anion exchange and cation exchange chromatographies was developed for purification of rHu-IFN-gamma from inclusion bodies. The established purification process is reproducible and the total recovery of rHu-IFN-gamma was ~30% (100 mg rHu-IFN-gamma g(-1) dry cell wt). The purity of the rHu-IFN-gamma was determined using HPLC. Sterility, pyrogenicity, and DNA content tests were conducted to assure the absence of toxic materials and other components of E. coli in the final product. The final purified rHu-IFN-gamma has a specific antiviral activity of ~2 x 10(7) IU/mg protein, as determined by viral cytopathic effect assay. These results certify the product for clinical purposes.
Liver regeneration after adult living donor and deceased donor split-liver transplants (2004)

As the number of living donor (LD) and deceased donor (DD) split-liver transplants (SLTs) have increased over the last 5 years, so too has the interest in liver regeneration after such partial-liver transplants. We looked at liver regeneration, as measured by computed tomography (CT) volumetrics, to see if there were significant differences among LDs, right-lobe LD recipients, and SLT recipients. We measured liver volume at 3 months postoperatively by using CT, and we compared the result to the patient's ideal liver volume (ILV), which was calculated using a standard equation. The study group consisted of 70 adult patients who either had donated their right lobe for LD transplants (n = 24) or had undergone a partial-liver transplant (right-lobe LD transplants, n = 24; right-lobe SLTs, n = 11; left-lobe SLTs, n = 11). DD (vs. LDs) were younger (P < 0.01), were heavier (P = 0.06), and had longer ischemic times (P < 0.01). At 3 months postoperatively, LDs had attained 78.6% of their ILV, less than the percentage for right-lobe LD recipients (103.9%; P = 0.0002), right-lobe SLT recipients (113.6%; P = 0.01), and left-lobe SLT recipients (119.7%; P = 0.0006). When liver size at the third postoperative month was compared with the liver size immediately postoperatively, LDs had a 1.85-fold increase. This was smaller than the increase seen in right-lobe LD recipients (2.08-fold), right-lobe SLT recipients (2.17-fold), and left-lobe SLT recipients (2.52-fold). In conclusion, liver regeneration, as measured by CT volume, seems to be greatest in SLT recipients. LD recipients seem to have greater liver growth than their donors. The reason for this remains unclear.
Invadable self-assembly: combining robustness with efficiency (2004)

DNA self-assembly is emerging as a key paradigm for nano-technology, nano-computation, and several related disciplines. In nature, DNA self-assembly is often equipped with explicit mechanisms for both error prevention and error correction. For artificial self-assembly, these problems are even more important since we are interested in assembling large systems with great precision. So far, theoretical studies of DNA self-assembly have primarily focused on the efficiency of the assembly process in terms of the program size and the running time. In this paper, we perform a preliminary study of algorithms for DNA self-assembly that are both robust and efficient.Strand invasion is an important error-correction mechanism observed in several natural self-assembling systems. We first define invadable self-assemblies as self-assembling systems which can effectively use the strand invasion mechanism for error-correction. We then show that O(log2n/ log log n) tiles are sufficient to assemble an n × n square in this model. The running time of our system is O (n). We obtain our result by growing a counter which simulates Chinese remaindering. The running time and the program size of our invadable system are within polylogarithmic factors of known lower bounds for general systems, i.e. the efficiency penalty for obtaining robustness is small in our model. We also show how to simulate an arbitrary Turing machine using an invadable self-assembly system.
Both CD4 and CD8 T Cells Mediate Equally Effective In Vivo Tumor Treatment When Engineered with a Highly Avid TCR Targeting Tyrosinase (2010)

Tyrosinase, an enzyme involved in melanin synthesis, is expressed in nearly all primary and metastatic melanoma lesions and thus is an attractive target for TCR-based gene therapy using adoptive cell transfer. The TCR alpha- and beta-chain genes from a tumor-infiltrating lymphocyte, which recognized the tyrosinase 368-376 peptide in the context of HLA-A2, were cloned into a gamma-retroviral vector. Following transduction of PBL, specific reactivity was confirmed by cytokine production following coculture with tumor targets. Experiments using Ab blockade and CD4/CD8 sorting of the transduced PBLs demonstrated that this antityrosinase TCR was CD4/CD8 independent. The introduction of a second disulfide bond between the TCR constant regions and/or creation of a chimeric protein in which the human constant regions were replaced by murine homologs resulted in enhanced TCR expression as demonstrated by tetramer staining and improved tumor reactivity that was comparable to PBL transduced with either anti-melanoma Ag recognized by T cells-1 or anti-gp100 TCR vectors currently used in clinical trials. The chimeric TCR also allowed us to test antitumor function of in HLA-A2/K(b)-transgenic mice. Transfer of the antityrosinase TCR into mouse splenocytes conferred CD4/CD8-independent, HLA-A2-restricted Ag reactivity against B16/A2K(b) murine melanoma in vitro. Furthermore, adoptive transfer of transduced splenocytes mediated B16/A2K(b) melanoma tumor regression in lymphodepleted mice, and, surprisingly, both CD8 and CD4 T cells were equally effective in mediating tumor regression. These results suggest that this highly active tyrosinase-specific TCR could be of value in adoptive cell transfer for melanoma.
Influence of beam shape on in-vitro cellular transformations in human skin fibroblasts (2005)

A variety of strategies have been utilised for prevention and treatment of chronic wounds such as leg ulcers, diabetic foot ulcers and pressure sores<sup>1</sup>. Low Level Laser Therapy (LLLT) has been reported to be an invaluable tool in the enhancement of wound healing through stimulating cell proliferation, accelerating collagen synthesis and increasing ATP synthesis in mitochondria to name but a few<sup>2</sup>. This study focused on an in-vitro analysis of the cellular responses induced by treatment with three different laser beam profiles namely, the Gaussian (G), Super Gaussian (SG) and Truncated Gaussian (TG), on normal wounded irradiated (WI) and wounded non-irradiated (WNI) human skin fibroblast cells (WS1), to test their influence in wound healing at 632.8 nm using a helium neon (HeNe) laser. For each beam profile, measurements were made using average energy densities over the sample ranging from 0.2 to 1 J, with single exposures on normal wounded cells. The cells were subjected to different post irradiation incubation periods, ranging from 0 to 24 hours to evaluate the duration (time) dependent effects resulting from laser irradiation. The promoted cellular alterations were measured by increase in cell viability, cell proliferation and cytotoxicity. The results obtained showed that treatment with the G compared to the SG and TG beams resulted in a marked increase in cell viability and proliferation. The data also showed that when cells undergo laser irradiation some cellular processes are driven by the peak energy density rather than the energy of the laser beam. We show that there exist threshold values for damage, and suggest optimal operating regimes for laser based wound healing.
Methotrexate reduces antibody responses to recombinant humanα-galactosidase A therapy in a mouse model of Fabry disease (2004)

SUMMARY Therapeutic enzymes are often recognized as foreign by the immune system of patients undergoing enzyme replacement therapy. The antibodies that develop may alter pharmacokinetics and biodistribution of the therapeutic protein, may be able to neutralize the activity of the enzyme, or may cause immune reactions in certain patients. We have explored treatment regimens to reduce the antibody response to human α-galactosidase A (r-hαGAL) in Fabry (αGAL knock-out) and normal BALB/c mice. A wide variety of treatment modalities were tested, including high dose tolerance induction, increased frequency of therapeutic doses and immunosuppressive drugs in combination with administration of enzyme. The most substantial effects were observed in mice injected intravenously with r-hαGAL in combination with methotrexate (MTX), which significantly lowered r-hαGAL-specific serum antibody levels. A short course of treatment with MTX was able to reduce antibody and spleen cell proliferative responses to long-term r-hαGAL treatment. MTX was able to suppress the development of r-hαGAL-specific IgG in antigen-primed mice. However, MTX was not effective in dampening robust ongoing antibody responses. These experiments provide a framework for the design of clinical protocols to prevent the drug-specific antibody responses of patients undergoing enzyme replacement therapy.