gebhart/patrepeval huggingface dataset:
Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. (1997)

We have selected a panel of human tumor xenografts for in vitro and in vivo studies that allows an indication of selectivity of action of novel chemotherapeutic agents. We report here the antitumor activity of the flavone flavopiridol (previously designated L86-8275), which has been selected for further studies based in part on its behavior in the anticancer drug screening system of the United States National Cancer Institute. Eighteen human tumor and five cell line-derived xenografts established by serial passage in nude mice in our laboratory were used as tumor models for in vitro investigations using a modified double-layer soft agar assay. In vivo investigations were completed in nude mice bearing advanced-stage s.c. growing prostate cancer xenografts. Antitumor activity in vitro (test/control </= 30%) of flavopiridol was observed at the very low concentration of 0.1 ng/ml in three of four prostatic xenografts and in one melanoma xenograft. Overall, in 14 of 23 (61%) tumor xenografts, drug treatment resulted in a IC70 of <10 ng/ml, demonstrating the high antiproliferative potential of flavopiridol. Toxicity to in vitro bone marrow cultures was evident only at 100 ng/ml, indicating potential high selectivity for susceptible tumor cells. Comparison of tumor cells with bone marrow samples tested showed clear prostate carcinoma and moderate melanoma selectivity. In vivo studies of flavopiridol confirmed antitumor activity in both prostate cancer xenografts investigated. At the maximal tolerated dose of 10 mg/kg/day administered p.o. on days 1-4 and 7-11, flavopiridol effected tumor regression in PRXF1337 and tumor stasis lasting for 4 weeks in PRXF1369. We conclude that flavopiridol shows strong prostate-and moderate melanoma-specific antitumor activity in vitro. The prostate antitumor activity is also reflected by the two in vivo models studied. Initial clinical efforts with flavopiridol might consider early evaluation in patients with prostate carcinoma.
Identification by differential display of alpha 6 integrin as a candidate tumor suppressor gene (1993)

A new method of differential expression cloning called differential display (DD) has been used to screen for novel tumor suppressor genes involved in breast cancer. The screen is based on positive selection at the mRNA level for genes expressed in normal mammary epithelial cells but decreased or lost in corresponding tumor cells. A candidate tumor suppressor gene recovered by DD is integrin alpha-6 (alpha 6), a component of the heterodimeric integrin receptors alpha 6 beta 1 and alpha 6 beta 4. Loss of alpha 6 expression was confirmed in total RNAs by Northern blot analysis and by immunostaining with alpha 6 antibodies. Consistent with these cell culture findings, previous immunostaining of mammary tissue sections has identified decreased alpha 6 protein expression during breast tumor progression. Southern blot analysis demonstrated that alpha 6 gene is present in tumor cell lines, suggesting that reexpression may be inducible by pharmacological intervention. The likelihood that alpha 6 may have tumor suppressing activity is supported by growing evidence of a central role for integrins in transducing growth control and differentiation signals from growth factors and the extracellular matrix (ECM).
Loss of Tumorigenicity and Metastatic Potential in Carcinoma Cells Expressing the Extracellular Domain of the Type 1 Insulin-Like Growth Factor Receptor (2004)

The receptor for the type 1 insulin-like growth factor (IGF-IR) was identified as a major regulator of the malignant phenotype and a target for cancer therapy. In the present study, a novel IGF-IR mutant consisting of the entire extracellular domain of the receptor (IGFIR(933)) was genetically engineered and expressed in highly metastatic H-59 murine lung carcinoma cells. We show here that the cells expressed a truncated heterotetramer (beta(m)-alpha-alpha-beta(m)) that was secreted into the medium and could neutralize the effects of exogenous IGF-I, thus diminishing IGF-I-induced signaling and blocking IGF-I-mediated cellular functions such as cell proliferation, invasion, and survival. In vivo, tumor incidence and growth rate were markedly reduced in mice inoculated s.c. with H-59/IGFIR(933) cells. Moreover, after the intrasplenic/portal inoculation of these cells, there was a 90% reduction in the incidence of hepatic metastases and a significant increase in the long-term, disease-free survival of the mice compared with controls. Our results identify the IGFIR(933) as a potent antitumorigenic and antimetastatic agent with potential applications for cancer gene therapy.
Room Temperature Single Electron Transistor by Local Chemical Modification of Carbon Nanotubes (2001)

A single electron transistor that operates at room temperature has been fabricated from single-walled carbon nanotubes by using a mask technique. The quantum dot with a length of ∼10 nm was created within an individual thin nanotube bundle via local chemical modification. Conductance oscillations as a function of gate voltage as well as differential conductance peaks versus bias voltage were observed up to room temperature. The series of conductance peaks is explained by the contribution of discrete energy levels within the modified nanotube segment. Assuming similar capacitive couplings to the source and drain electrode, the level separation is estimated to be ΔE ∼ 38 meV.
Genetics of Early-Onset Alzheimer Dementia (2003)

Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the epsilon4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOEepsilon4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies.
Inotropes in the beta-blocker era (2000)

Beta-adrenergic blocking agents are now standard treatment for mild to moderate chronic heart failure (CHF). However, although many subjects improve on beta blockade, others do not, and some may even deteriorate. Even when subjects improve on beta blockade, they may subsequently decompensate and need acute treatment with a positive inotropic agent. In the presence of full beta blockade, a beta agonist such as dobutamine may have to be administered at very high (> 10 micrograms/kg/min) doses to increase cardiac output, and these doses may increase afterload. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain their full hemodynamic effects in the face of beta blockade. This is because the site of PDEI action is beyond the beta-adrenergic receptor, and because beta blockade reverses receptor pathway desensitization changes, which are detrimental to PDEI response. Moreover, when the combination of a PDEI and a beta-blocking agent is administered long term in CHF, their respective efficacies are additive and their adverse effects subtractive. The PDEI is administered first to increase the tolerability of beta-blocker initiation by counteracting the myocardial depressant effect of adrenergic withdrawal. With this combination, the signature effects of beta blockade (a substantial decrease in heart rate and an increase in left ventricular ejection fraction) are observed, the hemodynamic support conferred by the PDEI appears to be sustained, and clinical results are promising. However, large-scale placebo-controlled studies with PDEIs and beta blockers are needed to confirm these results.
Effects of Extracellular Matrices and Growth Factors on the Development of Isolated Porcine Blastomeres1 (1991)

The effects of extracellular matrices and growth factors on the development of isolated blastomeres derived from intact 4-, 8-, and 16-cell porcine embryos (termed, respectively, 1/4, 1/8, and 1/16 blastomeres) were investigated in vitro and in vivo. Blastomeres were incubated in extracellular matrix components fibronectin (FIN) or swine skin gelatin (SSG)-precoated culture dishes containing either modified Krebs' Ringer Bicarbonate solution (mKRB) supplemented with 10% heat-inactivated lamb serum, or Hanks' solution supplemented with 10% heat-inactivated newborn calf serum (NBCS) or Waymouth medium supplemented with 10% NBCS or in noncoated dishes in mKRB supplemented with either insulin (10, 100, or 1,000 micrograms/ml), transferrin (10, 100, or 1,000 micrograms/ml), or cAMP (0.2 or 2.0 micrograms/ml). Cultures observed at 24-h intervals and morphological development was recorded. Blastomeres were classified into three categories according to their morphology: (1) regular blastocysts, (2) trophectodermal vesicles, or (3) no development. After 96 h, culture was determined; the overall diameter of the blastocysts was determined and the nuclei were counted. Blastomeres/blastocysts did not adhere to the bottom of the culture dishes coated with extracellular matrices. Blastocyst formation rate was highest when FIN/mKRB was used and reached 44.3%, 41.8%, and 36.5% for 1/4, 1/8, and 1/16 blastomeres, respectively. The respective blastocysts contained an average of 31.2 +/- 5.8, 58.2 +/- 8.4, and 18.5 +/- 3.5 nuclei and had an overall diameter of 250.0 +/- 10.1, 235.0 +/- 12.8, and 172.5 +/- 13.7 microns, 1/8 blastomeres displayed a better (p less than 0.05) growth rate than 1/4 and 1/16 blastomeres, and 1/8 blastomeres in FIN/mKRB grew better (p less than 0.01) when cultured in an open system than in a microdrop under oil (35.5% vs. 5.0% blastocysts). Neither cAMP nor transferrin had a significant stimulating effect on blastocyst development of 1/8 blastomeres when mKRB plus serum was used as the medium. Insulin supplementation (10 or 100 micrograms/ml) to mKRB plus lamb serum significantly (p less than 0.05) stimulated blastocyst formation rate compared with controls (58.6% and 38.9% vs. 17.7%, respectively; 32.6 +/- 2.5, 58.5 +/- 11.8, and 45.1 +/- 4.6 nuclei, respectively). Transfer of 457 blastocysts grown for 24 h in FIN/mKRB to 16 recipients gilts led to three pregnancies, and two litters were born from 1/8 blastomere-derived blastocysts following 116 days of gestation.4+ is
Intrathecal Long-Term Gene Expression by Self-Complementary Adeno-Associated Virus type 1 Suitable for Chronic Pain Studies in Rats (2006)

sc-rAAVl mediates stable IT transgene expression for > or = 3 mo. Our findings support the underlying hypothesis that IT target cells for gene transfer lack the machinery for efficient conversion of the single-stranded rAAV genome into double-stranded DNA and favor uptake of serotype 1 vectors over 2. Experiments presented here will provide a rational basis for utilizing IT rAAV gene transfer in basic and translational studies on chronic pain.
The release profile of a controlled release preparation of 5-aminosalicylic acid (Rowasa I®) in humans (1990)

5-Aminosalicylic acid and its metabolite, N-ac-5-ASA, were measured in the plasma, urine, and ileostomy effluent of 24 ileostomates who ingested 750 mg Rowasa I following an overnight fast. Twelve subjects previously had a small-bowel resection or had part of their small bowel out of circuit (mean 95 cm) (Group I) while 12 had an intact small bowel (Group II). The mean peak plasma concentration of N-ac-5-ASA was 1.11 micrograms/ml in Group 1 subjects compared with 2.80 micrograms/ml in Group II subjects (P = N.S.). On average, 53.0 percent of the ingested Rowasa I was detected in the 24-hr ileostomy effluent of Group I subjects compared with 45.3 percent in the Group II subjects (P = N.S.). The mean recovery of 5-ASA and N-ac-5-ASA in urine was 8.5 percent in Group I and 35.6 percent in Group II subjects (P less than 0.001). These studies demonstrate that 5-ASA is released and present in the small bowel following oral ingestion of Rowasa I in patients who have or have not had small bowel resections.
Sequential study of IgG antibody response in immunized rabbit and development of immunization protocol for raising monospecific antibody. (1996)

The present study was planned to develop an immunization protocol to decide the bleeding modalities for harvesting anti IgG antibody from the immunized rabbit. A fourteen dose immunization protocol (four primary and ten boosters) of the purified human IgG spread over the one calendar year was executed. The antibody titre estimated by Reverse Single Radial Immunodiffusion displayed a six-phased pattern. The titre following the initial immunization ranged between nil to 1.02, characteristic of the primary response while the titres after 7th and 8th boosters (phase V) ranged between 0.5 to 3.87 consistent with secondary response. Phase II, III, IV had moderately elevated titres. The antibody titre amongst the six phases reached to its peak generally by the 12th day after the last dose of protocol and it took about 60 days to reach to its basal level. Administration of antigen with the higher levels of residual antibody did not produce high titre antibody and is probably ascribed to elimination of antigen through an immunecomplex mechanism. Based on the data we recommend that 15 batches. (3 per phase, phase I to phase V) with a total yield of 100 to 120 ml of serum can be procured from one immunised animal over the span of one calendar year and that should make the programme cost effective.
Carrier design: Conformational studies of amino acid (X) and oligopeptide (X‐DL‐Alam) substituted poly(L‐lysine) (1993)

The present study was undertaken to examine the influence of the reversal of the side-chain sequential order on the conformation of branched polypeptides. At the same time, the influence of the optically active amino acid joined directly to the poly (L-Lys) backbone and the DL-Ala oligomer grafted as chain-terminating fragment were separately analyzed. Therefore two sets of polypeptides were synthesized corresponding to the general formula poly[Lys-(Xi)] (XK) and poly[Lys-(DL-Alam-Xi)] (AXK) when X = Ala, D-Ala, Leu, D-Leu, Phe, D-Phe, Ile, Pro, Glu, D-Glu, or His. For coupling amino acid X to polylysine, three types of active ester methods were compared: the use of pentafluorophenyl or pentachlorophenyl ester, and the effect of the addition of an equimolar amount of 1-hydroxy-benzotriazole. After cleavage of protecting groups, AXK polypeptides were synthesized by grafting short oligo(DL-Ala) chains to XK by using N-carboxy-DL-Ala anhydride. The CD measurements performed in water solutions of various pH values and ionic strengths were used for classification of the polypeptide conformations as either ordered (helical) or unordered. Different from what was observed with the unsubstituted poly (L-Lys), poly[Lys-(Xi)] type polypeptides can adopt ordered structure even under nearly physiological conditions (pH 7.3, 0.2M NaCl). These data suggest that the introduction of amino acid residue with either (ar) alkyl side chain (Ala, Leu, Phe) or negatively charged side chain (Glu) promotes markedly the formation of ordered structure. Comparison of chiroptical properties of poly[Lys-(DL-Alam-Xi)] and of poly[Lys-(Xi)] reveals that side-chain interactions play an important role in the stabilization of ordered solution conformation of AXK type branched polypeptides. The results give rather conclusive evidence that not only hydrophobic interactions, but also ionic attraction, can be involved in the formation and stabilization of helical conformation of branched polypeptides.
Sequence homology between the subunits of two immunologically and functionally distinct types of fimbriae of Actinomyces spp (1990)

Nucleotide sequencing of the type 1 fimbrial subunit gene of Actinomyces viscosus T14V revealed a consensus ribosome-binding site followed by an open reading frame of 1,599 nucleotides. The encoded protein of 533 amino acids (Mr = 56,899) was predominantly hydrophilic except for an amino-terminal signal peptide and a carboxy-terminal region identified as a potential membrane-spanning segment. Edman degradation of the cloned protein expressed in Escherichia coli and the type 1 fimbriae of A. viscosus T14V showed that both began with alanine at position 31 of the deduced amino acid sequence. The amino acid compositions of the cloned protein and fimbriae also were comparable and in close agreement with the composition of the deduced protein. The amino acid sequence of the A. viscosus T14V type 1 fimbrial subunit showed no significant global homology with various other proteins, including the pilins of gram-negative bacteria. However, 34% amino acid sequence identity was noted between the type 1 fimbrial subunit of strain T14V and the type 2 fimbrial subunit of Actinomyces naeslundii WVU45 (M. K. Yeung and J. O. Cisar, J. Bacteriol. 170:3803-3809, 1988). This homology included several different conserved sequences of up to eight identical amino acids that were distributed in both the amino- and carboxy-terminal thirds of each Actinomyces fimbrial subunit. These findings indicate that the different types of fimbriae on these gram-positive bacteria share a common ancestry.
Catalytic Asymmetric Synthesis of Diarylacetates and 4,4-Diarylbutanoates. A Formal Asymmetric Synthesis of (+)-Sertraline (1999)

The intermolecular C−H insertion chemistry of phenyldiazoacetates catalyzed by dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) can be effectively carried out on cyclohexadienes, leading to the asymmetric synthesis of diarylacetates. The reaction of vinyldiazoacetates with cyclohexadienes results in an unprecedented carbenoid reaction that is formally a combined C−H insertion/Cope rearrangement. The synthetic utility of this novel transformation was demonstrated by its utilization in a formal asymmetric synthesis of (+)-sertraline.
HLA allele selection for designing peptide vaccines (1996)

A central problem in developing vaccines against rapidly evolving viruses such as HIV and Influenza is the mutability of their antigens. In principle, the problem can be mitigated by using peptides from conserved portions of viral proteins. However, because cytotoxic T lymphocytes (CTLs), which such vaccines would stimulate, recognize pathogenic peptides only in association with class I products of the Major Histocompatibility Complex (MHC), and because human leukocyte antigen genes (HLA; the human MHC) are highly polymorphic, a peptide vaccine would have to bind a number of different HLA products. A natural question then, which is pertinent to the safety of the vaccine is, which HLA molecules should be targeted to achieve a prespecified coverage (say 90%) of a population. Taking account of disequilibrium between linked HLA loci, we identify 3-6 class I HLA alleles, depending on ethnic group, which cover about 90% of the population. While this leaves large numbers of individuals uncovered, a high level of herd immunity, and hence eradication of the virus, can be achieved through such a vaccine.
C1- and R-dependent expression of the maize Bz1 gene requires sequences with homology to mammalian myb and myc binding sites. (1991)

Tissue-specific expression of the maize anthocyanin Bronze-1 (Bz1) gene is controlled by the products of several regulatory genes. These include C1 or Pl and R or B that share homology to the myb proto-oncogenes and myc-like genes, respectively. Bz1 expression in embryo tissues is dependent on C1 and an R-sc allele of R. Transient expression from mutated and deleted versions of the Bz1 promoter fused to a luciferase reporter gene was measured in C1, Rscm2 embryos after gene transfer by microprojectiles. This analysis revealed that the sequences between -76 base pairs (bp) and -45 bp and a 9-bp AT-rich block between -88 bp and -80 bp were critical for Bz1 expression. The -76 bp to -45 bp region includes two short sequences that are homologous to the consensus binding sites of the myb- and myc-like proteins. Site-specific mutations of these "myb" and "myc" sequences reduced Bz1 expression to 10% and 1% of normal, respectively. Additionally, a trimer of a 38-bp oligonucleotide containing these myb and myc sites increased the expression of a cauliflower mosaic virus 35S minimal promoter by 26-fold. This enhancement was dependent on both C1 and R. Because the sites critical for Bz1 expression are homologous to the myb and myc consensus binding sequences and the C1 and R proteins share homology with the myb and myc products, respectively, we propose that C1 and R interact with the Bz1 promoter at these sites.
Major tyrosine identity determinants in Methanococcus jannaschii and Saccharomyces cerevisiae tRNATyr are conserved but expressed differently (2001)

Using in vitro tRNA transcripts and minihelices it was shown that the tyrosine identity for tRNA charging by tyrosyl-tRNA synthetase (TyrRS) from the archaeon Methanococcus jannaschii is determined by six nucleotides: the discriminator base A73 and the first base-pair C1-G72 in the acceptor stem together with the anticodon triplet. The anticodon residues however, participate only weakly in identity determination, especially residues 35 and 36. The completeness of the aforementioned identity set was verified by its tranfer into several tRNAs which then become as efficiently tyrosylatable as the wild-type transcript from M. jannaschii. Temperature dependence experiments on both the structure and the tyrosylation properties of M. jannaschii and yeast tRNA(Tyr) transcripts show that the archaeal transcript has greater structural stability and enhanced aminoacylation behaviour than the yeast transcript. Tyrosine identity in M. jannaschii is compared to that in yeast, and the conservation of the major determinant in both organisms, namely the C1-G72 pair, gives additional support to the existence of a functional connection between archaeal and eukaryotic aminoacylation systems.