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1.
J Invasive Cardiol ; 36(5)2024 May.
Article in English | MEDLINE | ID: mdl-38422533

ABSTRACT

A 60-year-old male presented to the emergency department of our hospital with persistent dull pain in the lower and middle sternum with generalized sweating after a heated argument with another person, and his symptoms did not resolve after 3 hours of onset.


Subject(s)
Coronary Angiography , Coronary Vasospasm , Electrocardiography , Humans , Male , Middle Aged , Coronary Vasospasm/diagnosis , Coronary Vasospasm/physiopathology , Coronary Angiography/methods , Coronary Vessels/diagnostic imaging
2.
Biomed Environ Sci ; 36(4): 324-333, 2023 Apr 20.
Article in English | MEDLINE | ID: mdl-37105907

ABSTRACT

Objective: Foreign studies have reported that coronary artery disease (CAD) patients with high baseline low-density lipoprotein cholesterol (LDL-C) may have a good prognosis, which is called the "cholesterol paradox". This study aimed to examine whether the "cholesterol paradox" also exists in the Chinese population. Methods: A total of 2,056 patients who underwent the first percutaneous coronary intervention (PCI) between 2014 and 2016 were enrolled in this retrospective cohort study and classified into two groups based on baseline LDL-C = 2.6 mmol/L (100 mg/dL). The outcomes of interest included major adverse cardiovascular events (MACE), all-cause mortality, recurrent nonfatal myocardial infarction, unexpected coronary revascularization, or any nonfatal stroke. Results: All-cause mortality occurred in 8 patients (0.7%) from the low-LDL-C group and 12 patients (2.4%) in the high-LDL-C group, with a significant difference between the two groups (adjusted hazard ratio: 4.030, 95% confidence interval: 1.088-14.934; P = 0.037). However, no significant differences existed for the risk of MACE or other secondary endpoints, such as unexpected revascularization, nor any nonfatal stroke in the two groups. Conclusion: In this study, a high baseline LDL-C was not associated with a low risk of clinical outcomes in CAD patients undergoing first PCI, which suggested that the "cholesterol paradox" may be inapplicable to Chinese populations.


Subject(s)
Coronary Artery Disease , Percutaneous Coronary Intervention , Stroke , Humans , Cholesterol, LDL , Retrospective Studies , Percutaneous Coronary Intervention/adverse effects , Coronary Artery Disease/surgery , Cholesterol , Cholesterol, HDL , Stroke/etiology , Treatment Outcome , Risk Factors
3.
Ying Yong Sheng Tai Xue Bao ; 34(12): 3239-3244, 2023 Dec.
Article in Chinese | MEDLINE | ID: mdl-38511362

ABSTRACT

We investigated root growth of 1-year-old Juglans mandshurica seedlings under different light environments and varying doses of phosphorus fertilizer, to understand the relationship between root resource acquisition strategies and the variations of light and phosphorus availability. There were four shading intensities (full light, 65% full light, 35% full light, and 20% full light) along with three doses of phosphate fertilizer (0 (CK), 200% soil background available phosphorus, and 500% soil background available phosphorus). We measured in root morphology characteristics, architectural characteristics, and mycorrhizal colonization rates of first-order roots. The results showed that average diameter, average root length, and mycorrhizal colonization rates of first-order roots gradually decreased, and the specific root length, specific surface area, branching ratio and branching intensity showed a trend of first increasing and then decreasing with the increases of shading degree. As the phosphorus content decreased, the first-order root diameter gradually became thinner, and the mycorrhizal infection rate gradually increased. Root morphology and architecture of J. mandshurica would undergo adaptive changes under shade, adapting to the shading environment by expanding specific root length, specific surface area, branching ratio and branching intensity. Under phosphorus limitation, root system of J. mandshurica would increase phosphorus absorption through symbiosis with mycorrhizal fungi. When J. mandshurica was artificially regenerate in forest land with a light transmittance of 35%, root morphology and architecture would adapt to the shading environment. The symbiosis between J. mandshurica and mycorrhizal fungi would be enhanced under phosphorus limitation, which could improve phosphorus absorption of roots.


Subject(s)
Juglans , Mycorrhizae , Phosphorus, Dietary , Plant Roots , Phosphorus , Fertilizers , Soil
4.
Ying Yong Sheng Tai Xue Bao ; 31(2): 373-380, 2020 Feb.
Article in Chinese | MEDLINE | ID: mdl-32476328

ABSTRACT

The whole root excavation method was used to examine root configuration of Juglans mandshurica, with the age of 5-6 years in three habitats (forest edge, gap, and canopy) in a secondary forest on the western part of Zhangguangcailing Mountains. Root structure and fine root function were measured. The root topological index, average joint length, cross-sectional area ratio before and after root branching were calculated and fine root chemical compositions were analyzed. Roots of J. mandshurica at forest edge tended to be dichotomous branch (Topological index:TI=0.68), that under the canopy were herringbone-like branch (TI=0.79), and the gap was between the two (TI=0.72). The average connection length of roots among the three habitats was not significant. The cross-sectional area ratio of roots before and after root branching in three habitats was 1.06, 1.04 and 1.07, respectively, which was not affected by root diameter, in accordance with the Leonardo da Vinci rule. For the same order fine root in different habitats, its length and specific surface area gradually increased from the edge of the forest to the canopy. The N content decreased first and then increased, while the C content and C/N increased first and then decreased. From the forest edge to the gap and to the under canopy, roots tended to move from the dichotomous branch to the herringbone-like branch by reducing the overlap between the secondary branches and roots, increasing specific root length, specific surface area and changing the contents of C and N to cope with environmental change and improve nutrient absorption efficiency.


Subject(s)
Juglans , China , Ecosystem , Forests , Plant Roots
6.
Ying Yong Sheng Tai Xue Bao ; 22(8): 1999-2004, 2011 Aug.
Article in Chinese | MEDLINE | ID: mdl-22097360

ABSTRACT

One-year-old birch (Betula platyphylla) and larch (Larix olgensis) seedlings were respectively planted in pots with the soils taken from 35-year-old pure birch and larch plantations, and the seedlings growth, biomass increment, foliar nutrient content, and soil nutrient status were monitored, aimed to evaluate the fertility levels of the two soils and the possible interspecific interaction in mixed larch-birch forest. Birch soil had significantly higher contents of total N and available N than larch soil, while larch soil had significantly higher contents of total P, available P, and total K than birch soil (P < 0.05). In the first growth season, the height and collar diameter growth and the biomass accumulation of birch seedlings growing on birch soil were 69%, 52%, and 65% (P < 0.05) higher than those growing on larch soil, and the larch seedlings also had 12%, 8%, and 37% gains of the indices, respectively. The foliar N concentration of both larch and birch seedlings growing on birch soil was higher than that on larch soil, while the foliar P concentration was higher when the seedlings were growing on larch soil than on birch soil. The birch soil had higher content of available N because of the higher litterfall, while the larch soil had greater available P because of the higher P mobilizing effect. It was predicted that in mixed birch-larch forest, the complementary interaction of soil N and P could benefit the growth of the two tree species.


Subject(s)
Betula/growth & development , Larix/growth & development , Nitrogen/analysis , Phosphorus/analysis , Soil/analysis , Ecosystem , Seedlings/growth & development
7.
Ying Yong Sheng Tai Xue Bao ; 22(12): 3138-44, 2011 Dec.
Article in Chinese | MEDLINE | ID: mdl-22384579

ABSTRACT

In this paper, the Betula platyphylla root-, branch-, and foliage aqueous extracts and Larix olgensis root-, branch-, foliage-, and bark aqueous extracts over a range of concentrations 5.0, 12.5, 25.0, 50.0, and 100.0 mg x mL(-1) were used to study their interspecific allelopathic effect on the seed germination and seedling growth of the two tree species. All the L. olgensis organs' extracts, except its root extracts at concentration 5.0 mg x mL(-1), had inhibition effect on B. platyphylla seed germination rate, which was 54%, 58%, 59%, and 66% under the effects of L. olgensis foliage-, branch-, bark-, and root extracts, respectively, as compared with the control. With increasing concentration, the inhibition effect of L. olgensis root- and branch extracts increased while that of L. olgensis foliage- and bark extracts decreased. The L. olgensis organs' extracts, especially the foliage extracts at concentration 100.0 mg x mL(-1), had strong inhibition effect on B. platyphylla seed radicle- and hypocotyl length growth, with a decrement of 38% and 55% (P < 0.05), respectively. L. olgensis branch- and foliage extracts promoted, but root- and bark extracts inhibited B. platyphylla seedling growth and biomass production. B. platyphylla organs' extracts promoted L. olgensis seed germination, root- and branch extracts promoted hypocotyl length growth, but foliage extracts at 50.0 and 100.0 mg x mL(-1) decreased the hypocotyl length growth by 27% and 28% (P < 0.05), respectively. B. platyphylla organs' extracts mainly promoted L. olgensis seedling growth, with the height- and collar diameter growth and biomass accumulation at B. platyphylla foliage extracts concentration 5.0 mg x mL(-1) increased by 54%, 60%, and 100% (P < 0.05), respectively. Our results suggested that there existed obvious allelopathic effect between B. platyphylla and L. olgensis, and thus, mixed planting B. platyphylla and L. olgensis could have promotion effects on the growth of the two tree species.


Subject(s)
Betula/chemistry , Germination/drug effects , Larix/chemistry , Pheromones/pharmacology , Seeds/growth & development , Pheromones/isolation & purification , Species Specificity
8.
Ying Yong Sheng Tai Xue Bao ; 20(3): 549-54, 2009 Mar.
Article in Chinese | MEDLINE | ID: mdl-19637590

ABSTRACT

This paper studied the effects of foliar spraying spermidine and spermine on the leaf antioxidant system of Celastrus orbiculatus under soil NaHCO3 stress. The results showed that under the stress, spraying spermidine and spermine could significantly decrease the leaf O2-* production rate, H2O2 and MDA contents, and electrolyte leakage of C. orbiculatus (P < 0.05). Spraying spermidine increased the leaf SOD, CAT, POD and APX activities and GSH, CAR and Pro contents obviously, but had no effect on leaf AsA content. Spraying spermine also increased leaf POD and APX activities and GSH, CAR and Pro contents obviously, but had lesser effect on leaf SOD activity and AsA content, and even, caused a significant decrease in leaf CAT activity. In the meantime, spermidine and spermine effectively improved the growth of C. orbiculatus seedlings. It was suggested that under soil NaHCO3 stress, exogenous spermidine and spermine could improve the functions of membrane protective system and decrease the O2-* accumulation in C. orbiculatus leaves, and consequently, increase the C. orbiculatus tolerance to NaHCO3 exposure.


Subject(s)
Celastrus/metabolism , Sodium Bicarbonate/pharmacology , Spermidine/pharmacology , Spermine/pharmacology , Superoxide Dismutase/metabolism , Celastrus/physiology , Peroxidases/metabolism , Soil/analysis , Stress, Physiological
9.
Ying Yong Sheng Tai Xue Bao ; 20(12): 2905-10, 2009 Dec.
Article in Chinese | MEDLINE | ID: mdl-20353055

ABSTRACT

Red pine (Pinus resinosa) is one of the most important tree species for timber plantation in North America, and preliminary success has been achieved in its introduction to the mountainous area of Northeast China since 2004. In order to expand its growth area in other parts of Northeast China, a pot experiment was conducted to study the adaptability of this tree species to varying soil acidity. P. resinosa seedlings were grown in soils with different acidity (pH = 4.5, 5.5, 6.5, 7.5, and 8.0) to test the responses of their photosynthesis and chlorophyll fluorescence parameters to soil pH levels, and the appropriate soil acidity was evaluated. Dramatic responses in chlorophyll a and b contents, Pn and chlorophyll fluorescence parameters (Fo, Fm, Fv, Fv/Fm, and phi(PS II)) were detected under different soil acidity (P < 0.05), with the highest chlorophyll content and Pn under soil pH 5.5, and significantly lower chlorophyll content and Pn under soil pH 7.5 and 8.0. The chlorophyll content and Pn were 41% and 50%, and 61% and 88% higher under soil pH 5.5 than under soil pH 7.5 and 8.0. The seedlings had a significant photosynthetic inhibition under soil pH 7.5 and 8.0, but the highest Fv/Fm and phi (PS II) under soil pH 5.5. Comparing with those under soil pH 7.5 and 8.0, the Fv/Fm and phi (PS II) under soil pH 5.5 were 8% and 12%, and 22% and 35% higher, respectively. It was suggested that soil pH 5.5 was most appropriate for P. resinosa growth.


Subject(s)
Chlorophyll/analysis , Photosynthesis/physiology , Pinus/physiology , Seedlings/physiology , Soil/analysis , Fluorescence , Hydrogen-Ion Concentration
10.
Proc Natl Acad Sci U S A ; 105(32): 11311-6, 2008 Aug 12.
Article in English | MEDLINE | ID: mdl-18678888

ABSTRACT

Recombinant immunotoxins are hybrid proteins composed of an Fv that binds to a tumor antigen fused to a bacterial or plant toxin. Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes.


Subject(s)
ADP Ribose Transferases/genetics , ADP Ribose Transferases/immunology , Antibodies/genetics , Antibodies/immunology , Bacterial Toxins/genetics , Bacterial Toxins/immunology , Enterotoxins/genetics , Enterotoxins/immunology , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Exotoxins/genetics , Exotoxins/immunology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Virulence Factors/genetics , Virulence Factors/immunology , ADP Ribose Transferases/therapeutic use , Amino Acid Substitution/immunology , Animals , Antibodies/therapeutic use , Bacterial Toxins/therapeutic use , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/immunology , Enterotoxins/therapeutic use , Exotoxins/therapeutic use , Humans , Leukemia, Hairy Cell/drug therapy , Leukemia, Hairy Cell/immunology , Mice , Mice, Inbred BALB C , Mice, SCID , Mutation, Missense/immunology , Rabbits , Recombinant Fusion Proteins/therapeutic use , Virulence Factors/therapeutic use , Pseudomonas aeruginosa Exotoxin A
11.
Ying Yong Sheng Tai Xue Bao ; 19(1): 65-70, 2008 Jan.
Article in Chinese | MEDLINE | ID: mdl-18419073

ABSTRACT

An in situ field experiment with lysimeter was conducted to study the effects of different fertilizations on the nutrient leaching loss from brown soil in the growth season of summer maize. The results showed that abundant rainfall and irrigation were the main factors affecting the leaching loss. The leaching amount was higher in the early growth period of summer maize, but decreased after then. The difference among different fertilization treatments also decreased with maize growth. Comparing with N fertilization, wheat stalk plus N application intensified the leaching. During the growth period of summer maize, the NO3- -N content in leached water in fertilization treatments had two peaks, while the NH4+ -N content had a trend of increased first and decreased then. The leaching loss of soil N was mainly in the form of NO3- -N. The accumulative leaching loss of NO3- -N was 12.90-46.53 kg * hm(-2), and that of NH4+ -N was 1.66-5.11 kg x hm(-2), both of which increased with increasing N application rate. The leaching rate of soil N was 6.53%-13.07% higher in treatment wheat stalk plus N application than in treatments of N fertilization, and 3.66%-10.10% higher in low N treatments than in high N treatments. The accumulative leaching loss of available P was only 0.148-0.235 kg x hm(-2), while that of available K was 7.08-13.00 kg x hm(-2). In the late growth period of summer maize, wheat stalk plus N application increased the leaching loss of soil available P and K, while nitrogen application affected it slightly.


Subject(s)
Fertilizers , Nitrogen/analysis , Quaternary Ammonium Compounds/analysis , Soil/analysis , Zea mays/growth & development , Phosphorus/analysis , Rain , Seasons
12.
Guang Pu Xue Yu Guang Pu Fen Xi ; 27(5): 961-5, 2007 May.
Article in Chinese | MEDLINE | ID: mdl-17655114

ABSTRACT

The technical pure azo dye FRL was purified by recrystallization with the solvent composed of ethanol and water whose volume ratio is 1:1. The azo dye FRLP was obtained by coincidence reaction with phen after reoxidation reaction by purified FRL and sodium nitrite, which can be cooperated with Cu2+. And at room temperature the UV-Vis spectrum of FRLP-Cu2+ was studied. The form of the complex was confirmed by successive changing equal number of moles, which is in the B-R solution from pH 6 to pH 9, and the ratio of the complex (Cu2+:FRLP) is 1:2. In the B-R solution (pH 8.8) the mol absorption parameter of the complex is epsilon590 nm = 9.5 x 10(4) L x mol(-1) x cm(-1), and the apparent stable constant is K = 5.12 x 10(12). The property of ultraviolet band spectrum of FRLP-Cu2+ was studied, showing that the aqueous solution of the complex can absorb the ultraviolet radiation strongly from 200 nm to 305 nm. The complex mixing with PVAL can also absorb ultraviolet radiation strongly. At the maximum absorption wavelength in the visible zone and laid parallelly with the optical axis, the transmission of the single slice is 45%-50%, the transmission of two slices laid vertically is zero from 200 nm to 325 nm, and the averaged transmission from 325 nm to 400 nm is 10%.

13.
Bioconjug Chem ; 18(3): 773-84, 2007.
Article in English | MEDLINE | ID: mdl-17346030

ABSTRACT

Recombinant immunotoxins exhibit targeting and cytotoxic functions needed for cell-specific destruction. However, antitumor efficacy, safety, and pharmacokinetics of these therapeutics might be improved by further macromolecular engineering. SS1P is a recombinant anti-mesothelin immunotoxin in clinical trials in patients with mesothelin-expressing tumors. We have modified this immunotoxin using several PEGylation strategies employing releasable linkages between the protein and the PEG polymers, and observed superior performance of these bioconjugates when compared to similar PEG derivatives bearing permanent linkages to the polymers. PEGylated derivatives displayed markedly diminished cytotoxicity on cultured mesothelin-overexpressing A431-K5 cells; however, the releasable PEGylated immunotoxins exhibited increased antitumor activity in A431-K5 xenografts in mice, with a diminished animal toxicity. Most significantly, complete tumor regressions were achievable with single dose administration of the bioconjugates but not the native immunotoxin. Pharmacokinetic analysis of the releasable PEGylated derivatives in mice demonstrated an over 80-fold expansion of the area under the curve exposure of bioactive protein when compared to native immunotoxin. A correlation in degree of derivatization, release kinetics, and polymer size with potency was observed in vivo, whereas in vitro cytotoxicity was not predictive of efficacy in animal models. The potent antitumor efficacy of the releasable PEGylated mesothelin-targeted immunotoxins was not exhibited by similar untargeted PEG immunotoxins in this model. Since the bioconjugates can also exhibit the attributes of passive targeting via enhanced permeability and retention, this is the first demonstration of a pivotal role of active targeting for immunotoxin bioconjugate efficacy.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacokinetics , Carcinoma/drug therapy , Immunotoxins/chemistry , Immunotoxins/pharmacokinetics , Membrane Glycoproteins/antagonists & inhibitors , Polyethylene Glycols/chemistry , Animals , Antibodies, Monoclonal/therapeutic use , Carcinoma/metabolism , GPI-Linked Proteins , Humans , Immunotoxins/therapeutic use , Mesothelin , Mice , Mice, Inbred BALB C , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Xenograft Model Antitumor Assays
14.
Ying Yong Sheng Tai Xue Bao ; 18(12): 2681-6, 2007 Dec.
Article in Chinese | MEDLINE | ID: mdl-18333439

ABSTRACT

Soil samples were collected from forested, clear-cut, and grassy riparian zones under forest background and from forested and barren riparian zones under cropland background in the Maoershan mountainous region of China. The samples were incubated in laboratory, and their denitrification potentials were determined by nitrate-deduction method. The results showed that under crop-land background, soil denitrification rate was the highest in forested riparian zone and the lowest in barren riparian zone, with the deduction rate of nitrate varied from 46.79%-91.13% and 15.64% -81.84%, respectively. Under forest background, soil denitrification rate decreased in the order of clearcut > forested > grassy riparian zone, with the deduction rate of nitrate being 42.06%-90.39%, 28.24%-85.73% and 21.44%-83.11%, respectively. The denitrification rate was higher in subsurface layer than in deeper layer, and the denitrification potential was limited by the available carbon and nitrate, being the greatest in the forested riparian zone under cropland background.


Subject(s)
Ecosystem , Nitrogen/chemistry , Poaceae/growth & development , Soil/analysis , Trees/growth & development , China , Environmental Monitoring , Nitrates/analysis , Nitrogen/analysis , Soil Microbiology
15.
Ying Yong Sheng Tai Xue Bao ; 18(11): 2611-7, 2007 Nov.
Article in Chinese | MEDLINE | ID: mdl-18260472

ABSTRACT

Highland soil nitrogen can enter adjacent water body via erosion and leaching, being one of the important pollutants in terrestrial water bodies. Riparian buffer zone is a transitional zone between highland and its adjacent water body, and a healthy riparian buffer zone can retain and transform the incoming soil N through physical, biological, and biochemical processes. In this paper, the major pathways through which soil nitrogen enters terrestrial water body and the mechanisms the nitrogen was retained and transformed in riparian buffer zone were introduced systematically, and the factors governing the nitrogen retaining and transformation were analyzed from the aspects of hydrological processes, soil characters, vegetation features, and human activities. The problems existing in riparian buffer zone study were discussed, and some suggestions for the further study in China were presented.


Subject(s)
Ecosystem , Nitrogen/analysis , Soil/analysis , Water Pollutants, Chemical/analysis , Biodegradation, Environmental , Nitrogen/metabolism , Plant Development , Plants/metabolism , Water/analysis , Water Movements , Water Pollutants, Chemical/metabolism
16.
Guang Pu Xue Yu Guang Pu Fen Xi ; 26(8): 1508-12, 2006 Aug.
Article in Chinese | MEDLINE | ID: mdl-17058958

ABSTRACT

The interaction of alizarin yellow R(AYR) and bovine serum albumin (BSA) was investigated by fluorescence method in alkali buffer solution. It was shown that AYR had a powerful ability to quench the BSA fluorescence at excitation and emission wavelengths of lambda(ex) = 393 nm and lambda(em) = 641 nm in the medium solution of pH 11.00, and there were five binding sites of AYR to BSA; The combination reaction of AYR with BSA was a static quenching process, and from the effects of temperature on the fluorescence quenching rate of AYR-BSA and the Stern-Volmer quenching constant (K(SV)) and the Lineweaver-Burk quenching constant (K(LB)), the binding constant was calculated to be K = 1.6 x 10(4) L x mol(-1); as the enthalpy change deltaH(theta) < 0 and entropy change deltaS(theta) < 0, and AYR has an ability to quench the BSA-CBBG fluorescence, it can be deduced that the Van der Walls force and hydrogen bond are the main binding forces between AYR and BSA.


Subject(s)
Azo Compounds/chemistry , Coloring Agents/chemistry , Fluorescence , Serum Albumin, Bovine/chemistry , Spectrometry, Fluorescence/methods , Alkalies/chemistry , Animals , Azo Compounds/metabolism , Cattle , Coloring Agents/metabolism , Hydrogen-Ion Concentration , Kinetics , Molecular Structure , Protein Binding , Serum Albumin, Bovine/metabolism , Solutions/chemistry , Thermodynamics
18.
J Leukoc Biol ; 80(5): 1175-82, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16923920

ABSTRACT

Highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection dramatically suppresses viral load, leading to marked reductions in HIV-1 associated morbidity and mortality. However, infected cell reservoirs and low-level replication persist in the face of suppressive HAART, leading invariably to viral rebound upon cessation of treatment. Toxins engineered to target the Env glycoprotein on the surface of productively infected cells represent a complementary strategy to deplete these reservoirs. We described previously highly selective killing of Env-expressing cell lines by CD4(178)-PE40 and 3B3(Fv)-PE38, recombinant derivatives of Pseudomonas aeruginosa exotoxin A containing distinct targeting moieties against gp120. In the present report, we compare the in vitro potency and breadth of these chimeric toxins against multiple clinical HIV-1 isolates, replicating in biologically relevant primary human target cell types. In PBMCs, 3B3(Fv)-PE38 blocked spreading infection by all isolates examined, with greater potency than CD4(178)-PE40. 3B3(Fv)-PE38 also potently inhibited spreading HIV-1 infection in primary macrophages. Control experiments demonstrated that in both target cell types, most of the 3B3(Fv)-PE38 activity was due to selective killing of infected cells, and not merely to neutralization by the antibody moiety of the chimeric toxin. High-dose treatment of rhesus macaques with 3B3(Fv)-PE38 did not induce liver toxicity, whereas equivalent dosage of CD4(178)-PE40 induced mild hepatotoxicity. These findings highlight the potential use of 3B3(Fv)-PE38 for depleting HIV-infected cell reservoirs persisting in the face of HAART.


Subject(s)
Anti-HIV Agents/pharmacology , HIV/drug effects , Immunotoxins/pharmacology , Leukocytes, Mononuclear/drug effects , Macrophages/drug effects , Animals , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Chemical and Drug Induced Liver Injury , Dose-Response Relationship, Drug , Exotoxins/administration & dosage , Exotoxins/adverse effects , Exotoxins/pharmacology , HIV/isolation & purification , Humans , Immunotoxins/administration & dosage , Immunotoxins/adverse effects , Injections, Intravenous , Leukocytes, Mononuclear/virology , Liver Diseases/pathology , Macaca , Macrophages/virology , Models, Animal , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacology , Structure-Activity Relationship , Virus Replication/drug effects
19.
Clin Cancer Res ; 11(10): 3814-20, 2005 May 15.
Article in English | MEDLINE | ID: mdl-15897581

ABSTRACT

PURPOSE: Mesothelin is a glycosyl-phosphatidylinositol-anchored glycoprotein present on the cell surface. Mesothelin is a differentiation antigen that is highly expressed on mesothelioma, ovarian cancer, and pancreatic cancer. The existence of a spontaneous humoral immune response to mesothelin in humans has not been fully studied. Here we addressed the issue of whether mesothelin elicits a humoral immune response in patients with mesothelioma and ovarian cancer. EXPERIMENTAL DESIGN: Using an ELISA, we analyzed immunoglobulin G antibodies specific for mesothelin in sera from patients with mesothelioma and epithelial ovarian cancer. Tumor specimens were examined by immunohistochemistry for mesothelin protein expression. RESULTS: Elevated levels of mesothelin-specific antibodies were detected in the sera of 39.1% of patients with mesothelioma (27 of 69 patients) and 41.7% with epithelial ovarian cancer (10 of 24 patients) when compared with a normal control population (44 blood donors; P < 0.01 for both mesothelioma and ovarian cancer). We also found that 53% to 56% of patients with mesothelin immunostaining-positive mesothelioma and ovarian cancer had antibodies specific for mesothelin, whereas only 0% to 8% of patients with negative mesothelin immunostaining had detectable mesothelin-specific antibodies (chi(2) test: P < 0.01 for mesothelioma and P = 0.025 for ovarian cancer). CONCLUSIONS: Our findings indicate that mesothelin is a new tumor antigen in patients with mesothelioma and ovarian cancer and the immunogenicity of mesothelin is associated with its high expression on the tumor cells. Mesothelin represents an excellent target for immune-based therapies.


Subject(s)
Antibody Formation/immunology , Membrane Glycoproteins/pharmacology , Mesothelioma/immunology , Ovarian Neoplasms/immunology , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm , Blood Proteins , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , GPI-Linked Proteins , Humans , Immunoglobulin G/analysis , Immunohistochemistry , Immunotherapy , Male , Mesothelin , Middle Aged
20.
J Am Soc Nephrol ; 16(4): 1013-23, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15758046

ABSTRACT

This study aimed to generate a mouse model of acquired glomerular sclerosis. A model system that allows induction of podocyte injury in a manner in which onset and severity can be controlled was designed. A transgenic mouse strain (NEP25) that expresses human CD25 selectively in podocytes was first generated. Injection of anti-Tac (Fv)-PE38 (LMB2), an immunotoxin with specific binding to human CD25, induced progressive nonselective proteinuria, ascites, and edema in NEP25 mice. Podocytes showed foot process effacement, vacuolar degeneration, detachment and downregulation of synaptopodin, WT-1, nephrin, and podocalyxin. Mesangial cells showed matrix expansion, increased collagen, mesangiolysis, and, later, sclerosis. Parietal epithelial cells showed vacuolar degeneration and proliferation, whereas endothelial cells were swollen. The severity of the glomerular injury was LMB2 dose dependent. With 1.25 ng/g body wt or more, NEP25 mice developed progressive glomerular damage and died within 2 wk. With 0.625 ng/g body wt of LMB2, NEP25 mice survived >4 wk and developed focal segmental glomerular sclerosis. Thus, the study has established a mouse model of acquired progressive glomerular sclerosis in which onset and severity can be preprogrammed by experimental maneuvers.


Subject(s)
Disease Models, Animal , Genetic Engineering , Glomerulosclerosis, Focal Segmental/physiopathology , Mice , Animals , Antibodies, Monoclonal , Exotoxins , Glomerulosclerosis, Focal Segmental/genetics , Glomerulosclerosis, Focal Segmental/pathology , Humans , Imaging, Three-Dimensional , Immunotoxins , Kidney/metabolism , Kidney/pathology , Kidney Glomerulus/ultrastructure , Mice, Transgenic , Microscopy, Electron , Microscopy, Electron, Scanning , Nephrotic Syndrome/chemically induced , Receptors, Interleukin-2/metabolism , Severity of Illness Index
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