Showing papers by "Rakesh K. Jain published in 1999"

Transport of molecules, particles, and cells in solid tumors.

Abstract: Extraordinary advances in molecular biology and biotechnology have led to the development of a vast number of therapeutic anti-cancer agents. To reach cancer cells in a tumor, a blood-borne therapeutic molecule, particle, or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, which it then must migrate through. Unfortunately, tumors often develop in ways that hinder these steps. The goal of research in this area is to analyze each of these steps experimentally and theoretically and integrate the resulting information into a unified theoretical framework. This paradigm of analysis and synthesis has fostered a better understanding of physiological barriers in solid tumors and aided in the development of novel strategies to exploit and/or overcome these barriers for improved cancer detection and treatment.

Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor.

Abstract: The goal of this investigation was to measure changes in vascular permeability, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEGF), placenta growth factor (PIGF-1 and PIGF-2), or basic fibroblast growth factor (bFGF). Two human and two murine tumors were implanted in the dorsal skin chamber or cranial window. Vascular permeability to BSA (approximately 7 nm in diameter) and extravasation of polyethylene glycol-stabilized long-circulating liposomes (100-400 nm) and latex microspheres (approximately 800 nm) were determined by intravital microscopy. Vascular permeability was found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) significantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increase permeability in pial vessels, suggesting that different tissues exhibit different dose thresholds for VEGF activity. Furthermore, VEGF superfusion (1000 ng/ml) increased vascular permeability to albumin in a hypopermeable human glioma xenograft in cranial window, whereas VEGF superfusion (10-1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumors grown in dorsal skin chamber. Interestingly, low-dose VEGF treatment (10 ng/ml) doubled the maximum pore size (from 400 to 800 nm) and significantly increased the frequency of large (400 nm) pores in human colon carcinoma xenografts. PIGF-1, PIGF-2, or bFGF did not show any significant effect on permeability or pore size in tumors. These findings suggest that exogenous VEGF may be useful for augmenting the transvascular delivery of larger antineoplastic agents such as gene targeting vectors and encapsulated drug carriers (typical range, 100-300 nm) into tumors.

Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications.

Abstract: Elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors. The etiology of tumor interstitial hypertension is poorly understood. We have postulated that the solid stress generated by tumor cells growing in a confined space compresses blood vessels and increases tumor microvascular pressure and IFP. To test the hypothesis that neoplastic cell loss would decompress blood vessels and lower IFP, we induced apoptosis in tumors with paclitaxel and docetaxel. Taxanes inhibited the growth of the murine mammary carcinoma (MCa-IV) and of the human soft tissue sarcoma (HSTS-26T). Taxanes induced apoptosis and reduced the density of intact neoplastic cells in both MCa-IV and HSTS-26T. To determine whether neoplastic cell loss decompressed blood vessels, we measured the diameter of tumor vessels in HSTS-26T tumors implanted in transparent dorsal skin fold chambers. At 48 and 96 h after paclitaxel, the diameter of tumor vessels was significantly increased. The increase in vascular diameters was associated with reductions in microvascular pressure and IFP. The changes in neoplastic cell density and IFP were also correlated. In the human glioblastoma U87, which is resistant to paclitaxel, the IFP and cellular density were not modified by paclitaxel treatment. Collectively, these results support the hypothesis that solid stress generated by neoplastic cell proliferation increases vascular resistance and IFP. The increase in vessel diameter induced by paclitaxel and docetaxel suggests that taxanes could improve tumor response by increasing the vascular surface area for delivery of therapeutic agents.

Enhancement of fluid filtration across tumor vessels: Implication for delivery of macromolecules

Abstract: Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulation of tumor MVP enhances transvascular fluid filtration, leading to a 40% increase in total uptake of the specific antibody within 4 hr of its administration. Conversely, neither continuous nor periodic infusion of AII induced any increase in uptake of nonspecific antibodies. Strategies to improve delivery of macromolecules and limitations of this approach are identified.

Degradation of phenanthrene by different bacteria: evidence for novel transformation sequences involving the formation of 1-naphthol

Abstract: Four polycyclic aromatic hydrocarbon (PAH)-degrading bacteria, namely Arthrobacter sulphureus RKJ4, Acidovorax delafieldii P4-1, Brevibacterium sp. HL4 and Pseudomonas sp. DLC-P11, capable of utilizing phenanthrene as the sole source of carbon and energy, were tested for its degradation using radiolabelled phenanthrene. [9-14C]Phenanthrene was incubated with microorganisms containing 100 mg/l unlabelled phenanthrene and the evolution of 14CO2 was monitored: within 18 h of incubation, 30.1, 35.6, 26.5 and 2.1% of the recovered radiolabelled carbon was degraded to 14CO2 by RKJ4, P4-1, HL4 and DLC-P11, respectively. When mixtures of other PAHs such as fluorene, fluoranthene and pyrene, in addition to phenanthrene, were added as additional carbon sources, there was a 36.1 and 20.6% increase in 14CO2 production from [9-14C]phenanthrene in the cases of RKJ4 and HL4, respectively, whereas P4-1 and DLC-P11 did not show any enhancement in 14CO2 production. Although, a combination of many bacteria enhances the degradation of organic compounds, no enhancement in the degradation of [9-14C]phenanthrene was observed in mixed culture involving all four microorganisms together. However, when different PAHs, as indicated above, were used in mixed culture, there was a 68.2% increase in 14CO2 production. In another experiment, the overall growth rate of P4-1 on phenanthrene could be enhanced by adding the non-ionic surfactant Triton X-100, whereas RKJ4, HL4 and DLC-P11 did not show any enhancement in growth. Pathways for phenanthrene degradation were also analysed by thin-layer chromatography, gas chromatography and gas chromatography-mass spectrometry. Common intermediates such as o-phthalic acid and protocatechuic acid were detected in the case of RKJ4 and o-phthalic acid was detected in the case of P4-1. A new intermediate, 1-naphthol, was detected in the cases of HL4 and DLC-P11. HL4 degrades phenanthrene via 1-hydroxy-2-naphthoic acid, 1-naphthol and salicylic acid, whereas DLC-P11 degrades phenanthrene via the formation of 1-hydroxy-2-naphthoic acid, 1-naphthol and o-phthalic acid. Both transformation sequences are novel and have not been previously reported in the literature. Mega plasmids were found to be present in RKJ4, HL4 and DLC-P11, but their involvement in phenanthrene degradation could not be established.

Tumor–host interactions in the gallbladder suppress distal angiogenesis and tumor growth: Involvement of transforming growth factor β1

Abstract: Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

Return of lymphatic function after flap transfer for acute lymphedema.

Abstract: OBJECTIVE: The goals of this work were to develop animal models of lymphedema and tissue flap transfer, and to observe physiologic changes in lymphatic function that occur in these models over time, both systemically with lymphoscintigraphy (LS) and locally using fluorescence microlymphangiography (FM) SUMMARY BACKGROUND DATA: Although lymphedema has been managed by a combination of medical and surgical approaches, no effective long-term cure exists Surgical attempts aimed at reconnecting impaired lymphatic channels or bypassing obstructed areas have failed METHODS: The tails of rats (A groups) and mice (B groups) were used because of their different features Lymphedema was created by ligation of the lymphatics at the tail base and quantified by diameter measurements there In the experimental group, rectus abdominis myocutaneous flap was transferred across the ligation In addition to the ligation (A1 and B1) and ligation + flap (A2 and B2) groups, three control groups were included: sham flap with ligation (B4), sham flap alone (B5), and normal (A3 and B3) animals Observations were made at weekly time points for lymphatic function and continuity RESULTS: Lymphedema was successfully created in the mouse ligation groups (B1 and B4) and sustained for the entire length of observation (up to 14 weeks) Lymphatic continuity was restored in those animals with transferred flaps across the ligation site (A2 and B2), as seen both by LS and FM Sham flaps did not visibly affect lymphatic function nor did they cause any visible swelling in the tail CONCLUSIONS: Acute lymphedema developing after ligation of tail lymphatics in mice can be prevented by myocutaneous flap transfer Restored lymphatic continuity and function were demonstrable using lymphoscintigraphy and fluorescence microlymphangiography

Understanding barriers to drug delivery: high resolution in vivo imaging is key.

Abstract: In this issue of Clinical Cancer Research , Lankelma et al. [(1)][1] report on doxorubicin gradients in biopsies of breast tumors from patients. The gradients are pronounced 2 h after i.v. injection and become negligible 24 h later. Gradients of anthracyclins in tumor spheroids [(2][2] [, 3)][3] ,

Stereospecific Solution- and Solid-Phase Glycosylations. Synthesis of β-Linked Saccharides and Construction of Disaccharide Libraries Using Phenylsulfenyl 2-Deoxy-2-Trifluoroacetamido Glycopyranosides as Glycosyl Donors1

Abstract: An efficient strategy to construct β-O-2-amino-2-deoxyglycopyranosidic linkages using glycosyl sulfoxides is demonstrated. Phenylsulfenyl 2-deoxy-2-trifluoroacetamido glycopyranosides were found to be reactive glycosyl donors in both solid- and solution-phase glycosylations, affording the corresponding β-glycosides exclusively and in high yield. The trifluoroacetamido group was removed under mild conditions, allowing orthogonal derivatization of multiple protected amino groups on an oligosaccharide or glycoconjugate. On the basis of the results with these glycosyl donors, a solid-phase β-linked disaccharide library was constructed. The scope and flexibility of this approach will be discussed.

Cells shed from tumours show reduced clonogenicity, resistance to apoptosis, and in vivo tumorigenicity.

Abstract: The goal of this study was to compare growth characteristics of cells shed from a tumour with the native tumour cells. The human colon adenocarcinoma LS174T and its highly metastatic subline LS LiM 6 were grown as tissue-isolated tumours in nude mice and perfused to collect shed cells. The tumours were then excised and prepared into single-cell suspensions. Clonogenicity in 0.3-0.9% agarose, apoptotic fraction, and in vivo tumorigenicity were determined for each population. In both tumour lines, shed cells were less clonogenic, more apoptotic and less tumorigenic than cells isolated directly from their native tissue. These findings suggest that shed cells have a low metastatic potential compared to native tumour cells, most likely because they represent an apoptotic population.

Discovery of novel disaccharide antibacterial agents using a combinatorial library approach.

Abstract: The increase in bacterial resistance to conventional chemotherapy has resulted in a resurgent interest in the discovery and development of antibacterial agents.1-4 The search for novel antibiotics active against resistant phenotypes is increasingly focused on identification of novel chemotypes or antibiotics with novel mechanisms of action.5,6 The bacterial cell wall is an attractive target for developing novel antibacterial agents. The cell wall of both Gram-positive and Gram-negative bacteria is essential for cell viability. Of the many enzymes involved in bacterial cell wall biosynthesis, only transpeptidases responsible for cross-linking the growing glycan chain are targeted by existing clinically useful chemotherapeutic agents. As a strategy for developing novel antibacterial agents that would be effective against resistant phenotypes, we focused on the transglycosylase enzyme activity associated with the penicillin-binding proteins (PBPs). This activity functions to lengthen the peptidoglycan polymer and may also be required to initiate synthesis of a new chain. Our approach for developing novel inhibitors of transglycosylase focused on exploring moenomycin A (1) (Chart 1) as a lead. The moenomycins are a family of natural product antibiotics which are known to inhibit the synthesis of bacterial cell wall peptidoglycan through inhibition of transglycosylase.7-11 Moenomycin A is a pentasaccharide containing a long lipid attached to the reducing sugar (F) through a phosphoglycerate unit. By degradation studies and limited directed analogue synthesis, Welzel and co-workers showed that cell wall inhibitory activity was retained in a disaccharide core structure 2.12-22 In addition, they showed that certain structural elements were important for retaining transglycosylase inhibitory activity. The activity of moenomycin-derived disaccharides encouraged us to investigate the construction and screening of a library of disaccharides related to moenomycin A with the goal of identifying novel bacterial transglycosylase inhibitors. Access to a library of moenomycin disaccharides required that we develop a general solid-phase synthetic strategy that would allow us to explore carbohydrate diversity and chemical diversity at sites known to be linked to biological activity. Welzel had shown that the carbamate at C-3, the amide at C-2′, and the phosphoglycerate moiety at C-1 were important in overall biological activity.12-22 However, structural variations at these sites were never explored. The complexity of the moenomycin disaccharide system in combination with our desire to investigate multiple structural variations combinatorially posed a formidable synthetic challenge. Although solution syntheses of several moenomycin-type disaccharides had been reported by Welzel and others, these syntheses lacked the generality and efficiencynecessaryforconstructingcomplexlibraries.12-22 In this paper, we describe the solid-phase synthesis of a library of moenomycin disaccharide analogues and the identification of novel antibacterial agents from this library. Our basic synthetic approach envisioned constructing appropriately functionalized and protected disaccharide lactols that would allow us to explore modifications at C-1, C-3, and C-2′ and explore limited variation in the * Address for correspondence: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492-7660. E-mail: sofiam@bms.com. © Copyright 1999 by the American Chemical Society

Evidence for plasmid-mediated chemotaxis of Pseudomonas putida towards naphthalene and salicylate.

Abstract: A naphthalene (Nap) and salicylate (Sal) degrading microorganism, Pseudomonas putida RKJ1, is chemotactic towards these compounds. This strain carries a 83 kb plasmid. A 25 kb EcoRI fragment of the plasmid contains the genes responsible for Nap degradation through Sal. RKJ5, the plasmid-cured derivative of RKJ1, is neither capable of degradation nor is chemotactic towards Nap or Sal. The recombinant plasmid pRKJ3, which contained a 25 kb EcoRI fragment, was transferred back into the plasmid-free wild-type strain RKJ5, and the transconjugant showed both degradation and chemotaxis. The recombinant plasmid pRKJ3 was also transferred into motile, plasmid-free P. putida KT2442. The resulting transconjugant (RKJ15) showed chemotaxis towards both Nap and Sal. Two mutant strains carrying deletions in pRKJ3 (in KT2442) with phenotypes Nap- Sal+ and Nap- Sal-, were also tested for chemotaxis. It was found that the Nap- Sal+ mutant strain showed chemotaxis towards Sal only, whereas the Nap- Sal- mutant strain is non-chemotactic towards both the compounds. These results suggest that the metabolism of Nap and Sal may be required for the chemotactic activity.

Creatine and cyclocreatine treatment of human colon adenocarcinoma xenografts: 31P and 1H magnetic resonance spectroscopic studies.

Abstract: Creatine (Cr) and cyclocreatine (cyCr) have been shown to inhibit the growth of a variety of human and murine tumours. The purpose of this study was to evaluate the anti-tumour effect of these molecules in relation to drug accumulation, energy metabolism, tumour water accumulation and toxicity. Nude mice carrying a human colon adenocarcinoma (LS174T) with a creatine kinase (CK) activity of 2.12 units mg−1 protein were fed Cr (2.5% or 5%) or cyCr (0.025%, 0.1% or 0.5%) for 2 weeks and compared with controls fed standard diet. Cr concentrations of 2.5% and 5% significantly inhibited tumour growth, as did 0.1% and 0.5% cyCr. In vivo 31P magnetic resonance spectroscopy (MRS) after 2 weeks of treatment showed an increase in [phosphocreatine (PCr)+phosphocyclocreatine (PcyCr)]/nucleoside triphosphate (NTP) with increasing concentrations of dietary Cr and cyCr, without changes in absolute NTP contents. The antiproliferative effect of the substrates of CK was not related to energy deficiency but was associated with acidosis. Intratumoral substrate concentrations (measured by 1H-MRS) of 4.8 μmol g−1 wet weight Cr (mice fed 2.5% Cr) and 6.2 μmol g−1 cyCr (mice fed 0.1% cyCr) induced a similar decrease in growth rate, indicating that both substrates were equally potent in tumour growth inhibition. The best correlant of growth inhibition was the total Cr or (cyCr+Cr) concentrations in the tissue. In vivo, these agents did not induce excessive water accumulation and had no systemic effects on the mice (weight loss, hypoglycaemia) that may have caused growth inhibition. © 1999 Cancer Research Campaign

Angiogenesis in the huPBL-SCID model of human transplant rejection

Abstract: Background. Angiogenesis is characteristic of chronic inflammatory reactions. The process of angiogenesis is reported to be proinflammatory in part due to enhanced adhesion events and in part due to increased perfusion and permeability to sites of inflammation. However, little is known about the association between angiogenesis and rejection. Methods. Severe combined immune deficient mice are permissive for the growth of human skin allografts and human peripheral blood mononuclear cells (PBMC). Human PBMC were injected into mice by intravenous or intraperitoneal injection. The infiltration of cells and the associated angiogenesis reactions in the skin allografts were analyzed temporally by videomicroscopy and spatially by immunohistochemistry. Results. Human alloreactive mononuclear cells migrated to human skin but not mouse skin within hours after the intravenous infusion of PBMC. Within 3 days, areas of angiogenesis were observed in the skin grafts at the sites of infiltrates. The vessel densities in skin grafts were 24±6 vessels per calibrated grid at baseline on the day of the infusion and increased to 55±16 vessels per calibrated field by day 10. Skin grafts harvested from humanized severe combined immune deficient mice 7-14 days after the intraperitoneal infusion of human PBMC showed a similar increased density of vessels that were spatially associated with mononuclear cell infiltrates. Conclusions. A significant angiogenesis response was associated with the cell infiltrates in the human skin allografts. The onset of angiogenesis appeared after the initial development of localized infiltrates and preceded the development of microvascular destruction. These findings suggest that alloreactive T cells and/or monocytes mediate the angiogenesis response in skin allografts.

CT-guided preoperative needle localization of MR imaging-detected mammographically occult lesions.

Abstract: R esearch has shown that dynamic high-resolution MR imaging of the breast using a dedicated breast coil and IV gadolinium can clinically and mammographically detect occult breast carcinoma [ I 1; delineate the extent of disease in many mammographically detectable or palpable cancers [2]; identify many primary breast lesions in patients presenting with an unknown primary or metastatic axillary lymphadenopathy [3]; and characterize a mammographically or sonographically detected lesion as benign or malignant [4]. MR imaging of the breast has the potential to detect breast cancer earlier than mammography and/or physical examina-

Cellular Membrane Permeability of Anthracyclines Does Not Correlate with Their Delivery in a Tissue-isolated Tumor

Abstract: The clearance of anthracyclines from the vasculature was studied in perfused tissue-isolated tumors. Human tumor lines MCF-7, U87, and LS174T were implanted in the ovarian fat pad of immune-deficient mice and grown isolated from the surrounding tissue. The initial and continuous tissue uptakes of doxorubicin, daunorubicin, and idarubicin were measured. The clearance of these anthracyclines from the perfused vasculature of the tissue-isolated tumor was calculated using BSA as an intravascular marker. The measured clearances ranged from 50-200 microl/min/g tumor tissue, and the fractional clearances were between 0.30 and 0.70. On the basis of the in vitro cellular uptake rates of the anthracyclines, we expected a higher clearance of idarubicin than of doxorubicin. No significant differences were found among the clearances of the anthracyclines or among the tumor lines. The observed similarities in clearance of the anthracyclines was largely explained by differences in their protein binding and tissue diffusion gradients.

Characterization of distinct Gal:3-O-sulfotransferase activities in human tumor epithelial cell lines and of calf lymph node GlcNAc : 6-O-sulfotransferase activity.

Abstract: We found earlier in human breast and colon tumors, an augmented level of Gal : 3-O-sulfotransferase activities showing, respectively, an acceptor preference to blood group T-hapten (Group A enzymes) or Galbeta1,4GlcNAc (Group B enzymes) on the mucin Core 2 structure [Chandrasekaran EV, Jain RK, Vig R, and Matta KL (1997) Glycobiology 7: 753-68]. The present study reports these enzyme activities in human tumor cell lines and additional tumor specimens. The human colon tumor epithelial cell lines, akin to their parent tumors, express Group B enzyme activity. The acceptor specificity and kinetic properties, such as divalent metal ion activation and pH dependent activity profile, of the colon cancer line LS180 enzyme activity are identical to those of colon tissue specimens. Consistent with breast tumor specimens, the Group A enzyme activity is present in human breast tumor epithelial cell lines, with some exceptions. The Gal : 3-O-sulfotransferases show specific binding to Aleuria aurantia lectin, suggesting the presence of asparagine linked carbohydrate chains containing an inner core alpha1,6-fucosyl residue on these enzymes. Calf lymph nodes contain GlcNAc : 6-O-sulfotransferase as well as Group A Gal : 3-O-sulfotransferase activities, which differ in pH dependent profiles, pH optima (7.6 and 7.0, respectively) and the influence of Mn2+.

Methods to potentiate cancer therapies

Abstract: Disclosed are methods for potentiating the anti-cancer properties of an anti-cancer therapy in a mammal by administering with the therapy a compound (such as relaxin or γ-IFN) that has a tissue tensile modulus-reducing property, an ability to reduce the interstitial viscosity of the cancer, an ability to increase the hydraulic conductance of the cancer, or an ability to increase collagen turnover or decrease collagen formation at or near the cancer, where the therapy and the compound are administered at dosages which together are sufficient to destroy, slow, or arrest the cancer. Also disclosed is a method for treating cancer in a mammal involving the administration of relaxin and/or γ-IFN peptides and an anti-cancer therapy to the mammal, where the peptides and the therapy are administered at dosages which together are sufficient to destroy, slow, or arrest the cancer.

In vitro and in vivo quantification of adhesion between leukocytes and vascular endothelium.

Abstract: When a leukocyte enters a blood vessel, it may continue to move with flowing blood, collide with the vessel wall, adhere transiently or stably, and finally extravasate (1). These interactions are governed by both local hydrodynamic and adhesive forces. The former are determined by the vessel diameter, fluid velocity, viscosity, and hematocrit, and the latter by the number, strength and kinetics of bond formation between adhesion molecules, and by surface area of contact (1-6). Cellular deformability affects both types of forces (7-9). Two families of cell adhesion molecules (CAMs) are involved in leukocyte rolling and stable adhesion. In general, the selectins (P, L, and E) mediate rolling, while the IgG superfamily members (ICAM-1 and VCAM-1) on endothelial cells, with their cognate receptors (β(2) and β(1) integrin receptors) on the leukocytes, mediate firm adhesion, with some overlap in these functions (10-12). The expression of CAMs on the endothelial cells and leukocytes can be modulated by cytokines secreted by a variety of cells (e.g., cancer cells, fibroblasts, macrophages) (13,14). Cellular deformability can be modulated by altering the cytoskeleton, membrane, or cytoplasm, with the cytoskeleton playing the dominant role (7,15,16). In this chapter, we describe methods to quantitate cellular deformability in vitro, CAM expression in vitro, leukocyte-endothelial interaction (LEI) in vitro, and LEI in vivo.

Carbohydrate-based scaffold compounds, combinatorial libraries and methods for their construction

Abstract: A compound of structure (I) wherein X is O or S; Z is O or NH; Y is COOH, COOR2, CH2OR3, CH3, or CH(s)Y2(3-s) where Y2 is F, Cl, Br or I, and s is 0, 1, or 2 or Y and one of ZR4 and OR5 are linked to form a 6-membered cyclic acetal; p is O or 1; m is 0 or 1; n is 1 or 2. A library of compounds of structure (II) wherein X is O or S; A1 is a residue of an α-amino acid attached through a terminal amino, a peptide residue comprising residues of from 2 to 10 α-amino acids and attached through a terminal amino, R1O, R1S, R1, R1NH or R1N-alkyl; A2 is a residue of an α-amino acid attached through a terminal carboxyl, a peptide residue comprising residues of from 2 to 10 α-amino acids and attached through a terminal carboxyl, R2SO2, R2NHCO, R2OP(O) (OR6), R2P(O) (OR6) or R2, or A2, A3 and N combine to form a nitrogen heterocycle; A3 is hydrogen when A3 is not combined with A2 and N; A4 is OR4, NHR4, CH2OR4 or CH3; A5 is O, NH or N-alkyl; p, q and r are independently 0 or 1; Y1 and Y2 are independently O or CH2; each of L1 and L2 is independently a difunctional alkyl, aryl, aralkyl, alkanoyl, aroyl or aralkanoyl group; L3 is a single bond, CH2, carbonyl, OP(O) (OR7), NHP(O) (OR7), P(O) (OR7) or (III) wherein W is O, NH, N-alkyl or S, and Z is NH, O or S; m is 0 or 1; and n is 1 or 2.

Thinning and Rupture of Aqueous Surfactant Films on Silica

Abstract: The thinning and rupture of aqueous surfactant films on silica is investigated using the interferometric technique and free bubbles, which approximate flotation more realistically than the captive bubble method. Different rupture mechanisms are observed at different pH values for aqueous films of dodecylamine on silica, explaining the pH dependence of quartz flotation using amine. While at low pH rupture is accompanied by the breaking off of a large drop in the center and subsequent formation of large irregular drops, at high pH ruptured spots grow to large circular drops.

CT portography by direct intrasplenic contrast injection: a new technique

Abstract: Background: The evaluation of percutaneous contrast injection into splenic parenchyma as an alternative technique for computed tomographic (CT) portography in the preoperative assessment of primary hepatobiliary tumors.

Lipid peroxide levels in chronic renal failure.

Abstract: To determine presence of oxidant stress in chronic renal failure and to evaluate the efficacy of vitamin E in its amelioration, we studied 34 patients (Group I, age 32.4 +/- 11 years, M:F 3:1) and 10 healthy controls (Group II, age 27.4 +/- 5 years, M:F 4:1). The difference in baseline values of lipid peroxide (nmol/ml) was statistically significant (Group I 4.19 +/- 1.69, Group II 1.87 +/- 1.39, p = 0.004). Values of vitamin E (mg/l) were also significantly lower in Group I as compared to Group II (12.18 +/- 4.27 vs. 19.32 +/- 2.03, p = 0.003). Serum lipid peroxide values decreased significantly after supplementation with 400 mg/day of vitamin E for six weeks in Group I (4.19 +/- 1.69 to 3.21 +/- 1.13, p = 0.053) but not in Group II (1.87 +/- 1.39 to 1.03 +/- 0.87). Levels of vitamin E increased in both the groups (Group I: 12.18 +/- 4.27 to 16.01 +/- 5.13, Group II: 19.32 +/- 2.03 to 23.21 +/- 1.94, p < 0.005). No significant difference was observed in values of serum creatinine and urea before and after intervention.

Procedes de potentialisation des cancerotherapies

Abstract: L'invention concerne differents procedes de potentialisation des proprietes curatives en cancerotherapie chez un mammifere, qui consistent a administrer au mammifere, simultanement a la therapie, un compose (du type relaxine ou interferon η-IFN) ayant une propriete de reduction de module d'elasticite tissulaire en traction, une capacite de reduction de la viscosite interstitielle du cancer, une capacite d'augmentation de la conductance hydraulique du cancer, ou bien une capacite d'augmentation du renouvellement du collagene ou de diminution de la formation du collagene a l'emplacement du cancer ou pres de cet emplacement. On dose la therapie et le compose de sorte que la combinaison des deux suffise a annihiler, ralentir ou interrompre le cancer. L'invention concerne egalement un procede relatif au traitement du cancer chez un mammifere, qui consiste a administrer les peptides du type relaxine et/ou ηIFN simultanement a la cancerotherapie, en respectant des doses qui, dans la combinaison des deux, suffisent a annihiler, ralentir ou interrompre le cancer.