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R K Jain

Publications and source records attributed to R K Jain.

At least 145 records · Page 8Linked to original sources
PubMed1998

Dynamic T1-weighted magnetic resonance imaging and positron emission tomography in patients with lung cancer: correlating vascular physiology with glucose metabolism.

The management of primary lung cancer relies on sophisticated imaging methods to assist in the diagnosis, staging, and evaluation of tumor regression during treatment. The information provided is generally anatomical in nature, except for that provided by positron emission tomography with [18F]fluorodeoxyglucose, a modality that yields physiological data that have been shown to be useful in identifying neoplasia, based on an elevated glucose metabolic rate. Because the metabolism of malignant tissue depends intimately on neovascularization to provide oxygen and glucose in sufficient quantities to allow tumor growth, the characterization of tumor vascular physiology could be an important tool for assessing and predicting the likely effectiveness of treatment. Our goal was to show the feasibility and practical value of parameters of tumor vascular physiology obtained using dynamic T1-weighted magnetic resonance imaging (MRI), to correlate them with glucose metabolism and to demonstrate changes in these parameters during and after treatment in patients with lung cancer. Parameters of vascular physiology [permeability-surface area (PS) product and extracellular contrast agent distribution volume] and glucose metabolism were assessed in 14 patients with lung cancer. Glucose metabolism was measured by using [18F]fluorodeoxyglucose-positron emission tomography. Vascular physiology was assessed by dynamic T1-weighted, contrast-enhanced MRI. The mean PS product in tumor was 0.0015 +/- 0.0002 s(-1) (n = 13) before, 0.0023 +/- 0.0003 s(-1) (n = 3, P = 0.053) midway through, and 0.00075 +/- 0.0002 s(-1) (n = 5, P < 0.03) 2 weeks after treatment. Values for the extracellular contrast distribution space were 0.321 +/- 0.03 before, 0.289 +/- 0.02 midway through, and 0.195 +/- 0.02 (P < 0.01) 2 weeks after therapy. The glucose metabolic rate was significantly correlated with the PS product (P < 0.01) but not with the extracellular contrast distribution space. Our results demonstrate that tumor PS product correlates with glucose metabolism, that chemo- and radiotherapy induce observable and quantifiable changes in these parameters, and that such changes can be measured by in vivo dynamic MRI. Quantitative dynamic T1-weighted MRI of tumor vascular physiology may have a useful role in the clinical management of lung cancer.

Aged↗
PubMed1998

Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium.

OBJECTIVE: Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo. METHODS: E-selectin-deficient (E-/-) mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) in dermal microvessels with low blood flow (dorsal skin-fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow. RESULTS: E-/- mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E-/- mice without inflammatory stimulation. After local administration of TNF alpha, rolling increased modestly and equivalently in both genotypes. The main effect of TNF alpha was a dramatic increase in leukocyte stable adhesion and, unlike rolling, this manifestation of endothelial activation was significantly reduced in E-/- animals. This reflected fewer dermal microvessels supporting higher adhesion densities in E-/- mice, and a similar trend was observed in mesenteric microvessels. CONCLUSIONS: E-selectin plays a previously unappreciated role in facilitating and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.

Animals↗
PubMed1997

Fucosylation of disaccharide precursors of sialyl LewisX inhibit selectin-mediated cell adhesion.

We showed previously that HL-60 and F9 mouse embryonal carcinoma cells will take up and deblock peracetylated Galbeta1-4GlcNAcbeta-O-naphthalenemethanol (Galbeta1-4GlcNAc-NM) and use the disaccharide as a primer of oligosaccharide chains (Sarkar, A. K., Fritz, T. A., Taylor, W. H., and Esko, J. D. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 3323-3327). We now report that another disaccharide, acetylated GlcNAcbeta1-3Gal-naphthalenemethanol (GlcNAcbeta1-3Gal-NM), has even greater potency and that both compounds will inhibit sialyl LewisX (sLex)-dependent cell adhesion. When fed to U937 cells, acetylated forms of Galbeta1-4GlcNAc-NM and GlcNAcbeta1-3Gal-NM primed oligosaccharides in a dose-dependent manner. Analysis of compounds assembled on Galbeta1-4GlcNAc-NM showed only one product, namely Galbeta1-4(Fucalpha1-3)GlcNAc-NM. In contrast, GlcNAcbeta1-3Gal-NM generated Galbeta1-4GlcNAcbeta1-3Gal-NM, Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-3Gal-NM, NeuAcalpha2-3Galbeta1-4GlcNAcbeta1-3Gal-NM, and NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAcbeta1- 3Gal-NM. Both compounds decreased the incorporation of [3H]fucose into cellular glycoconjugates, without affecting the incorporation of [3H]mannosamine, a precursor of sialic acid residues. Moreover, the overall extent of sialylation was not affected based on the reactivity of cells to fluorescein isothiocyanate-conjugated Maackia amurensis lectin. Priming inhibited expression of sLex on cell surface glycoconjugates, which reduced E-selectin-dependent cell adhesion to tumor necrosis factor-alpha-activated human umbilical vein endothelial cells. GlcNAcbeta1-3Gal-NM and Galbeta1-4GlcNAc-NM represent starting points for making enzyme-specific, site-directed inhibitors of glycosyltransferases that could act in living cells.

Acetylation↗
PubMed1997

Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.

No growth factors specific for the lymphatic vascular system have yet been described. Vascular endothelial growth factor (VEGF) regulates vascular permeability and angiogenesis, but does not promote lymphangiogenesis. Overexpression of VEGF-C, a ligand of the VEGF receptors VEGFR-3 and VEGFR-2, in the skin of transgenic mice resulted in lymphatic, but not vascular, endothelial proliferation and vessel enlargement. Thus, VEGF-C induces selective hyperplasia of the lymphatic vasculature, which is involved in the draining of interstitial fluid and in immune function, inflammation, and tumor metastasis. VEGF-C may play a role in disorders involving the lymphatic system and may be of potential use in therapeutic lymphangiogenesis.

Animals↗
PubMed1997

Direct in vivo measurement of targeted binding in a human tumor xenograft.

Binding is crucial to the function of most biologically active molecules, but difficult to quantify directly in living tissue. To this end, fluorescence recovery after photobleaching was used to detect the immobilization of fluorescently labeled ligand caused by binding to receptors in vivo. Measurements of mAb affinity to target antigen within human tumor xenografts revealed a saturable binding isotherm, from which an in vivo carcinoembryonic antigen density of 0.56 nmol/g (5.0 x 10(5)/cell) and an association constant of Ka < or = 4 x 10(7) M(-1) were estimated. The present method can be adapted for in vivo studies of cell signaling, targeted drugs, gene therapy, and other processes involving receptor-ligand binding.

Animals↗
PubMed1997

Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker.

BACKGROUND AND OBJECTIVES: The median of pO2 values in tumor measured by Eppendorf "Histograph" with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured "absolute pO2 values." The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf "Histograph" among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitromidazole adducts. METHODS: C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf "Histograph" and immunohistochemical hypoxic marker. RESULTS: All laboratories showed that the FSaII tumor was hypoxic with at least 77% of measured points under 10 mmHg in pO2 and with a median pO2 value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO2 values measured by Eppendorf "Histograph" can be useful. However, the median values of tumor pO2 varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO2 of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes. CONCLUSIONS: Caution needs to be exercised in using the absolute, median, or distribution of pO2 values measured by the Eppendorf "Histograph" to compare the data between laboratories or to predict the radiation response in an individual subject.

Animals↗
PubMed1997

Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors.

The growth of tumors and their response to treatment are determined by delivery of diffusible substances to cancer cells and hence by their blood supply. Relative to most normal tissues, tumor blood flow is highly heterogeneous. Several hypotheses have been postulated to explain this anomalous behavior of tumor microcirculation, but the underlying mechanisms for these heterogeneities are not fully understood. In this study we consider a potential source of nonuniformity in the blood flow: the enhanced fluid exchange between the vascular and interstitial space mediated by the high leakiness of tumor vessels which could lead to a coupling between vascular, transvascular, and interstitial fluid flow. A simple network model is presented to describe the basic features of flow through a network of permeable and compliant vessels embedded in an isotropic porous medium. Two vascular geometries are considered: a regular mesh of identical vessels and a pair of countercurrent vessels of equal diameter. In each case, the flow through each vessel of the network is described by Poiseuille's law; the transmural flow between the vessels and the external porous medium is governed by Starling's law; the fluid movement through the porous medium is described by Darcy's law; and the vessel wall is assumed to be elastic. Our results show that the behavior of microcirculation may be strongly modified as a result of vascular compliance and enhanced vascular leakiness of tumor vessels. We found not only that the vascular pressure generates the well-known, high central interstitial fluid pressure, but also that the elevated interstitial pressure in turn alters the vascular pressure distribution. These changes in vascular pressure distribution result in a modification of the blood flow pattern. As the leakiness and compliance of the vessels increase, the blood is diverted away from the center of the tumor to a more peripheral path. The clinical significance of these results is that drug delivery for chemotherapy and oxygenation needed for radiotherapy may well be hampered in the central region of the tumor, despite the presence of highly permeable vessels in these regions.

Biological Transport↗
PubMed1997

Spectrometrically monitored selection experiments: quantitative laser desorption mass spectrometry of small chemical libraries.

BACKGROUND: Selection experiments involving chemical libraries are routinely used in the pharmaceutical industry for finding and optimizing lead compounds. In principle, almost any process involving a binding event or a reaction could be probed systematically with chemical libraries prepared by combinatorial synthesis. Traditionally, however, the vast majority of library members cannot be monitored during the selection, making a systematic correlation of structure and activity difficult. To interpret selection experiments on the level of all library components, monitoring technologies are required that give a unique and quantitative spectroscopic signal for every compound in a mixture. RESULTS: Quantitative matrix-assisted laser desorption mass spectrometry of libraries of porphyrins and peptide-DNA hybrids consisting of 2-35 compounds is described. Porphyrin libraries were subjected to in vitro selections for liposome incorporation and binding to a protein pocket. It was shown that mesohydroxyphenyl substituted porphyrins, known high activity photosensitizers of tumors, are preferentially incorporated in liposome membranes. A mixture of peptide-DNA hybrids was assayed for the nuclease stability of its components. CONCLUSIONS: Small libraries of non-isobaric compounds can be exhaustively or near-exhaustively monitored by mass spectrometry. Monitored selection experiments can yield detailed structure-activity maps in a single experiment, speeding up drug discovery and the probing of biochemically relevant recognition events. It is proposed that monitored assays for target binding, membrane partitioning, and biostability could be run in parallel, to select drug candidates combining several favorable properties in 'multidimensional' selection experiments.

DNA↗
PubMed1997

Interstitial fluid pressure in intracranial tumours in patients and in rodents.

Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 +/- 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.

Adult↗
PubMed1997

Solid stress inhibits the growth of multicellular tumor spheroids.

In normal tissues, the processes of growth, remodeling, and morphogenesis are tightly regulated by the stress field; conversely, stress may be generated by these processes. We demonstrate that solid stress inhibits tumor growth in vitro, regardless of host species, tissue of origin, or differentiation state. The inhibiting stress for multicellular tumor spheroid growth in agarose matrices was 45 to 120 mm Hg. This stress, which greatly exceeds blood pressure in tumor vessels, is sufficient to induce the collapse of vascular or lymphatic vessels in tumors in vivo and can explain impaired blood flow, poor lymphatic drainage, and suboptimal drug delivery previously reported in solid tumors. The stress-induced growth inhibition of plateau-phase spheroids was accompanied, at the cellular level, by decreased apoptosis with no significant changes in proliferation. A concomitant increase in the cellular packing density was observed, which may prevent cells from undergoing apoptosis via a cell-volume or cell-shape transduction mechanism. These results suggest that solid stress controls tumor growth at both the macroscopic and cellular levels, and thus influences tumor progression and delivery of therapeutic agents.

Animals↗
PubMed1997

Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation.

The partial pressure of oxygen (pO2) and pH play critical roles in tumor biology and therapy. We report here the first combined, high-resolution (< or = 10 microns) measurements of interstitial pH and pO2 profiles between adjacent vessels in a human tumor xenograft, using fluorescence ratio imaging and phosphorescence quenching microscopy. We found (1) heterogeneity in shapes of pH and pO2 profiles; (2) a discordant relation between local pH profiles and corresponding pO2 profiles, yet a strong correlation between mean pH and pO2 profiles; (3) no correlation between perivascular pH/pO2 and nearest vessel blood flow; and (4) well-perfused tumor vessels that were hypoxic and, consequently, large hypoxic areas in the surrounding interstitium. Such multiparameter measurements of the in vivo microenvironment provide unique insights into biological processes in tumors and their response to treatment.

Adenocarcinoma↗
PubMed1997

The enzymatic sulfation of glycoprotein carbohydrate units: blood group T-hapten specific and two other distinct Gal:3-O-sulfotransferases as evident from specificities and kinetics and the influence of sulfate and fucose residues occurring in the carbohydrate chain on C-3 sulfation of terminal Gal.

Enzymatic 3-O-sulfation of terminal beta-Gal residues was investigated by screening sulfotransferase activity present in 37 human tissue specimens toward the following synthesized acceptor moieties: Galbeta1,3GalNAc alpha-O-Al, Galbeta1,4GlcNAcbeta-O-Al, Galbeta1,3GlcNAcbeta-O-Al, and mucin-type Galbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAc alpha-O-Bn structures containing a C-3 methyl substituent on either Gal. Two distinct types of Gal: 3-O-sulfotransferases were revealed. One (Group A) was specific for the Galbeta1, 3GalNAc alpha- linkage and the other (Group B) was directed toward the Galbeta1,4GlcNAc branch beta1,6 linked to the blood group T hapten. Enzyme activities found in breast tissues were unique in showing a strict specificity for the T-hapten. Galbeta-O-allyl or benzyl did not serve as acceptors for Group A but were very active with Group B. An examination of activity present in six human sera revealed a specificity of the serum enzyme toward beta1,3 linked Gal, particularly, the T-hapten without beta1,6 branching. Group A was highly active toward T-hapten/acrylamide copolymer, anti-freeze glycoprotein, and fetuin O-glycosidic asialo glycopeptide; less active toward fetuin triantennary asialo glycopeptide; and least active toward bovine IgG diantennary glycopeptide. Group B was moderately and highly active, respectively, with the latter two glycopeptides noted and least active with the first two. Competition experiments performed with Galbeta1,3GalNAc alpha-O-Al and Galbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAc alpha-O-Bn having a C-3 substituent (methyl or sulfate) on either Gal reinforced earlier findings on the specificity characteristics of Group A and Group B. Group A displayed a wider range of optimal activity (pH 6.0-7.4), whereas Group B possessed a peak of activity at pH 7.2. Mg2+ stimulated Group A 55% and Group B 150%, whereas Mn+2 stimulated Group B 130% but inhibited Group A 75%. Ca2+ stimulated Group B 100% but inhibited Group A 35%. Group A and Group B enzymes appeared to be of the same molecular size (<100,000 Da) as observed by Sephacryl S-100 HR column chromatography. The following effects upon Gal: 3-O-sulfotransferase activities by fucose, sulfate, and other substituents on the carbohydrate chains were noted. (1) A methyl or GlcNAc substituent on C-6 of GalNAc diminished the ability of Galbeta1,3GalNAc alpha-O-Al to act as an acceptor for Group A. (2) An alpha1,3-fucosyl residue on the beta1,6 branch in the mucin core structure did not affect the activity of Group A toward Gal linked beta1,3 to GalNAc alpha-. (3) Lewis x and Lewis a terminals did not serve as acceptors for either Group A or B enzymes. (4) Elimination of Group B activity on Gal in the beta1,6 branch owing to the presence of a 3-fucosyl or 6-sulfo group on GlcNAc did not hinder any action toward Gal linked beta1,3 to GalNAc alpha. (5) Group A activity on Gal linked beta1,3 to GalNAc remained unaffected by 3'-sulfation of the beta1,6 branch. The reverse was true for Group B. (6) The acceptor activity of the T-hapten was increased somewhat upon C-6 sulfation of GalNAc, whereas, C-6 sialylation resulted in an 85% loss of activity. (7) A novel finding was that Galbeta1,4GlcNAcbeta-O-Al and Galbeta1,3GlcNAcbeta-O-Al, upon C-6 sulfation of the GlcNAc moiety, became 100% inactive and 5- to 7-fold active, respectively, in their ability to serve as acceptors for Group B.

Animals↗
PubMed1997

Increased incidence of biliary sludge and normal gall bladder contractility in patients with high spinal cord injury.

BACKGROUND: Patients with spinal cord injury (SCI) have an increased prevalence of gallstones. AIMS: To study prospectively the incidence of gallstones and gall bladder contractility in patients with SCI. PATIENTS AND METHODS: Thirty six consecutive patients with SCI were studied: 18 patients with SCI above thoracic 10 neuronal segment (> T10) and 18 patients with SCI below T10 (< T10). An equal number each of disease controls (multiple fractures) and healthy controls were also studied. All patients and controls underwent serial ultrasonography to detect development of gallstones and ultrasonographic measurement of gall bladder contractility. RESULTS: A significantly higher number (9/18) of patients with SCI > T10 developed biliary sludge compared with patients with SCI < T10 (2/18), disease controls (2/18), and healthy controls (1/18) (p < 0.05). No patient developed gallstones. The gall bladder fasting volume was significantly decreased in patients with SCI > T10 (20.56 ml; 95% confidence intervals (CI) 19.74 to 21.38) compared with that in patients with SCI < T10 (27.33 ml, 95% CI 26.17 to 28.49; p < 0.05), disease controls (27.92 ml, 95% CI 26.69 to 29.15; p < 0.05), and healthy controls (28.35 ml, 95% CI 27.25 to 29.45; p < 0.05). Gall bladder contractility was normal in patients with SCI as shown by normal gall bladder residual volume and emptying time. CONCLUSIONS: Patients with SCI above T10 have an increased incidence of biliary sludge and a decreased gall bladder fasting volume. Gall bladder contractility is, however, normal.

Adult↗
PubMed1997

Fractal characteristics of tumor vascular architecture during tumor growth and regression.

OBJECTIVE: Tumor vascular networks are different from normal vascular networks, but the mechanisms underlying these differences are not known. Understanding these mechanisms may be the key to improving the efficacy of treatment of solid tumors. METHODS: We studied the fractal characteristics of two-dimensional normal and tumor vascular networks grown in a murine dorsal chamber preparation and imaged with an intravital microscopy station. RESULTS: During tumor growth and regression, the vasculature in the tumor has scaling characteristics that reflect the changing state of the tissue. Growing tumors show vascular networks that progressively deviate from their normal pattern, in which they seem to follow diffusion-limited aggregation to a pathological condition in which they display scaling similar to percolation clusters near the percolation threshold. The percolation-like scaling indicates that the key determinants of tumor vascular architecture are local substrate properties rather than gradients of a diffusing substance such as an angiogenic growth factor. During tumor regression the fractal characteristics of the vasculature return to an intermediate between those of growing tumors and those of healthy tissues. Previous studies have shown that percolation-like scaling generally inhibits transport. CONCLUSIONS: In the present context, the percolation-like nature of tumor vasculature implies that tumor vascular networks possess inherent architectural obstacles to the delivery of diffusible substances such as oxygen and drugs.

Animals↗
PubMed1997

The Eugene M. Landis Award Lecture 1996. Delivery of molecular and cellular medicine to solid tumors.

To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiologic barriers in solid tumors and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.

Animals↗