Analysis of treatment goal alignment between Japanese psoriasis patients and their paired treating physicians.

BACKGROUND: Appropriate goal-oriented treatment strategies are important for optimal treatment outcomes and may prevent under-treatment. As treatment goals vary by patient, a study to examine treatment goals is more meaningful when patients and their physicians are paired. There has not been any study that examines alignment between paired psoriasis patients and physicians in real-world clinical practice using skin clearance as a treatment goal indicator. OBJECTIVES: To evaluate treatment goal alignment between psoriasis patients and their paired physicians, and to quantitatively identify factors associated with goal misalignment. METHODS: The study was a nationwide multicenter cross-sectional observational study. Subjects were physician-reported moderate-to-severe psoriasis patients with a history of systemic treatments, directly paired with their treating physicians. Subjects completed surveys independently. Treatment goals included seven categories, and patient-physician pairs were grouped as 'aligned' or 'misaligned' when the answers were the same or different, respectively. RESULTS: A total of 425 pairs (mean response rate, 94.7%) of responses were collected from 54 sites (64.8% general practitioners or clinics; 35.2% university or large hospitals). Treatment goal misalignment was found in 67.9% of the patient-physician pairs. The misalignment was mainly 'patient predominant' (60.9%) indicating that patients had higher goals ('complete clearance') than physicians. In the multivariate logistic regression analyses, patients' treatment expectation for 'complete clearance' [odds ratio (OR): 1.927; 95% confidential interval (CI): 1.232-3.016] and physician rating of 'level of understanding on treatment options' being low (OR: 1.552, 95% CI; 1.082-2.227) were significant factors for treatment goal misalignment. CONCLUSIONS: The majority of treatment goal misalignment was found between paired psoriasis patients and their treating physicians in Japan. The most important contributing factors to misalignment were patients' treatment expectation for 'complete clearance' and physicians' rating of their patients' 'level of understanding on treatment options' being low.

CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Dependence of the V/III Ratio on Indium Incorporation in InGaN Films Grown by Metalorganic Vapour Phase Epitaxy.

InGaN epitaxial layers were grown on c-plane sapphire substrates using the metalorganic vapour phase epitaxy (MOVPE) system at 760 °C. By varying the total flow rate of group-III sources (TMI+TEG) with a fixed molar ratio of group-III sources [TMI/(TMI+TEG)], the influence of V/III ratio were investigated from 4500 to 20000. The grown N-polar InGaN layers were investigated by atomic force microscopy and it is found that the surface roughness decreases with increasing the V/III ratios. High resolution X-ray diffraction analyses show that the phase separation decreases with increasing the V/III ratios. Photoluminescence measurements reveal that the peak position of the band-edge emission shifted toward the shorter wavelength with increasing the V/III ratios. Reciprocal space mapping (RSM) analyses were carried out on InGaN films. At low V/III ratio, the phase separation can be detected in InGaN films.

Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis.

Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3-signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.

Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways.

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.

Negative regulation of cytokine signaling by CIS/SOCS family proteins and their roles in inflammatory diseases.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases (JAKs) and STAT transcription factors. The CIS (cytokine-inducible SH2 protein) and SOCS (suppressors of cytokine signaling) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the inflammatory systems. In this review, we focused on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in inflammatory diseases. Furthermore, we illustrate several approaches for treating inflammatory diseases by modulating extracellular and intracellular signaling pathways.

[Off-pump coronary artery bypass in high-risk patients].

In this study, 110 consecutive patients who had undergone off-pump coronary artery bypass (OPCAB) in the past 2 years were evaluated for early results of OPCAB. Patients were classified as a high-risk group (H group: 68 patients consisting of 46 men and 22 women) and a low-risk group (L group: 42 patients consisting of 31 men and 11 women), respectively, and were evaluated for the early operative results. No differences were noted between the H and L groups in the mean number of bypass grafts (2.9 +/- 0.9 in the H group, 2.9 +/- 0.9 in the L group), the rates of complete revascularization (85% in the H group, 93% in the L group), those of various graft materials bypassed, or those of sequential bypass. In all patients, we were able to undergo coronary revascularization by the aortic no-touch technique using arterial grafts exclusively. In the H group, 1 patient (1.5%) died in hospital, but no patients developed cerebral infarction postoperatively, and the frequency of complications was similar to that in the L group. The results of OPCAB for high-risk patients were good, and it was suggested that OPCAB using in situ arterial grafts was very useful particularly in patients with cerebrovascular diseases.

[Aortic valve replacement for calcified aortic valve and annulus with ultrasonic decalcification].

UNLABELLED: We conducted ultrasonic decalcification on calcified annulus in patients with aortic stenosis (AS) using an ultrasonic operator, Sonopet (UST 2001) prior to aortic valve replacement (AVR). We studied the reliability of this method. SUBJECT AND METHOD: From January 2002 to August 2005, AVR was conducted for AS using the Sonopet in 45 patients, comprising of 18 male and 27 female subjects. The mean age was 73.3 +/- 9.7. RESULT: Artificial valves were successfully inserted at the intra-annular level in 37 patients and at the supra-annular level in 8 patients without conducting annular enlargement. In the patients with narrow annuli of less than 19 mm (23 patients), the preoperative mean annular diameter was 18.2 +/- 1.0 mm, but significantly larger artificial valves with an average diameter of 19.3 +/- 1.5 mm (p=0.003) were successfully inserted. CONCLUSION: AVR was proved to be safe and easy by previous ultrasonic decalcification of the annuls using the Sonopet. This method was very useful because it required no enlargement of aortic annulus.

Self-assembled peptide fibers from valylvaline bola-amphiphiles by a parallel beta-sheet network.

A series of dipeptide-based bola-amphiphiles, bis(N-alpha-amide-L-valyl-L-valine) 1, n-alkane dicarboxylate (n=4-12), have been synthesized. The bola-amphiphiles with n=4 and 6 self-assembled to form crystalline solids in water, whereas those with n=7-12 produced peptide fibers. FT-IR spectroscopy and X-ray diffraction patterns revealed that the peptide fibers have parallel-type beta-sheet networks between the valylvaline units. FT-IR deconvolution study of carboxyl regions indicated that these crystalline solids and peptide fibers are stabilized by interlayer bifurcated and intralayer lateral hydrogen-bond networks between the end carboxylic acid groups, respectively.

VAM-1: a new member of the MAGUK family binds to human Veli-1 through a conserved domain.

The MAGUKs (membrane-associated guanylate kinase homologues) constitute a family of peripheral membrane proteins that function in tumor suppression and receptor clustering by forming multiprotein complexes containing distinct sets of transmembrane, cytoskeletal, and cytoplasmic signaling proteins. Here, we report the characterization of the human vam-1 gene that encodes a novel member of the p55 subfamily of MAGUKs. The complete cDNA sequence of VAM-1, tissue distribution of its mRNA, genomic structure, chromosomal localization, and Veli-1 binding properties are presented. The vam-1 gene is composed of 12 exons and spans approx. 115 kb. By fluorescence in situ hybridization the vam-1 gene was localized to 7p15-21, a chromosome region frequently disrupted in some human cancers. VAM-1 mRNA was abundant in human testis, brain, and kidney with lower levels detectable in other tissues. The primary structure of VAM-1, predicted from cDNA sequencing, consists of 540 amino acids including a single PDZ domain near the N-terminus, a central SH3 domain, and a C-terminal GUK (guanylate kinase-like) domain. Sequence alignment, heterologous transfection, GST pull-down experiments, and blot overlay assays revealed a conserved domain in VAM-1 that binds to Veli-1, the human homologue of the LIN-7 adaptor protein in Caenorhabditis. LIN-7 is known to play an essential role in the basolateral localization of the LET-23 tyrosine kinase receptor, by linking the receptor to LIN-2 and LIN-10 proteins. Our results therefore suggest that VAM-1 may function by promoting the assembly of a Veli-1 containing protein complex in neuronal as well as epithelial cells.

A large contribution of a cyclic AMP-independent pathway to turtle olfactory transduction.

Although multiple pathways are involved in the olfactory transduction mechanism, cAMP-dependent pathway has been considered to contribute mainly to the transduction. We examined the degree of contribution of cAMP-independent pathway to the turtle olfactory response by recording inward currents from isolated cells, nerve impulses from cilia and olfactory bulbar responses. The results obtained by the three recordings were essentially consistent with each other, but detail studies were carried out by recording the bulbar response to obtain quantitative data. Application of an odorant cocktail to the isolated olfactory neuron after injection of 1 mM cAMP from the patch pipette elicited a large inward current. Mean amplitude of inward currents evoked by the cocktail with 1 mM cAMP in the patch pipette was similar to that without cAMP in the pipette. Application of the cocktail after the response to 50 microM forskolin was adapted also induced a large inward current. Application of the odorant cocktail to the olfactory epithelium, after the response to 50 microM forskolin was adapted, brought about an appreciable increase in the impulse frequency. The bulbar response to forskolin alone reached a saturation level around 10 microM. After the response to 50 microM forskolin was adapted, 11 species of odorants were applied to the olfactory epithelium. The magnitudes of responses to the odorants after forskolin were 45-80% of those of the control responses. There was no essential difference in the degree of the suppression by forskolin between cAMP- and IP3-producing odorants classified in the rat, suggesting that certain part of the forskolin-suppressive component was brought about by nonspecific action of forskolin. Application of a membrane permeant cAMP analogue, cpt-cAMP elicited a large response, and 0.1 mM citralva after 3 mM cpt-cAMP elicited 51% of the control response which was close to the response to citralva after 50 microM forskolin. A membrane permeant cGMP analogue, db-cGMP elicited a small response and the response to 0.1 mM citralva was unaffected by db-cGMP. It was concluded that cAMP-independent (probably IP3-independent) pathway greatly contributes to the turtle olfactory transduction.

The effect of peripheral blood adherent cells from patients with aplastic anemia on in vitro hematopoiesis.

To investigate the pathogenetic significance of peripheral blood adherent cells in aplastic anemia, the inhibitory effects of adherent cells obtained from the peripheral blood of 10 patients with aplastic anemia on the growth of CFUE and CFUC were compared with those of normal controls. The inhibitory effects of adherent cells were studied by means of co-culture with normal allogeneic bone marrow cells. The suppression of these inhibitory effects was also examined by adding indomethacin to the co-culture system. In addition, PGE2 concentrations in the adherent cell-conditioned media were assayed. The inhibition of the colony growth by peripheral blood adherent cells from the aplastic anemia patients was not significantly different from controls. Both the suppression of the inhibitory effects by indomethacin and the level of PGE2 production showed no significant difference between the patients and controls.

Dual effect of monocyte-conditioned medium on in vitro hematopoiesis.

To investigate the effects of the conditioned medium on regulation of hematopoietic stem cells, serial volumes of monocyte-conditioned medium were added to the culture systems of CFUE and CFUC. Small volumes of the conditioned medium possessed stimulatory activity and large volumes inhibitory activity for both CFUE and CFUC. These findings suggest that the monocyte-conditioned medium regulates both CFUE and CFUC dualistically in accordance with the volume of the medium added to the culture system. The suppression of the growth of CFUE and CFUC by monocyte-conditioned medium was completely protected when the medium made in the presence of indomethacin was added. Monocyte mediated suppression was partially recovered when both monocytes and indomethacin were added. E series prostaglandins appear to be inhibitory mediators of monocyte and monocyte-conditioned medium mediated suppression, but some other mechanism seems to be involved in the monocyte mediated suppression.

A tetrazolium method for staining peroxidase labels in blotting assays.

A sensitive staining method of horseradish peroxidase-labeled immunoglobulins on nitrocellulose membrane was established by employing a reaction chain leading to formazan formation with phenol as a substrate of peroxidase and NADH as a hydrogen donor to reduce nitro blue tetrazolium. Higher concentrations of NADH relative to phenol were necessary to increase the intensity of staining and to ensure a wide dose-response range of color production with respect to the applied enzyme activities. By an optimized tetrazolium method in combination with antibody-affinity blotting, as low as 4 ng/ml alpha-fetoprotein was detected and 3-4-fold greater color intensities in a working assay range as compared with those of existing methods were obtained. The present technique of peroxidase staining may prove to have a wide application for the enzyme immunoassay using blotting modalities.

Nitric oxide synergistically potentiates interleukin-1 beta-induced increase of cyclooxygenase-2 mRNA levels, resulting in the facilitation of substance P release from primary afferent neurons: involvement of cGMP-independent mechanisms.

We previously demonstrated that cultured rat dorsal root ganglion (DRG) cells respond to stimulation with interleukin-1 beta (IL-1 beta) by releasing substance P (SP), and this response is regulated via the cyclooxygenase (COX)-2 pathway. In this study, to ascertain the interaction between nitric oxide (NO) and prostaglandins in primary afferent neurons, we investigated the effect of NO on the IL-1 beta-induced release of SP in cultured DRG cells. An NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), did not in itself evoke SP release. However, it potentiated the IL-1 beta-induced release of SP. Similarly, while SNAP did not elicit the expression of COX-2 mRNA, it potentiated the expression induced by IL-1 beta in cultured DRG cells, and this potentiation was significantly suppressed by the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). Moreover, SNAP also potentiated the expression of COX-2 protein induced by IL-1 beta in cultured DRG cells. The stimulatory effect of SNAP on the IL-1 beta-induced release of SP was completely inhibited on co-incubation with a selective COX-2 inhibitor, NS-398. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a potent inhibitor of soluble guanylate cyclase, did not suppress, and a membrane-permeable cGMP analogue, 8-Br-cGMP, did not mimic the stimulatory effects of SNAP in DRG cells. These results suggest that in cultured DRG cells, NO potentiates the IL-1 beta-induced increase in COX-2 expression via a soluble guanylate cyclase-cGMP-independent pathway, resulting in facilitation of SP release. The interaction between NO and COX in primary afferent neurons might contribute to the change in nociceptive perception in inflammatory hyperalgesia.

Influences of dietary omega-3 polyunsaturated fatty acids on the recovery of cardiac and renal functions after preservation in hyperlipidemic rats.

BACKGROUND: The effects of a soybean oil diet and a high-cholesterol oil (HC) diet, and an HC diet with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) supplementation, on basal and postpreservative cardiac function of the hearts and on postpreservative renal function of the kidneys from older rats were examined. METHODS: Groups 1 through 4 of 100-week-old rats were fed either soybean oil, HC, HC with EPA, or HC with DHA, respectively, for 12 weeks. Blood was collected for analysis of plasma fatty acids, and the heart and left kidney were removed from the rat. In experiment 1, the heart was perfused on a Langendorff apparatus. After evaluation of the cardiac function of each rat, the heart was stored in histidine-tryptophan-ketoglutarate solution for 8 hr at 4 degrees C. The heart was reperfused and the recovery of cardiac function was evaluated. The coronary perfusate during reperfusion was collected to measure 6-keto prostaglandin F1alpha and thromboxane B2. Coronary flow (CF) perfused with Krebs-Henseleit bicarbonate (KHB) solution containing 5-hydroxytryptamine (5-HT) and nitroglycerin were evaluated in the Langendorff mode with atrial pacing (330 beats/min). In experiment 2, the excised left kidney was immediately flushed and preserved with University of Wisconsin solution for 8 hr at 4 degrees C. The kidney was then reperfused with KHB solution and renal function was evaluated. RESULTS: The plasma and cardiac EPA levels in group 3 were significantly higher than the levels found in the other groups. The plasma and cardiac ratios of EPA to arachidonic acid were significantly higher in groups 3 and 4 than in groups 1 and 2. There were no significant differences in basal cardiac function among any of the diet-fed rats. The percentage values of the recovery of aortic flow, cardiac output (CO), and left ventricular max dp/dt in group 3 and CO in group 4 were significantly higher than in group 2. In addition, the recovery of CF in group 3 tended to be higher than in group 2 (P=0.07). The percentage values of the recovery of aortic flow, CF, CO, and left ventricular max dp/dt in group 1 were significantly lower than in the other dietary groups. CF reperfused with KHB solution containing 5-HT was significantly higher in group 3 than in groups 1 and 2. CF reperfused with KHB solution containing 5-HT was significantly higher in group 4 than in group 1. CF reperfused with KHB solution containing nitroglycerin in group 3 tended to be higher than in groups 1 and 2 (P=0.07). The thromboxame B2 concentrations in the coronary perfusate during reperfusion in groups 3 and 4 were significantly lower than in groups 1 and 2. Fractional sodium reabsorption in group 3 was significantly higher than in group 2. Inulin clearance in groups 3 and 4 was significantly higher than in group 1. The postpreservative urinary flow in group 3 was significantly higher than in groups 1 and 2. The urinary flow was significantly higher in group 4 than in group 1. CONCLUSIONS: These results suggest that EPA administration may attenuate preservation and reperfusion injury and improve the recovery of cardiac and renal functions in hyperlipidemic and older rats. DHA administration may also show beneficial effects on kidney preservation in hyperlipidemic rats.

Involvement of P-type calcium channels in high potassium-elicited release of neurotransmitters from rat brain slices.

Several types of voltage-dependent calcium channels appear to occur in neurons, although coupling of the particular subtype of calcium channels to the release of neurotransmitter has not been clearly understood. We have examined the effects of subtype-specific inhibitors of the calcium channels on depolarization-induced release of endogenous neurotransmitters from brain slices. High potassium-induced release of glutamate and aspartate from hippocampal and striatal slices was almost completely inhibited by a P-type channel blocker, omega-agatoxin IVA. omega-Agatoxin IVA also completely inhibited the release of serotonin from the hippocampal slices with almost the same potency as in the case of glutamate, whereas the potency in blocking the release of serotonin and dopamine from striatal slices was lower than that from the hippocampal slices. Another calcium channel blocker, omega-agatoxin TK, that was recently found to block P-type channels with very similar selectivity and potency to omega-agatoxin IVA, also inhibited the release of amino acid transmitters and monoamines, though its potency was lower than that of omega-agatoxin IVA. An N-type channel blocker, omega-conotoxin GVIA, partially inhibited the neurotransmitter release, but an L-type channel blocker, nifedipine was ineffective. We propose that the activation of P-type calcium channels makes a major contribution to depolarization-elicited neurotransmitter release in the CNS and that multiple P-type channels sensitive to omega-agatoxin IVA and omega-agatoxin TK modulate the neurotransmitter release.

Long-term follow-up (8 to 17 years) after thromboexclusion operation for thoracic aortic aneurysms.

BACKGROUND: It has been reported that the thromboexclusion operation is a good method for managing certain difficult thoracic aortic aneurysms. METHODS: Forty-four patients underwent graft replacement (group 1) and 14, the thromboexclusion operation (group 2). We reviewed the long-term results of the thromboexclusion operation and compared them with those of graft replacement in our institutions. RESULTS: The hospital mortality rate in groups 1 and 2 was 29.5% (13 patients) and 35.7% (4 patients), respectively. In group 1, the one late death (2.3%) was due to heart failure and in group 2, three of the four late deaths (28.6%) were due to rupture of the excluded thoracic aorta, and one late death was due to heart failure. Long-term follow-up was possible for 23 patients in group 1 and 5 patients in group 2. Survival 3 years after operation was significantly better in group 1 than in group 2 (p < 0.05). Long-term follow-up with blood pressure measurements, chest roentgenograms, electrocardiograms, and echocardiograms showed no significant differences between the preoperative and postoperative findings. However, in group 2, left ventricular hypertrophy and hypertension, which had not been present preoperatively, were found in all of the patients. Also, 1 patient has had persistent hemoptysis. CONCLUSIONS: The thromboexclusion operation has introduced unanticipated problems that were recognized at long-term follow-up.

Sarcomatous Wilms tumor associated with consumption coagulopathy.

This is a case report of a sarcomatous Wilms tumor complicating disseminated intravascular coagulation with gastrointestinal bleeding, ascites, pleural effusion, and hepatitis after the second course of actinomycin D. A sarcomatous Wilms tumor is believed to have an unfavorable prognosis even if multimodal therapy is given. Arteriovenous fistulae which we created for purposes of chemotherapy and hyperalimentation by microvascular-sleeve anastomosis functioned well for three years in spite of repeated punctures.

Topoisomerase II alpha content and topoisomerase II catalytic activity cannot explain drug sensitivities to topoisomerase II inhibitors in lung cancer cell lines.

PURPOSE: Topoisomerase II alpha content, topoisomerase II catalytic activity and drug sensitivities to the topoisomerase II inhibitors, doxorubicin and etoposide, were examined in a panel of 14 unselected human lung cancer cell lines in order to determine the relationship between topoisomerase II and drug sensitivities to the topoisomerase II inhibitors. METHODS: Drug sensitivities were determined using a microculture tetrazolium assay. The topoisomerase II alpha levels were determined by Western blot analysis and the topoisomerase II catalytic activity was determined using a decatenation assay of kinetoplast DNA, using nuclear protein from cells of each cell line. RESULTS: Drug sensitivity tests revealed that small-cell lung cancer (SCLC) cell lines were more sensitive to drugs than non-small-cell lung cancer (NSCLC) cell lines. The relative topoisomerase II alpha levels and relative topoisomerase II catalytic activity from SCLC cell lines (mean +/- SD 0.89 +/- 0.54 and 5.3 +/- 3.4, respectively) were slightly higher than those from NSCLC cell lines (0.78 +/- 0.56 and 4.0 +/- 2.8, respectively), but the differences were not statistically significant, and not sufficient to account for the variation in drug sensitivities. Moreover, no clear association was observed between the topoisomerase II alpha levels or the topoisomerase II catalytic activity and drug sensitivities in the cell lines studied. CONCLUSIONS: These findings suggest that the difference in drug sensitivities to doxorubicin and etoposide in human lung cancer cell lines might not be explainable by the topoisomerase II alpha levels and topoisomerase II catalytic activity. Moreover, our results suggest that the topoisomerase II alpha levels and topoisomerase II catalytic activity may play a minor role in the determination of clinical drug resistance of human lung cancers.