Cellular and molecular analyses of major histocompatibility complex (MHC) restricted and non-MHC-restricted effector cells recognizing renal cell carcinomas: problems and perspectives for immunotherapy

 Renal cell carcinomas belong to the small group of tumors that are able to induce antitumor responses. Here we describe two general types of cytotoxic effector lymphocytes that can eliminate autologous tumor cells and discuss the role that major histocompatibility complex encoded molecules play in governing their specificities. Improved understanding of the cellular and molecular basis of renal cell carcinoma recognition opens new avenues of research with the potential to develop better immunotherapies for patients with metastatic disease. Received: 24 July 1996 / Accepted: 1 November 1996     

Interrelations between age and plasma renin,aldosterone and cortisol,urinary catecholamines,and the body sodium/volume state in normal man

Summary Interrelations between age and plasma renin, aldosterone and cortisol levels, urinary catecholamines, plasma and blood volumes, exchangeable body sodium and blood pressure were studied in 28 young (19 to 29 years), 16 middle-aged (32 to 58 years) and 15 elderly (60 to 74 years) healthy subjects. Supine and upright plasma renin and supine aldosterone levels decreased while urinary noradrenaline excretion rate increased progressively with aging (r0.34;p<0.05), with significant differences in mean values between young and elderly subjects (p<0.02). There was also an age-related decrease in upright plasma aldosterone concentration, although this was not statistically significant. Furthermore, mean plasma cortisol concentrations increased in response to upright posture in elderly (+50%;p<0.02), but not in young (–10%) or middle-aged (–8%) subjects. Blood pressure correlated with age (r=0.35;p<0.05) or noradrenaline excretion rate (r=0.34) in the entire study population and with blood volume in the elderly (r=0.68), but not in the young or middle-aged study groups. There were no significant age-related differences in the body sodium/volume state, basal plasma cortisol levels or urinary adrenaline excretion rate, and plasma renin or aldosterone levels did not correlate with these parameters or with blood pressure. It is concluded that the influence of age on plasma renin or aldosterone levels, plasma cortisol responsiveness to upright posture, and urinary noradrenaline excretion should be taken into consideration, whenever these factors have to be interpreted in patients with arterial hypertension or other clinical disorders. Furthermore, these data are consistent with the possibility that in normal man increases in supine blood pressure with aging may be related at least partly to concomitant changes in free peripheral noradrenaline.This investigation was supported by the Swiss National Science Foundation     

Biochemical and antitumor activity of trimidox,a new inhibitor of ribonucleotide reductase

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC₅₀) at 5 M, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC₅₀ of 500 M. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 M, a concentration that inhibits cell proliferation by 50% (IC₅₀) or at 100 M for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC₅₀ values of 7.5 and 50 M, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC₅₀ values of 12 and 87 M, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82 in male mice and 112% in female mice). The antitumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.Abbreviations Didox N,3,4-trihydroxybenzamide - MTT {3-[4,5-dimethyl-thiazo-2yl]}-2,5-diphenyl tetrazolium bromide - PBS phosphate-buffered saline - trimidox 3,4,5-trihydroxybenzamidoxime HCl     

Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus–Di?erences in Etiology, Epidemiology and Prevention

Incidence of esophageal carcinoma With more than 300 000 new cases per year, cancerof the esophagus, predominantly squamous cell carcinoma(SCC), is one of the 10 most frequently diagnosed tumortypes. Esophageal cancer occurs often in developing coun-tries and shows great regional di?erences[1]. While in re-cent history the incidence of SCC has decreased slightly inregions of high risk and stayed constant in the USA andWestern Europe, the rate of adenocarcinoma of the esoph-agus (AC) has…     

Influence of gender,BMI and body shape on theoretical injection outcome at the ventrogluteal and dorsogluteal sites

Aims and objectives

This study aimed to determine the influences of gender, BMI and observed body shape on subcutaneous fat and muscle thicknesses, and theoretical injection outcome, at the ventrogluteal and dorsogluteal intramuscular injection sites.

Background

Debate continues as to whether the dorsogluteal or ventrogluteal injection site is more reliable for a successful intramuscular injection outcome. Subcutaneous fat and muscle thicknesses at the injection site are direct determinants of intramuscular injection outcome. BMI and observed body shape influence gluteal subcutaneous fat and muscle thicknesses, and therefore injection outcome, with potentially distinct effects at the ventrogluteal and dorsogluteal sites.

Design

This was a cross‐sectional study.

Methods

Demographic data were collected, and subcutaneous fat and muscle thicknesses were quantified bilaterally at the dorsogluteal and ventrogluteal injection sites using ultrasound, for 145 participants (57% female).

Results

Subcutaneous fat and muscle were significantly thicker at the dorsogluteal than the ventrogluteal site, and 75% and 86% of participants would receive a successful intramuscular injection at these sites, respectively. There were significant effects of gender, BMI and observed body shape on subcutaneous fat thickness and theoretical injection outcome at both sites. Females, obese individuals and endomorph individuals had thicker subcutaneous fat and were more likely to have a subcutaneous injection outcome.

Conclusions

Gender, BMI and observed body shape could be used to guide site and needle length selection when administering gluteal intramuscular injections to increase the likelihood of a successful intramuscular injection outcome.

Relevance to clinical practice

Both gluteal injection sites should be avoided in obese individuals and endomorph individuals. An intramuscular injection will be successful: using a 32‐mm needle at the ventrogluteal site for all males and normal‐weight females and using a 38‐mm needle for all females at the ventrogluteal site, and for all males and at least 98% of females at the dorsogluteal site.     

The mouse Pax21Neu mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney

We describe a new mouse frameshift mutation (Pax2^1Neu) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183–2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the mid-hindbrain region, loss of Pax2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.     

Determinants and patient-reported long-term outcomes of physician empathy in oncology: a structural equation modelling approach

OBJECTIVE: The aim of the present cross-sectional study was to explore patient- and physician-specific determinants of physician empathy (PE) and to analyse the influence of PE on patient-reported long-term outcomes in German cancer patients. METHODS: A postal survey was administered to 710 cancer patients, who had been inpatients at the University Hospital Cologne (response rate 49.5%). PE was measured with the German translation of the consultation and relational empathy (CARE) measure, and patient-reported long-term outcomes were assessed using the major (ICD-10) depression inventory (MDI) and the EORTC quality of life (Qol) questionnaire QLQ-C30. Hypotheses were tested by structural equation modelling. RESULTS: PE had (a) a moderate indirect effect on "depression" and a smaller indirect effect on "socio-emotional-cognitive Qol" by affecting "desire for more information from the physician regarding findings and treatment options" and (b) a moderate indirect effect on "socio-emotional-cognitive Qol" and a smaller effect on "depression" via "desire for more information about health promotion". The determinant with the greatest importance was "patient-perceived general busyness of hospital staff": it had a strong negative influence on PE, indirectly influencing "desire for more information from the physician regarding findings and treatment options" and also patients' "depression". CONCLUSION: PE seems to be an important pre-requisite for information giving by physicians and through this pathway having a preventive effect on depression and improving Qol. Conversely, physicians' stress negatively influences these relationships. PRACTICE IMPLICATIONS: The research findings suggest that reducing physicians' stress at the organizational and individual may be required to enhance patient-physician communication. Empathy, as an outcome-relevant professional competence needs to be assessed and developed more intensively in medical students and physicians.     

GM-CSF: modulation of biochemical and cytotoxic effects of tiazofurin in HL-60 cells

Summary. Cytokines, such as granulocyte macrophage colony stimulating factor (GM-CSF) or interleukin-3 (IL-3) recruit quiescent cells into the cell cycle and sensitize these cells towards cell cycle specific chemotherapeutic agents. We examined the in vitro effects of GM-CSF on HL-60 cells and tested its modulatory influence on biochemical and cytotoxic effects seen with tiazofurin, a potent and specific inhibitor of IMP dehydrogenase. Incubation of HL-60 cells with 500 U/ml GM-CSF for 4 d enhanced cell proliferation, which was accompanied by a significant increase in IMP dehydrogenase activity (from 2·22 in control cells to 3·70 nmol/mg/h in cells pretreated with GM-CSF). When HL-60 cells were incubated with 100 μm tiazofurin for 2 h, intracellular GTP decreased to 46% of untreated control cells. In HL-60 cells pretreated with GM-CSF, GTP pools decreased to 38% of control after incubation with tiazofurin which is 69% of the predicted value for additive effect. The MTT chemosensitivity assay yielded significantly decreased IC₅₀ values for tiazofurin in HL-60 cells, preincubated with GM-CSF (IC₅₀ decreased from 13 μ m to 10 μ m ). Therefore our results suggest that combination therapy with GM-CSF and tiazofurin may be beneficial for the treatment of refractory leukaemia patients.