Non-surgical oncology - Guidelines on Parenteral Nutrition, Chapter 19.

Reduced nutritional state is associated with unfavourable outcomes and a lower quality of life in patients with malignancies. Patients with active tumour disease frequently have insufficient food intake. The resting energy expenditure in cancer patients can be increased, decreased, or remain unchanged compared to predicted values. Tumours may result in varying degrees of systemic pro-inflammatory processes with secondary effects on all significant metabolic pathways. Therapeutic objectives are to stabilise nutritional state with oral/enteral nutrition and parenteral nutrition (PN) and thus to prevent or reduce progressive weight loss. The maintenance or improvement of quality of life, and the increase in the effectiveness and a reduction in the side-effects of antitumor therapy are further objectives. Indications for PN in tumour patients are essentially identical to those in patients with benign illnesses, with preference given to oral or enteral nutrition when feasible. A combined nutritional concept is preferred if oral or enteral nutrition are possible but not sufficient. There are generally no accepted standards for ideal energy and nutrient intakes in oncological patients, particularly when exclusive artificial nutrition is administered. The use of PN as a general accompaniment to radiotherapy or chemotherapy is not indicated, but PN is indicated in chronic severe radiogenic enteritis or after allogenic transplantation with pronounced mucositis or GvH-related gastrointestinal damage for prolonged periods, with particular attention to increased risk of bleeding and infection. No PN is necessary in the terminal phase.

Ethical and legal points of view in parenteral nutrition - Guidelines on Parenteral Nutrition, Chapter 12.

Adequate nutrition is a part of medical treatment and is influenced by ethical and legal considerations. Patients, who cannot be sufficiently fed via the gastrointestinal tract, have the fundamental right to receive PN (parenteral nutrition) even so patients who are unable to give their consent. General objectives in nutrition support are to supply adequate nutrition with regards to the prevention of malnutrition and its consequences (increased morbidity and mortality), and thereby promoting improved outcome and/or quality of life for the patient considering always the patient's needs and wishes. The requests of the patient to renounce PN should be respected where a signed living will is helpful. During the course of a terminal illness the nutrition has to be adapted individually according to the needs and wishes of a patient in the corresponding phase. Capability of consent should be checked in each individual case and for each measure on an individual basis. Consent should only be accepted if the patient is capable of recognizing the nature, meaning and importance of the intervention as well as the consequences of relinquishment of such an intervention, and is capable to make a self-determined decision. If the patient is not capable of consenting, the patient's living will is the most important document when determining their assumed will and legally binding. Otherwise a guardian appointed by the patient, or the representative appointed by the court (if the patient has made no provisions) can make the decision.

A novel member of the testis specific serine kinase family, tssk-3, expressed in the Leydig cells of sexually mature mice.

We have recently characterized two members of a novel family of murine testis specific serine kinases, tssk-1 and tssk-2, expressed exclusively in spermatids undergoing spermiogenesis. Using a differential screening approach we have isolated a third family member, tssk-3. The open reading frame of tssk-3 encodes a protein of 275 amino acids, consisting essentially of a serine/threonine protein kinase domain only. In contrast, tssk-1 and -2 have distinct, approximately 100 amino acid domains located C-terminally to the kinase domain. Immunoprecipitation experiments revealed that while tssk-1 and tssk-2 form detergent resistant complexes, tssk-3 is not associated with either protein. Expression of tssk-3 was induced at puberty, persisted during adulthood and was restricted to the interstitial Leydig cells of post-pubertal males.

Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis.

Morphogenesis of the mammary gland occurs mainly during adult life and is dependent on a complex interplay of hormonal, cell-cell and cell-matrix interactions. The molecular mechanisms involved in pattern formation of the mammary epithelium in adult life are poorly understood. Recently, several members of the Eph family of receptor tyrosine kinases and their ligands have been shown to participate in pattern formation during embryogenesis and conceivably may fulfill similar functions during adult morphogenesis. We have investigated the expression of a member of this family, EphB4, and its cognate ligand, ephrin-B2, during normal and malignant mouse mammary morphogenesis. A spatially, temporarily and hormonally coordinated expression of both the receptor and ligand was observed. The receptor was predominantly localized in the myoepithelial cells surrounding the ducts and alveoli whereas ligand expression was limited to the luminal epithelial cells. Expression of both was induced at the onset of gland morphogenesis at puberty and was differentially regulated during the estrus cycle. Ovariectomy of pre-pubertal or adult females abolished the expression of both receptor and ligand and administration of estrogen alone was sufficient to restore their normal expression. Disruption of the balanced expression was observed during experimental mouse mammary carcinogenesis. Ligand expression was lost at the onset of tumorigenesis and receptor expression shifted from myoepithelial to epithelial cells with progressive malignancy. These results implicate both the EphB4 receptor and its ligand ephrin-B2 in the hormone dependent morphogenesis of the mammary gland. Furthermore, their deregulated expression may contribute to mammary carcinogenesis.

A novel family of serine/threonine kinases participating in spermiogenesis.

The molecular mechanisms regulating the spectacular cytodifferentiation observed during spermiogenesis are poorly understood. We have recently identified a murine testis-specific serine kinase (tssk) 1, constituting a novel subfamily of serine/threonine kinases. Using low stringency screening we have isolated and molecularly characterized a second closely related family member, tssk 2, which is probably the orthologue of the human DGS-G gene. Expression of tssk 1 and tssk 2 was limited to the testis of sexually mature males. Immunohistochemical staining localized both kinases to the cytoplasm of late spermatids and to structures resembling residual bodies. tssk 1 and tssk 2 were absent in released sperms in the lumen of the seminiferous tubules and the epididymis, demonstrating a tight window of expression restricted to the last stages of spermatid maturation. In vitro kinase assays of immunoprecipitates containing either tssk 1 or tssk 2 revealed no autophosphorylation of the kinases, however, they led to serine phosphorylation of a coprecipitating protein of approximately 65 kD. A search for interacting proteins using the yeast two-hybrid system with tssk 1 and tssk 2 cDNA as baits and a prey cDNA library from mouse testis, led to the isolation of a novel cDNA, interacting specifically with both tssk 1 and tssk 2, and encoding the coprecipitated 65-kD protein phosphorylated by both kinases. Interestingly, expression of the interacting clone was also testis specific and paralleled the developmental expression observed for the kinases themselves. These results represent the first demonstration of the involvement of a distinct kinase family, the tssk serine/threonine kinases, together with a substrate in the cytodifferentiation of late spermatids to sperms.

Protein tyrosine kinase expression during the estrous cycle and carcinogenesis of the mammary gland.

The susceptibility of the mammary epithelium to neoplastic transformation is linked to the exposure to estrogen during the estrous cycle. The effects of the estrous cycle on the mouse mammary gland have been investigated by analyzing 3H-thymidine incorporation, milk protein gene expression and DNA fragmentation. We found that the mammary epithelium undergoes limited proliferation, differentiation and apoptosis in a cycle-dependent manner. The estrous-responsive regulators of the mammary epithelium are unknown; however, considering the integral role of protein tyrosine kinases (PTKs) in the control of normal and malignant development, members of this family of enzymes are likely candidates for such regulatory molecules. Using a RT-PCR-based cloning strategy, we have undertaken a survey of PTKs expressed in the mammary gland at defined stages of development, with special emphasis on the estrous cycle. We identified 21 known and 4 novel PTKs. Their expression was analyzed throughout mammary gland development and in mammary neoplasias using a transgenic mouse model for invasive and non-invasive carcinogenesis. Most of the identified PTKs showed highest expression during the estrous cycle and were down-regulated during pregnancy and lactation. Deregulated expression was rarely observed in the non-invasive mammary tumors. In contrast, 10 of 19 PTKs expressed during the estrous cycle were also over-expressed in the invasive carcinomas, mostly involving members of the receptor family of PTKs.