Phosphatidylinositol 4-kinase IIIß mediates contraction-induced GLUT4 translocation and shows its anti-diabetic action in cardiomyocytes.

In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Phosphatidylinositol-4-kinase-IIIß (PI4KIIIß) is a lipid kinase downstream of protein kinase D1 (PKD1) that mediates Golgi-to-plasma membrane vesicular trafficking in HeLa-cells. In this study, we evaluated whether PI4KIIIß is involved in myocellular GLUT4 translocation induced by contraction or oligomycin (an F1F0-ATP synthase inhibitor that activates contraction-like signaling). Pharmacological targeting, with compound MI14, or genetic silencing of PI4KIIIß inhibited contraction/oligomycin-stimulated GLUT4 translocation and glucose uptake in cardiomyocytes but did not affect CD36 translocation nor LCFA uptake. Addition of the PI4KIIIß enzymatic reaction product phosphatidylinositol-4-phosphate restored oligomycin-stimulated glucose uptake in the presence of MI14. PI4KIIIß activation by PKD1 involves Ser294 phosphorylation and altered its localization with unchanged enzymatic activity. Adenoviral PI4KIIIß overexpression stimulated glucose uptake, but did not activate hypertrophic signaling, indicating that unlike PKD1, PI4KIIIß is selectively involved in GLUT4 translocation. Finally, PI4KIIIß overexpression prevented insulin resistance and contractile dysfunction in lipid-overexposed cardiomyocytes. Together, our studies identify PI4KIIIß as positive and selective regulator of GLUT4 translocation in response to contraction-like signaling, suggesting PI4KIIIß as a promising target to rescue defective glucose uptake in diabetics.

Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells.

We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors.

Erythropoietin-driven signalling and cell migration mediated by polyADP-ribosylation.

BACKGROUND: Recombinant human erythropoietin (EPO) is the leading biotechnology engineered hormone for treatment of anaemia associated with chronic conditions including kidney failure and cancer. The finding of EPO receptors on cancer cells has raised the concern that in addition to its action in erythropoiesis, EPO may promote tumour cell growth. We questioned whether EPO-induced signalling and consequent malignant cell manifestation is mediated by polyADP-ribosylation. METHODS: Erythropoietin-mediated PARP (polyADP-ribose polymerase-1) activation, gene expression and core histone H4 acetylation were examined in UT7 cells, using western blot analysis, RT-PCR and immunofluorescence. Erythropoietin-driven migration of the human breast epithelial cell line MDA-MB-435 was determined by the scratch assay and in migration chambers. RESULTS: We have found that EPO treatment induced PARP activation. Moreover, EPO-driven c-fos and Egr-1 gene expression as well as histone H4 acetylation were mediated via polyADP-ribosylation. Erythropoietin-induced cell migration was blocked by the PARP inhibitor, ABT-888, indicating an essential role for polyADP-ribosylation in this process. CONCLUSIONS: We have identified a novel pathway by which EPO-induced gene expression and breast cancer cell migration are regulated by polyADP-ribosylation. This study introduces new possibilities regarding EPO treatment for cancer-associated anaemia where combining systemic EPO treatment with targeted administration of PARP inhibitors to the tumour may allow safe treatment with EPO, minimising its possible undesirable proliferative effects on the tumour.

[Urinary bladder perforation caused by a loosened acetabular reinforcement ring]. / Harnblasenperforation durch Migration eines Burch-Schneider-Stützrings.

Reinforcement cages are widely used for the treatment of large acetabular bone defects. We report the case of a loosened Burch-Schneider reinforcement ring causing a recurrent macrohaematuria due to a perforation of the urinary bladder. After performing several diagnostic procedures, the patient underwent interdisciplinary revision surgery. Due to the severe destruction of the acetabular bone stock and an infection of the total hip prosthesis as confirmed by fresh frozen section, the hip prosthesis was explanted. At the last follow-up the patient was free of infect-related symptoms and was able to walk with one crutch.

[Incidence of anterior intertrochanteric ossifications after total hip arthroplasty--a retrospective long-term follow-up study]. / Inzidenz von anterioren intertrochantären Ossifikationen bei Hüfttotalendoprothesen--eine retrospektive Langzeituntersuchung.

AIM: This retrospective study investigates the incidence of anterior intertrochanteric ossifications (AIO), especially in comparison with heterotopic ossifications classified according to Brooker. A classification system of AIO regarding short-term results (< 1 year after surgery) was introduced in 2003: AIO occurred solely in 13 % of all cases (ossifications according to Brooker grade 0) and would have been "overlooked" without a lateral X-ray. The incidence of AIO combined with ossifications according to Brooker > 0 was 48.8 % of all cases. Our study reports long-term results, furthermore correlations between ossifications and clinical outcome, rated by the Harris hip score (HHS) and range of motion (ROM), are evaluated. MATERIAL AND METHODS: 149 cementless total hip arthroplasties (Hofer-Imhof threaded cup, straight stem), implanted into 140 patients from November 1991 to December 1994 underwent complete clinical and radiological follow-up from December 2005 to October 2006. The average age of the 81 female and 59 male patients at the time of implantation was 64 years. Without exception, a conventional, transgluteal approach (Bauer) was performed. All patients received indomethacin prophylaxis for 8 consecutive days after surgery. Current X-rays (a.-p. and lateral view) were evaluated in comparison with the former X-rays. RESULTS: AIO were found in 77 cases (51.7 %), heterotopic ossifications corresponding to Brooker in 93 cases (62.4 %), a combination of AIO and Brooker in 58 cases (38.9 %) and solitary AIO in 19 cases (12.8 %). HHS and ROM were not significantly altered by ossifications. CONCLUSION: Our long-term findings compare with the short-term results (indicating lack of new bone formation [heterotopic ossification] after more than one year after surgery, as previously described in the literature concerning ossifications according to Brooker) and verify the incidence rate of solitary AIO. Despite a minor correlation with clinical outcome, AIO could be considered as a possible indicator for predilection of heterotopic bone formation, especially if revision arthroplasty or THA of the contralateral side is needed.

[The interesting case: schwannoma of the nervus pudendus after triple pelvic osteotomy according to toennis]. / Der interessante Fall: Schwannom des Nervus pudendus nach Triple-Osteotomie nach Tönnis.

Schwannomas (neurilemmomas) are benign neural sheath tumours which commonly arise from cranial nerves and cutaneous nerves of the head and neck. The most common site is the acoustic neuroma of the 8th cranial nerve. Pelvic schwannomas are rare and often present with non-specific symptoms leading to misdiagnosis and prolonged morbidity. Most cases of pelvic schwannoma have been reported in the gynaecological and urological literature due to their presentation as a pelvic mass or from urinary tract compression. We present a schwannoma of the nervus pudendus with clinical, radiological, MRI scan and intraoperative findings together with a description of the technique of surgical resection.

[Septic arthritis caused by erysipelotrix rhusiopathiae: case report and review of the literature]. / Kniegelenksinfekt mit Erysipelotrix rhusiopathiae: Fallbericht und Ubersicht der internationalen Fachliteratur.

A 68-year-old man presented at our department with a suspected bacterial arthritis of the left knee. All diagnostic measures confirmed this diagnosis and the detected germ was Erysipelothrix rhusiopathiae. After arthroscopic debridement of the left knee, intravenous and oral antibiotic treatment for a total of 6 weeks, the patient was treated by total knee arthroplasty 6 months after the first presentation. The postoperative follow-up was without any pathological findings. There are only 4 other case reports in the international literature of Erysipelotrix rhusiopathiae linked to septic arthritis in humans. This case report of an infected knee further illustrates the pathogenicity of Erysipelothrix rhusiopathiae in humans.

[The interesting case: Nora's lesion of the big toe]. / Der interessante Fall: Nora-Läsion der Grosszehe.

"Bizarre parosteal osteochondromatous proliferations" are extremely rare manifestations first described by Nora and only a few more than 100 cases have been described in the international literature. In spite of clinically resembling an osteochondroma, a subungual exostosis or a parosteal osteosarcoma, the lesion is characterised by distinct radiological and histological findings. The lesion is defined as a reactive heterotopic ossification and is mostly found in the hands and feet of adults in the third decade of life. A high rate of local recurrence of up to 50% has been described, but since it is defined as a benign lesion no metastases can be found. We report the instructive case of a BPOP ("Nora's lesion") in the area of the proximal phalanx of the big toe in which, after performing a biopsy, a resection of the lesion under preservation of the big toe was performed. At the last follow-up examination (4 years postoperatively) the patient showed no sign of recurrence of the lesion. The clinical, radiological and MRI appearance of the lesion are described together with the distinct clinical findings.

[Total hip replacement in high total hip dislocation by performing a Z-shaped shortening osteotomy]. / Die endoprothetische Versorgung der Koxarthrose bei kongenitaler Hüftgelenksluxation: Implantation einer Hüfttotalendoprothese kombiniert mit Z-förmiger Verkürzungsosteotomie des Femurs.

AIM: Total hip arthroplasty for severe chronic proximal femoral migration, most commonly seen in congenital dislocation of the hip, has been associated with high rates of complications. Placement of the acetabular component in the true acetabulum has yielded the most durable results, but leads to significant limb lengthening. In this paper six cases of a total hip arthroplasty combined with a Z-shaped osteotomy of the proximal femur are described. METHOD: All patients presented with a complete congenital dislocation of the hip. In all procedures the acetabular component was placed in the true acetabulum and the proximal femur was shortened according to a preoperative drawing in a Z-shaped manner. RESULTS: The clinical and radiological results of the patient collective are presented in this study, the mean follow-up period was 60 months. At the last follow-up no nerve palsy, osteotomy pseudarthrosis or dislocation were detected objectively. CONCLUSION: The performed procedure seems to be a viable technique in the treatment of coxarthritis in high total hip dislocation.

PET detection of solitary distant skeletal muscle metastasis of esophageal adenocarcinoma.

A 67-year-old man with progressive dysphagia was recently diagnosed with a gastroesophageal junction adenocarcinoma. Contrast-enhanced CT scans of the abdomen and pelvis reported a large GE junction tumor without evidence of metastatic disease. FDG positron emission tomography revealed intense tracer accumulation in the soft tissue mass at the GE junction consistent with the primary neoplasm. In addition, PET scan also identified a solitary focus of intense FDG accumulation at the musculotendinous junction of the right gluteus minimus muscle. Subsequent MRI demonstrated mild enhancement and could not differentiate between tumor versus inflammation. Needle biopsy was performed and confirmed metastatic esophageal adenocarcinoma. A case of skeletal muscle metastases from late-stage (IV) gastroesophageal adenocarcinoma was previously reported. However, a solitary metastasis to a distant skeletal muscle without evidence of other lymphatic and hematogenous metastasis is quite unusual. The case supports the previous report that PET is superior in detecting distant metastases for initial staging of esophageal carcinoma over CT.

Subcutaneous tumor of the lower eyelid: a potential manifestation of a Dirofilaria repens infection.

PURPOSE: To report a case of Dirofilaria repens presenting as a subcutaneous tumor of the lower eyelid. METHODS: Interventional case report. RESULTS: A 29-year-old man of Greek origin without systemic symptoms presented with a 3-week history of a small painless mass localized in the medial part of the lower eyelid. There was no history of a preceding trauma, injury, or visual impairment; however, the patient had recently been on a holiday in Italy. The lesion persisted after systemic antibiotic treatment. Routine blood tests were normal and the efferent tear ducts were patent. Upon surgical intervention a yellowish, pea-sized cyst-like structure was found beneath the orbicularis muscle and removed in toto. Histologic examination revealed the presence of a wormlike structure with the characteristic features of a single adult Dirofilaria repens nematode. CONCLUSIONS: Infection with the nematode Dirofilaria repens has to be considered in the differential diagnosis of malignant and benign tumors of subcutaneous periocular tissues in patients who traveled to endemic areas.

[Polyethylene liner dislocation in Harris Galante acetabular components]. / Polyäthylen-Inlay-Dislokation des Harris-Galante-Pfannensystems.

AIM: Dislocation and subsequent dissociation of the polyethylene liner as a result of failure of the acetabular locking mechanism is a potential source of failure in the Harris-Galante acetabular component. The purposes of this study are to present seven cases with a liner dislocation due to failure of the liner locking mechanism. METHOD: Between March 1997 and December 2001, seven patients who had had a total hip arthroplasty presented with clinical and radiologic signs of liner dislocation and signs of polyethylene wear of the liner from a Harris Galante acetabular shell. In all cases the intraoperative findings showed evidence of failure of the liner locking mechanism and subsequent dislocation. The medical records, radiographs, operative notes and explanted retrieved components were reviewed. RESULTS: The components had been in situ for an average of 5.3 years (range 1-9 years). Two components were first generation, five were second generation. The symptoms developed spontaneously in five patients, the other two patients described a minor trauma. Radiographs showed eccentric position of the head in all cases. All acetabular components showed an excellent stability intraoperatively, nevertheless we had to remove the well fixed acetabular shell due to complete destruction of the liner locking mechanism in two cases. Treatment consisted of revision of the shell in two patients and exchange of the liner in five patients. All retrieved liners showed severe deformation and/or fracture of the rim. CONCLUSION: Harris Galante modular acetabular components have been used widely for primary and revision arthroplasty. The survival of this implant has been well documented in the literature. Failure of the liner locking mechanism and following dislocation or fracture of the polyethylene liner is a potential cause of failure which may possibly occur more often than the literature to date has documented. We report seven cases of liner dislocation, in which two acetabular components had to be removed completely due to destruction of the liner locking mechanism. In the other five cases exchange of the liner was possible thanks to well timed revision. We believe that, as the liner wears and becomes loose due to an inefficient locking mechanism, the load increases on the polyethylene rim until it deforms or fractures. As a consequence of the prosthetic design at that stage nothing can prevent the liner from rotating out of the shell.

[Anterior intertrochanteric ossification after total hip arthroplasty]. / Die anteriore intertrochantäre Ossifikation nach Hüfttotalendoprothesenimplantation.

AIM: Heterotopic paraarticular ossifications are usually identified by an anterior-posterior radiograph of the corresponding hip and are consecutively classified by the well accepted methods of Brooker, Arcq or deLee. In these methods ossifications are solely evaluated by the means of a single a-p radiograph, hence a major part of ossifications located in the anterior intertrochanteric region cannot be evaluated. Our study deals with the incidence of ossifications exclusively verifiable by an axial radiograph. METHOD: In the present study 209 patients' axial radiographs were retrospectively analysed by using our simple method of classification. In the axial projection these ossifications are situated anterior of the intertrochanteric region, therefore we created the term "anterior intertrochanteric ossification (AIO)". After developing a simple topographic scheme we classified these appearances by localisation and size. RESULTS: After total hip arthroplasty by using the transgluteal approach ossifications situated in the anterior intertrochanteric region can develop. These ossifications appear as bone islands, shield or clip like (without fixed connection to the femoral cortical bone) or as solid exostoses. Due to their strict anterior localisation these formations are often solely verifiable by the means of an axial (Lauenstein) radiograph. We were able to identify anterior intertrochanteric ossifications (AIO) in 97 out of 209 patients (48.4 %), 27 patients (13 %) developing an anterior intertrochanteric ossification were classified grade 0 according to the methods of Brooker, Arcq and deLee. CONCLUSION: According to the widely accepted methods of classification of paraarticular ossifications depending on a single a-p radiograph of the corresponding hip, 13 % of paraarticular ossifications would remain undocumented because of their strict anterior intertrochanteric position.

Neutrophil apoptosis in autoimmune Fas-defective MRL lpr/lpr mice.

The apoptosis-defective lpr (fas) mutation in MRL mice causes the early onset of a lupus-like autoimmune disease with concomitant inflammation. In order to analyse the consequences of the impaired Fas-dependent apoptosis on inflammation, the susceptibility to apoptosis of polymorphonuclear leukocytes (PMN), obtained from MRL lpr/lpr mice, has been studied. Peritoneal PMN from lpr/lpr and control (+/+) mice were recruited with a mild inflammatory stimulus. The number of cells collected from the peritoneal cavity of young lpr/lpr mice was comparable to that obtained from age-matched control mice, indicating that PMN homeostasis is maintained regardless of the loss-of-function Fas mutation. Recruited neutrophils were exposed in culture to apoptosis-inducing stimuli. Treatment with agonist anti-Fas antibody increased apoptosis of +/+ PMN, but did not affect lpr/lpr PMN which do not express Fas on their surface. However, lpr/lpr PMN could undergo both spontaneous and stimulus-induced apoptosis in a fashion comparable to or higher than that of control +/+ mice. Analysis of mRNA expression revealed that lpr/lpr PMN have reduced expression of IL-18, whereas IL-1beta, IFNgamma, caspase 1 and caspase 3 are expressed at levels comparable to those of +/+ cells. However, caspase-3-like activity was higher in PMN from lpr/lpr mice than in +/+ cells, and correlated with enhanced apoptosis. It could be concluded that in young, uncompromised lpr/lpr mice, PMN homeostasis is still fully regulated through the involvement of Fas-independent, compensatory, apoptotic mechanisms. This could include an increased participation of caspase 3 in the apoptotic pathway, consequent to enhanced activation of the enzyme and to the decreased production of IL-18, which acts as a competitive caspase 3 substrate.

Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models.

Recombinant human erythropoietin (rHuEpo) has been used successfully in the treatment of cancer-related anemia. Clinical observations with several patients with multiple-myeloma treated with rHuEpo has shown, in addition to the improved quality of life, a longer survival than expected, considering the poor prognostic features of these patients. Based on these observations, we evaluated the potential biological effects of rHuEpo on the course of tumor progression by using murine myeloma models (MOPC-315-IgAlambda(2) and 5T33 MM-IgG(2b)). Here we report that daily treatment of MOPC-315 tumor-bearing mice with rHuEpo for several weeks induced complete tumor regression in 30-60% of mice. All regressors that were rechallenged with tumor cells rejected tumor growth, and this resistance was tumor specific. The Epo-triggered therapeutic effect was shown to be attributed to a T cell-mediated mechanism. Serum Ig analysis indicated a reduction in MOPC-315 lambda light chain in regressor mice. Intradermal inoculation of 5T33 MM tumor cells followed by Epo treatment induced tumor regression in 60% of mice. The common clinical manifestation of myeloma bone disease in patients with multiple-myeloma was established in these myeloma models. Epo administration to these tumor-bearing mice markedly prolonged their survival and reduced mortality. Therefore, erythropoietin seems to act as an antitumor therapeutic agent in addition to its red blood cell-stimulating activity.

Lymphoscintigraphy using (99m)Tc filtered sulfur colloid in chylothorax: a case report.

OBJECTIVE: A 66-y-old man was diagnosed with esophageal carcinoma and underwent a right thoracotomy and esophagectomy. Postoperatively, a recurring right pleural effusion developed. Because an attempt at lymphangiography failed, lymphoscintigraphy was suggested. Because of the inability to obtain radiolabeled albumin, dextran, or nanocolloid, we used filtered sulfur colloid. (0.1 um). The study confirmed the diagnosis of chylothorax.

Lymphocytes from autoimmune MRL lpr/lpr mice are hyperresponsive to IL-18 and overexpress the IL-18 receptor accessory chain.

MRL lpr/lpr mice spontaneously develop a severe autoimmune lupus syndrome characterized by strong autoantibody production and massive lymphoproliferation, in which IFN-gamma plays a major pathogenic effect. The role of the IFN-gamma-inducing cytokine IL-18 in the autoimmune syndrome of lpr/lpr mice has been investigated. In response to IL-18, lymph node cells of lpr/lpr mice produce significant amounts of IFN-gamma and proliferate more potently as compared with cells from +/+ mice. Cells likely responsible for such hyperresponsiveness to IL-18 include NK cells and the CD4(+)/CD8(+) self-reactive T lymphocytes characteristically present in lymph nodes of lpr/lpr mice. Analysis of the expression of IL-18R complex revealed that mRNA for the IL-18R alpha-chain is constitutively expressed at similar level both in +/+ and lpr/lpr lymphocytes. In contrast, the expression of the accessory receptor chain IL-18R beta is low in unstimulated +/+ cells but significantly high in lpr/lpr cells. Thus, the abnormally high expression of the IL-18R chain IL-18R beta could be one of the causes of the hyperresponsiveness of lpr/lpr cells to IL-18 at the basis of consequent enhancement of IFN-gamma production and development of IFN-gamma-dependent autoimmune pathology.

Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor.

Hematopoietic cytokine receptors, such as the erythropoietin receptor (EpoR), are single membrane-spanning proteins. Signal transduction through EpoR is crucial for the formation of mature erythrocytes. Structural evidence shows that in the unliganded form EpoR exists as a preformed homodimer in an open scissor-like conformation precluding the activation of signaling. In contrast to the extracellular domain of the growth hormone receptor (GHR), the structure of the agonist-bound EpoR extracellular region shows only minimal contacts between the membrane-proximal regions. This evidence suggests that the domains facilitating receptor dimerization may differ between cytokine receptors. We show that the EpoR transmembrane domain (TM) has a strong potential to self interact in a bacterial reporter system. Abolishing self assembly of the EpoR TM by a double point mutation (Leu 240-Leu 241 mutated to Gly-Pro) impairs signal transduction by EpoR in hematopoietic cells and the formation of erythroid colonies upon reconstitution in erythroid progenitor cells from EpoR(-/-) mice. Interestingly, inhibiting TM self assembly in the constitutively active mutant EpoR R129C abrogates formation of disulfide-linked receptor homodimers and consequently results in the loss of ligand-independent signal transduction. Thus, efficient signal transduction through EpoR and possibly other preformed receptor oligomers may be determined by the dynamics of TM self assembly.

Sestamibi/iodine subtraction single photon emission computed tomography in reoperative secondary hyperparathyroidism.

BACKGROUND: Sestamibi/iodine subtraction single photon emission computed tomography (SPECT) has been used successfully for the preoperative localization of adenomatous and hyperplastic parathyroid tissue in primary hyperparathyroidism, but the clinical usefulness of this technique in secondary hyperparathyroidism remains uncertain. The purpose of this study was to evaluate parathyroid localization that uses sestamibi/iodine subtraction SPECT in patients with secondary hyperparathyroidism before reoperative parathyroid surgery. METHODS: Fourteen consecutive patients with chronic renal failure and secondary hyperparathyroidism who had previously undergone total parathyroidectomy combined with parathyroid autotransplantation in a sternocleidomastoid muscle were studied. Before reoperation, each patient received 400 microCi of sodium iodide I 123 orally and 20 to 25 mCi of technetium Tc 99m ((99m)Tc)-sestamibi intravenously, followed by sestamibi/iodine subtraction SPECT of the neck and chest. At surgery, the location, weight, and histopathologic results of all identified parathyroid tissue were recorded. RESULTS: At surgery, 1 hyperplastic parathyroid gland was resected from each of 13 patients; including 1 undescended gland, 6 parathyroid autotransplants, and 5 mediastinal glands. The mean weight of the resected parathyroid glands was 1707 mg (range, 85-5300 mg). Sestamibi/iodine subtraction SPECT correctly identified and localized all 13 parathyroid glands (100% sensitivity) and was negative in the 1 patient whose surgery was unsuccessful. CONCLUSIONS: The (99m)Tc-sestamibi/(123)I subtraction SPECT is able to correctly localize hyperplastic parathyroid tissue in patients with secondary hyperparathyroidism who have previously undergone parathyroid surgery and is a clinically useful study before reoperation.

Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment.

Advances in genetic engineering have created opportunities for improved understanding of the molecular basis of carcinogenesis. Through selective introduction, activation, and inactivation of specific genes, investigators can produce mice of unique genotypes and phenotypes that afford insights into the events and mechanisms responsible for tumor formation. It has been suggested that such animals might be used for routine testing of chemicals to determine their carcinogenic potential because the animals may be mechanistically relevant for understanding and predicting the human response to exposure to the chemical being tested. Before transgenic and knockout mice can be used as an adjunct or alternative to the conventional 2-year rodent bioassay, information related to the animal line to be used, study design, and data analysis and interpretation must be carefully considered. Here, we identify and review such information relative to Tg.AC and rasH2 transgenic mice and p53+/- and XPA-/- knockout mice, all of which have been proposed for use in chemical carcinogenicity testing. In addition, the implications of findings of tumors in transgenic and knockout animals when exposed to chemicals is discussed in the context of human health risk assessment.