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Biomedical subjects

F Otto

Publications and source records attributed to F Otto.

At least 19 recordsLinked to original sources
PubMed2006

Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer.

This phase II study was conducted to determine the efficacy and toxicity of a gemcitabine (GEM) and oxaliplatin (OX) chemotherapy protocol in patients with unresectable biliary tract cancer (BTC). Patients were treated with GEM 1000 mg m-2 (30 min infusion) on days 1, 8, 15, and OX 100 mg m-2 (2 h infusion) on days 1 and 15 (gemcitabine and oxaliplatin (GEMOX-3 protocol), repeated every 28 days. The data were collected according to the Simon 2-stage design for a single centre phase II study (alpha=0.05; beta=0.2). Primary end point was response rate; secondary end points were time-to-progression (TTP), median survival, and safety profile. Thirty-one patients were enrolled in the study between July 2002 and April 2005. Therapeutic responses were as follows: partial response in eight patients (26%, 95% confidence interval (CI) 14-44), stable disease in 14 patients (45%, 95%CI 29-62), resulting in a disease control rate of 71%. Nine patients (29%, 95%CI 16-47) had progressive disease. Median TTP was 6.5 months. Median overall survival was 11 months. Common Toxicity Criteria (CTC) Grade 3-4 toxicities were transient thrombocytopenia (23%), peripheral sensory neuropathy (19%), leucopenia (16%), and anaemia (10%). In conclusion the GEMOX-3 protocol is active and well tolerated in patients with advanced BTC. It can be applied in an outpatient setting with three visits per month only.

Adenocarcinoma↗
PubMed2005

The pentapeptide QYNAD does not inhibit neuronal network activity.

BACKGROUND: Controversial data was published about the sodium channel-blocking effect of the endogenous pentapeptide QYNAD, which is elevated in patients with multiple sclerosis and Guillain-Barré-syndrome. In some experiments with single cells and nerve preparations QYNAD inhibited sodium currents to the same extent as the known sodium channel blocker lidocaine whereas in other laboratory testing QYNAD failed to show any effect at all. METHODS: Micro-electrode arrays with cultured neuronal networks are highly suitable to determine neuroactive activity of applied substances. The impact on electrophysiological parameter changes was compared between QYNAD and the established sodium channel blockers lidocaine and tetrodotoxin (TTX). RESULTS: QYNAD did not alter network activity whereas the sodium channel blockers lidocaine (IC50 14.9 micorM) and tetrodotoxin (IC50 1.1 nM) reversibly decreased network activity in similar concentrations as in patch-clamp experiments. This decrease of spontaneous electrophysiological activity was achieved by prolonging the interburst-interval. CONCLUSION: Although QYNAD might have mild effects on single-cell sodium currents, there is no significant effect on neuronal network function. These results raise concerns about QYNAD exhibiting a relevant impact on functional disability of the central nervous system in patients.

Animals↗
PubMed2001

Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection.

To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.

Animals↗
PubMed2001

The prognostic value of the expression of collagenase IV, cathepsin D and metallothionein in squamous cell carcinomas of the skin determined by immunohistochemistry.

We analyzed 53 specimens from primary squamous cell carcinomas of the skin for the expression of collagenase IV, cathepsin D and metallothionein by means of immunohistochemistry along with histological data. We compared tumors that metastasized (30) with tumors that did not (23) during a follow-up period of at least 5 years. The expression of the two proteolytic enzymes cathepsin D and collagenase IV was also assessed at the invading front of the tumors. Statistical analyses revealed significant differences for the overall expression of cathepsin D (P < 0.05), expression of cathepsin at the invading front (P < 0.05) and the tumor thickness (P < 0.01). The results showed that cathepsin D may be a prognostic factor for squamous cell carcinomas of the skin. We then combined the results of parameters with statistically significant differences by multiplication. The prognostic value of such a combined risk-factor score showed higher confidence than any of the single parameters alone: a sensitivity of 63.3%, a specificity of 87.0% and an efficiency of 73.6%. This kind of combined risk-factor score might be used to more accurately detect patients at high risk of metastasis.

Aged↗
PubMed2001

Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis.

The human RUNX3/AML2 gene belongs to the 'runt domain' family of transcription factors that act as gene expression regulators in major developmental pathways. Here, we describe the expression pattern of Runx3 during mouse embryogenesis compared to the expression pattern of Runx1. E10.5 and E14.5-E16.5 embryos were analyzed using both immunohistochemistry and beta-galactosidase activity of targeted Runx3 and Runx1 loci. We found that Runx3 expression overlapped with that of Runx1 in the hematopoietic system, whereas in sensory ganglia, epidermal appendages, and developing skeletal elements, their expression was confined to different compartments. These data provide new insights into the function of Runx3 and Runx1 in organogenesis and support the possibility that cross-regulation between them plays a role in embryogenesis.

Animals↗
PubMed2001

Prognostic immunohistochemical markers of primary human melanomas.

BACKGROUND: Several clinical and histological factors of primary melanomas comprise a relatively large quantity of prognostic information. OBJECTIVE: To find immunohistochemical markers that can improve the prognostic accuracy achieved by factors that are available without extra laboratory work, i.e. mitotic rate, tumour thickness, ulceration, localization, gender and age. METHODS: Immunohistochemical markers were determined on frozen sections. Univariate and multivariate Cox regression analyses were performed after 5-10 years follow-up. RESULTS: Seven immunohistochemical markers were related to disease-free and overall survival in univariate Cox regression analysis: Ki-67, human leucocyte antigen (HLA) -DQ, HLA-DP, Muc 18, A-10-33, transferrin receptor, and H-2-8-10. Only Ki-67 (n = 399) and HLA-DQ (n = 452) retained prognostic significance when evaluated in multivariate analyses in several models together with tumour thickness alone and with tumour thickness, gender, mitotic rate, age, localization and ulceration. CONCLUSIONS: Ki-67 and HLA-DQ may be useful for risk assessments in primary melanomas.

Adolescent↗
PubMed2000

The p24 family member p23 is required for early embryonic development.

The p24 family of type I integral-membrane proteins, which are localised in the endoplasmic reticulum (ER), the intermediate compartment and the Golgi apparatus, are thought to function as receptors for cargo exit from the ER and in transport vesicle formation. Members of the p24 family have been found in a molecular complex and are enriched in COPI-coated vesicles, which are involved in membrane traffic between the ER and Golgi complex. Although expressed abundantly, simultaneous deletion of several family members does not appear to affect cell viability and protein secretion in yeast. In order to gain more insights into the physiological roles of different p24 proteins, we generated mice deficient in the expression of one family member, p23 (also called 24delta1, see for alternative nomenclature). In contrast to yeast genetics, in mice disruption of both p23 alleles resulted in early embryonic lethality. Inactivation of one allele led not only to reduced levels of p23 itself but also to reduced levels of other family members. The reduction in steady-state protein levels also induced structural changes in the Golgi apparatus, such as the formation of dilated saccules. The generation of mice deficient in p23 expression has revealed an essential and non-redundant role for p23 in the earliest stages of mammalian development. It has also provided genetic evidence for the participation of p24 family members in oligomeric complexes and indicates a structural role for these proteins in maintaining the integrity of the early secretory pathway.

Alleles↗
PubMed2000

Using handheld computers to document family practice resident procedure experience.

BACKGROUND AND OBJECTIVES: We examined the use of inexpensive handheld computers in documenting resident procedures. With a handheld computer, data is entered at the time of the procedure, eliminating the problem of double entry. METHODS: Connectivity and ease of use were important factors considered when choosing a handheld computer. All residents received a handheld computer for data entry. Residency staff downloaded the data to a desktop computer. At the same time, data useful to residents was placed on their devices. The process of generating individual and program reports required 2 hours of staff time each month. Survey data regarding use and acceptance by residents was collected. RESULTS: Eighty-eight percent of residents collected data on their handheld computer. Those residents responding to a survey felt that the handheld computer was "very useful," and 73% reported daily use. Initial costs were $310 per resident. CONCLUSIONS: Handheld computers streamlined the collection of procedure data for family practice residents. Handheld computers assisted in producing timely and useful procedural reports for both residents and the residency program. Additional uses of handheld computers were beneficial to the program and the residents.

Computers↗
PubMed2000

A receptor-type protein tyrosine phosphatase PTP zeta is expressed in human cutaneous melanomas.

We describe the expression of a receptor-type protein tyrosine phosphatase PTP zeta (or RPTP beta) in human cutaneous melanomas as detected by means of immunohistochemistry. The expression of PTP zeta has been described to be restricted to the central nervous system. In developing mice brain high levels of PTP zeta have been detected indicating its developmental importance; PTP zeta is also expressed in glioblastoma and neuroblastoma. By the use of immunohistochemistry we detected PTP zeta in human primary and metastatic melanomas. The melanocytes of healthy skin remained negative. Due to the developmental origin of the melanocytes from neural crest, this represents a further example for transformed cells switching back to express molecules related to their ontogenetic history. These promising initial results have to be verified in larger scaled studies; the inclusion of nevi will be necessary to further elucidate the role of PTP zeta in melanocyte transformation and melanoma development.

Antigens, Neoplasm↗
PubMed1999

Can immunohistochemical markers and mitotic rate improve prognostic precision in patients with primary melanoma?

BACKGROUND: In addition to tumor thickness, several other prognostic parameters have been identified in primary human melanomas. Some are available readily (localization, gender, age, and ulceration). Others must be evaluated with a moderate or even substantial amount of work (mitoses and immunohistochemical markers). This study was undertaken to determine whether this extra effort is justified because it actually improves the precision of prognostic statements. METHODS: Immunohistologic markers were determined on frozen sections from 691 biopsies of human melanomas with the immunoperoxidase method. Univariate and multivariate Cox regression analyses were performed with metastases and with death as endpoints. RESULTS: Fifteen parameters were related to disease free survival in univariate Cox regression analysis: tumor thickness, ulceration, localization, gender, age, mitoses, and the immunohistochemical markers very late antigen (VLA)-2, human leukocyte antigen (HLA)-ABC, HLA-DR, NKI-beteb, Mel 14, intercellular adhesion molecule (ICAM-1), K-1-2, G-7-E2, and H-2-4-7. Three of the easily available parameters exhibited independent significance in multivariate Cox regression analysis: tumor thickness, ulceration, and localization. If mitotic rate was included in this model, then it had independent prognostic significance but ulceration was no longer significant. However, the model that included tumor thickness, localization, and ulceration had a slightly higher overall chi-square test score, indicating a better performance compared with thickness, localization, and mitoses. The model that included tumor thickness, localization, and mitoses could not be improved by any of the immunohistochemical markers in this study. CONCLUSIONS: Nine immunohistochemical markers with established prognostic significance for primary human melanoma were not found to improve a prognostic model that included tumor thickness, localization, and mitoses. If mitoses was replaced by ulceration, then the model performed slightly better, although ulceration was not significant in the presence of mitoses.

Aged↗
PubMed1999

Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice.

Using lymphocyte function-associated antigen (LFA)-1(-/-) mice, we have examined the role of LFA-1 and other integrins in the recirculation of lymphocytes. LFA-1 has a key role in migration to peripheral lymph nodes (pLNs), and influences migration into other LNs. Second, the alpha4 integrins, alpha4beta7 and alpha4beta1, have a hitherto unrecognized ability to compensate for the lack of LFA-1 in migration to pLNs. These findings are confirmed using normal mice and blocking LFA-1 and alpha4 monoclonal antibodies. Unexpectedly, vascular cell adhesion molecule (VCAM)-1, which is essential in inflammatory responses, serves as the ligand for the alpha4 integrins on pLN high endothelial venules. VCAM-1 also participates in trafficking into mesenteric LNs and Peyer's patch nodes where mucosal addressin cell adhesion molecule 1 (MAdCAM-1), the alpha4beta7-specific ligand, dominates. Both alpha4beta1, interacting with ligand VCAM-1, and also LFA-1 participate in substantial lymphocyte recirculation through bone marrow. These observations suggest that organ-specific adhesion receptor usage in mature lymphocyte recirculation is not as rigidly adhered to as previously considered, and that the same basic sets of adhesion receptors are used in both lymphocyte homing and inflammatory responses.

Animals↗
PubMed1999

Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma.

Previous in vitro studies have demonstrated that endogenously produced human interleukin-8 (IL-8) can act as an important growth factor for human melanoma cells in vitro. The present study, has investigated whether IL-8 mRNA expression in primary melanomas may be of prognostic relevance with regard to melanoma progression and metastatic spread. In order to evaluate the clinical significance of IL-8 mRNA expression of melanoma cells in vivo, 59 melanocytic tissue specimens (37 primary melanomas and 22 melanocytic naevi) were studied using a semiquantitative in situ hybridization technique. Significant mRNA expression of IL-8 was found in 59 per cent (22/37) of melanomas. In 19 per cent (7/37) of the malignant melanomas, additional hybridization signals were noted within keratinocytes of the overlying epidermis. In contrast, paralesional normal-appearing epidermis and melanocytes in non-malignant lesions (melanocytic naevi) showed no IL-8 mRNA. Analysis of the relationship between IL-8 expression and clinico-histopathological features showed a significant association between IL-8 mRNA expression and the histological melanoma subtype (IL-8 mRNA: 14/19 in superficial spreading melanoma versus 4/12 in nodular melanoma, p< 0.05). Furthermore, IL-8 expression in primary tumours could be correlated with the patients' clinical course, with time to progression being significantly reduced in primary tumours expressing IL-8 in either the tumour cells or keratinocytes of the overlying epidermis. These results demonstrate for the first time that IL-8 expression, as detected by in situ hybridization in primary tumours, may serve as a significant prognostic factor for tumour progression in human malignant melanoma.

Adult↗
PubMed1999

The expression of proteolytic enzymes at the dermal invading front of primary cutaneous melanoma predicts metastasis.

The expression of three proteinases Cathepsin B (Cath. B), Cathepsin D (Cath. D) and Collagenase IV (Coll. IV) has been retrospectively analyzed within an immunohistochemical study on routinely fixed, paraffin embedded tissues from 147 primary cutaneous melanomas belonging to the classes pT3 and pT4. The development of these melanomas has been followed for at least five years. We compared the expression of these proteolytic enzymes in tumors that metastized during the follow-up-period with that in tumors that did not metastize. The expression at the dermal invading front of the tumors showed higher prognostic values (Cath. B chi 2 = 40.03, p < 0.001; Cath. D chi 2 = 90.95, p < 0.001; Coll. IV chi 2 = 44.46, p < 0.001) than the overall expression of these enzymes (Cath. B chi 2 = 5.63, p = 0.018; Cath. D chi 2 = 6.21, p = 0.010; Coll. IV chi 2 = 6.57, p = 0.010). The distribution of protease-expression inside the tumor turned out to be important for the prognostic value, which might also lead to higher prognostic confidence when applied to other tumors.

Cathepsin B↗
PubMed1999

Regulation of chondrocyte differentiation by Cbfa1.

Cbfa1, a developmentally expressed transcription factor of the runt family, was recently shown to be essential for osteoblast differentiation. We have investigated the role of Cbfa1 in endochondral bone formation using Cbfa1-deficient mice. Histology and in situ hybridization with probes for indian hedgehog (Ihh), collagen type X and osteopontin performed at E13.5, E14.5 and E17.5 demonstrated a lack of hypertrophic chondrocytes in the anlagen of the humerus and the phalanges and a delayed onset of hypertrophy in radius/ulna in Cbfa1-/- mice. Detailed analysis of Cbfa1 expression using whole mount in situ hybridization and a lacZ reporter gene reveled strong expression not only in osteoblasts but also in pre-hypertrophic and hypertrophic chondrocytes. Our studies identify Cbfa1 as a major positive regulator of chondrocyte differentiation.

Animals↗
PubMed1999

Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a dominantly inherited disorder characterized by patent fontanelles, wide cranial sutures, hypoplasia of clavicles, short stature, supernumerary teeth, and other skeletal anomalies. We recently demonstrated that mutations in the transcription factor CBFA1, on chromosome 6p21, are associated with CCD. We have now analyzed the CBFA1 gene in 42 unrelated patients with CCD. In 18 patients, mutations were detected in the coding region of the CBFA1 gene, including 8 frameshift, 2 nonsense, and 9 missense mutations, as well as 2 novel polymorphisms. A cluster of missense mutations at arginine 225 (R225) identifies this residue as crucial for CBFA1 function. In vitro green fluorescent protein fusion studies show that R225 mutations interfere with nuclear accumulation of CBFA1 protein. There is no phenotypic difference between patients with deletions or frameshifts and those with other intragenic mutations, suggesting that CCD is generally caused by haploinsufficiency. However, we were able to extend the CCD phenotypic spectrum. A missense mutation identified in one family with supernumerary teeth and a radiologically normal skeleton indicates that mutations in CBFA1 can be associated exclusively with a dental phenotype. In addition, one patient with severe CCD and a frameshift mutation in codon 402 had osteoporosis leading to recurrent bone fractures and scoliosis, providing first evidence that CBFA1 may help maintain adult bone, in addition to its function in bone development.

Bone and Bones↗
PubMed1999

Forces between like-charged plates in electrolyte solution: ion-solvent packing versus electrostatic effects.

The anisotropic hypernetted-chain approximation is solved numerically for mixtures of neutral hard-sphere solvent particles and divalent counterions between charged plates. A detailed analysis of the different components of force acting between the plates is given. At separations of a few solvent diameters, it is shown that even at relatively high surface charge and moderate solvent density, the ionic contribution to the force tends to be dominated by the hard-core or packing component. If the ions and solvent particles are of equal size, then the net pressure between the plates can be reasonably well approximated by adding the pressures of pure one-component ionic and solvent systems. However, if the ion and solvent diameters are significantly different the pressure curve is more complex, and the simple superposition of the ionic and solvent pressures no longer works. For this case, we show that to a good approximation it is still possible to divide the pressure into electrostatic and hard-core components, but now the appropriate hard-core system must itself be a mixture of neutral hard spheres.

Journal Article↗