Biomedical subjects

Peter Schafer

Publications and source records attributed to Peter Schafer.

7 recordsLinked to original sources

PubMed2026

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans↗

PubMed2006

Ethnographically informed community evaluation: a framework and approach for evaluating community-based initiatives.

OBJECTIVES: This paper describes ethnographically informed community evaluation (EICE), a framework for evaluating complex community-based interventions, and illustrates its use in the evaluation of Baltimore City Healthy Start, a federally funded infant mortality prevention project. EICE, which is influenced by cultural anthropology and assets-based community assessment, supports continuous program improvement, resident involvement, and measurement of community-level change. This approach takes into account both individual and contextual levels of analysis. METHODS: The evaluation coupled a participatory approach with qualitative and survey research methods to study community context and how it might contribute to infant mortality and influence program implementation, and to assess community change resulting from the program. Data collection included focus groups, key informant interviews, surveys, neighborhood mapping, journaling, and a study of community problem-solving. RESULTS: The evaluation provided program-related feedback to staff, contributed to a collective understanding of the local context, validated and augmented outcome findings, and imparted skills and a sense of empowerment to the neighborhood. Results reveal a community burdened by crime and social problems, yet showing great diversity in physical and social conditions when examined at the census block group level. Nevertheless, these social and physical hazards in the community are more salient than any specific health issue such as infant mortality. CONCLUSIONS: EICE is a powerful evaluation approach able to respond to the complexities of community-based maternal and child health initiatives designed to institute changes across multiple domains. EICE may be used, in whole or in part, as a supplement to traditional designs.

Anthropology, Cultural↗

PubMed2006

Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis.

Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor-alpha (TNF-alpha) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF-alpha and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF-alpha and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF-alpha and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF-alpha and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1alpha, and IL-1beta and increased IL-RA and TGF-beta1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.

Adult↗

PubMed2005

Keynote review: phosphodiesterase-4 as a therapeutic target.

Cyclic AMP (cAMP) is a key second messenger in all cells. It is compartmentalized within cells and its levels are controlled, as a result of spatially discrete signaling cassettes controlling its generation, detection and degradation. Underpinning compartmentalized cAMP signaling are approximately 20 members of the phosphodiesterase-4 (PDE4) family. The selective inhibition of this family generates profound, functional effects and PDE4 inhibitors are currently under development to provide potential, novel therapeutics for the treatment of inflammatory diseases, such as asthma, chronic obstructive pulmonary disease and psoriasis, as well as treating depression and serving as cognitive enhancers. Here, we delineate the range of PDE4 isoforms, their role in signaling, their structural biology and related preclinical and clinical pharmacology.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro.

The thalidomide analogue and immunomodulatory drug (IMiD) lenalidomide (CC-5013, REVLIMID) is emerging as a useful treatment for a number of cancers and has recently entered phase III trials for multiple myeloma. It has been suggested that the anti-tumor effect of lenalidomide is related to its anti-angiogenic potency. In this regard, we have previously shown that lenalidomide inhibits angiogenesis in both rat and human in vitro models but does not affect endothelial cell proliferation. We now show that oral administration of lenalidomide attenuates growth factor-induced angiogenesis in vivo; the rat mesenteric window assay was utilized to show that lenalidomide significantly inhibits vascularization in a dose-dependent manner. We also found that lenalidomide significantly inhibits growth factor-induced endothelial cell migration. This correlates with the inhibitory effect of lenalidomide on growth factor-induced Akt phosphorylation, thereby providing a potential mechanism for its anti-migratory and subsequent anti-angiogenic effects. These data further support the use of lenalidomide as an orally administered drug for the effective treatment of angiogenesis-dependent conditions, including cancer, and suggest a potential mechanism of action.

Administration, Oral↗

PubMed2003

A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins.

Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.

Animals↗

PubMedDate not supplied

Transport of thalidomide by the human intestinal caco-2 monolayers.

Studies in patients have indicated that the oral absorption of thalidomide is considerably variable at high doses (>200 mg/day). The aim of this study was to investigate the transport of racemic thalidomide using human colon cancer cell line (Caco-2) monolayers, which have been widely used to investigate drug permeability. A typical 21-day protocol was used to prepare Caco-2 monolayers. Thalidomide was determined by a validated high performance liquid chromatography method with ultraviolet detection. The integrity of Caco-2 monolayer was confirmed when the transepithelial electrical resistance (TEER) exceeded 300 Ohmz . cm2, and the leakage of 14C-manitol was <1% per hour. Uptake of thalidomide by Caco-2 cells was very limited (up to 2.1%). The transport of thalidomide appeared to be linear up to 1 hr. Our study indicated that the permeability coefficients (Papp) of thalidomide at 2.5-300 microM from the apical (AP) to basolateral (BL) and from BL to AP side was 2-6 x 10(-5) cm/sec, with a marked decrease in Papp values from AP to BL at increased thalidomide concentration. The transport of thalidomide was sodium-, temperature- and pH-dependent, as replacement of extracellular sodium chloride or reducing temperature and apical pH can result in significant decreases in the Papp values. Additional data indicated that transport of thalidomide is energy-dependent, as it was significantly (P < 0.05) inhibited by the ATP inhibitors, sodium azide and 2,4-dinitrophenol. In addition, DL-glutamic acid, cytidine, diprodomole, papaverine, quinidine, and cyclophosphamide significantly (P < 0.05) inhibited the transport of thalidomide, while the P-glycoprotein inhibitor verapamil and other nucleosides and nucleotides such as thymidine and guanine had no effect. These results indicated that thalidomide was rapidly transported by Caco-2 monolayers, and this might involve a saturable energy-dependent transporter.

Adenosine Triphosphate↗