Selective antibody-mediated targeting of class I MHC to EGFR-expressing tumor cells induces potent antitumor CTL activity in vitro and in vivo

Epidermal growth factor receptor (EGFR) is highly overexpressed in many tumor types. We present a new fusion molecule that can target solid tumors that express EGFR. The fusion molecule combines the advantage(s) of the well-established tumor targeting capabilities of high affinity recombinant fragments of antibodies with the known efficient, specific and potent killing ability of CD8 T lymphocytes directed against highly antigenic MHC/peptide complexes. A recombinant chimeric molecule was created by the genetic fusion of the scFv antibody fragment derived from the anti-EGFR monoclonal antibody C225, to monomeric single-chain HLA-A2 complexes containing immunodominant tumor or viral-specific peptides. The fusion protein can induce very efficiently CTL-dependent lysis of EGFR-expressing tumor cells regardless of the expression of self peptide-MHC complexes. Moreover, the molecule exhibited very potent antitumor activity in vivo in nude mice bearing preestablished human tumor xenografts. These in vitro and in vivo results indicate that recombinant scFv-MHC-peptide fusion molecules might represent a novel and powerful approach to immunotherapy of solid tumors, bridging antibody and T lymphocyte attack on cancer cells.     

Treatment outcome of female agoraphobics 3-9 years after exposure in vivo: a comparison with healthy controls

It is well documented that most agoraphobics, with or without panic disorder, respond to exposure in vivo. But only little data compared their anxiety levels at follow-up (FU) with those of healthy controls. Forty-two female agoraphobics with or without panic disorder participated in FUs 3-9 years after exposure in vivo. Agoraphobic symptoms were compared to data of 42 healthy controls, who were matched according to gender, age, marital and occupational status. Remission criteria were defined from agoraphobia scores of the controls. A total of 17 (40%) of the patients had no further agoraphobic symptoms at all. A total of 15 (36%) patients still had mild-to-moderate agoraphobic symptoms at FU. A total of 10 (24%) were non-responders and suffered from severe agoraphobia at FU. The percentage of treated patients with complete remission is much higher than previously reported. However, the majority still suffer from mild or severe agoraphobic symptoms and could possibly benefit from additional interventions.     

The relationship between chronic fatigue and somatization syndrome: a general population survey

OBJECTIVE: The objective of this study was to assess the prevalence of chronic fatigue (CF) and its association with somatization syndrome [Somatization Syndrome Index (SSI) 4/6: >/=4 somatoform symptoms in men, 6 in women] in the general population. METHODS: A representative sample of the German population (N=2412) completed a fatigue questionnaire and a screening instrument for current somatoform symptoms (Screening for Somatoform Symptoms 7). RESULTS: The prevalence rate of CF was 6.1% (n=147). Females were affected significantly more often as compared with males (7% vs. 5.1%). The mean number of somatoform symptoms was higher in CF cases than in control subjects without CF (11 vs. 2; P<.001). Seventy-two percent of the subjects with CF fulfilled the SSI4/6 criterion for somatization syndrome. Quality of life (EUROHIS-QOL and 8-item Short-Form Health Survey) and well-being (5-item WHO Well-Being Index) were markedly decreased in CF and SSI4/6. The results of regression analyses suggest that fatigue and somatization severity had a similar impact on quality of life. CONCLUSIONS: The results suggest that CF is relevant in the general population. Its substantial overlap with somatization syndrome supports the hypothesis that the two syndromes are only partially different manifestations of the same underlying processes.     

Memory bias for health-related information in somatoform disorders

OBJECTIVE: Cognitive processes are considered to be relevant to the etiology and maintenance of somatoform disorders (SFDs). The aim of this study was to assess explicit and implicit information-processing bias for disorder-congruent information in SFDs. METHODS: A clinical sample of 33 patients suffering from multiple somatoform symptoms (SSI-3/5) and 25 healthy controls performed an encoding task with computer-presented word lists (illness related, negative, positive, neutral content), subsequently followed by explicit memory tests (free recall and recognition) and an implicit test (word-stem completion). RESULTS: The somatoform group showed a memory bias for illness-related stimuli in the word-stem completion task, whereas the two groups did not differ in explicit memory tests. This effect could not be explained by comorbid depression. CONCLUSION: These results provide some support for current theories on SFDs.     

The fibrinogen gamma (FGG) 10034C>T polymorphism is associated with venous thrombosis

INTRODUCTION: Thrombin-induced conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in the stabilization of thrombi. Elevated plasma fibrinogen levels have been associated with both increased plasma viscosity and platelet aggregability. Recently, a haplotype-tagging single nucleotide polymorphism characterized by a C to T substitution at nucleotide 10034 of the fibrinogen gamma gene (FGG 10034C>T, rs2066865), has been proposed as a novel risk factor for deep venous thrombosis (DVT). Aim of the present study was to provide further data on the role of the FGG 10034C>T polymorphism for DVT. MATERIALS AND METHODS: FGG genotypes were determined by 5'-exonuclease assay (TaqMan) in 358 patients with documented DVT and a total of 783 control subjects. RESULTS: In a multivariate analysis adjusting for age, sex, presence of factor V Leiden and carriage of prothrombin 20210A, homozygosity for the FGG 10034 TT genotype yielded an odds ratio of 2.01 (95% CI 1.23-3.31; p=0.006) for DVT. CONCLUSIONS: Our data confirm the primary finding that the FGG 10034C>T polymorphism is associated with DVT risk.     

Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412

MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expression and functional role of MCL-1 in neoplastic MCs and sought to determine whether MCL-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemical examination, primary neoplastic MCs expressed MCL-1 mRNA and the MCL-1 protein in all SM patients examined. Moreover, MCL-1 was detectable in both subclones of the MC line HMC-1--HMC-1.1 cells, which lack the SM-related KIT mutation D816V, and HMC-1.2 cells, which carry KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to MCL-1-specific antisense oligonucleotides (ASOs) or MCL-1-specific siRNA resulted in reduced survival and increased apoptosis compared with untreated cells. Moreover, MCL-1 ASOs were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MCs, with synergistic effects observed with PKC412, AMN107, and imatinib in HMC-1.1 cells and with PKC412 in HMC-1.2 cells. Together, these data show that MCL-1 is a novel survival factor and an attractive target in neoplastic MCs.