X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Modeling and predicting optimal treatment scheduling between the antiangiogenic drug sunitinib and irinotecan in preclinical settings.

We present a system of nonlinear ordinary differential equations used to quantify the complex dynamics of the interactions between tumor growth, vasculature generation, and antiangiogenic treatment. The primary dataset consists of longitudinal tumor size measurements (1,371 total observations) in 105 colorectal tumor-bearing mice. Mice received single or combination administration of sunitinib, an antiangiogenic agent, and/or irinotecan, a cytotoxic agent. Depending on the dataset, parameter estimation was performed either using a mixed-effect approach or by nonlinear least squares. Through a log-likelihood ratio test, we conclude that there is a potential synergistic interaction between sunitinib when administered in combination with irinotecan in preclinical settings. Model simulations were then compared to data from a follow-up preclinical experiment. We conclude that the model has predictive value in identifying the therapeutic window in which the timing between the administrations of these two drugs is most effective.

Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.

The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.

Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth.

Monoclonal antibodies (mAbs) to HER2 are currently used to treat breast cancer, but low clinical efficacy, along with primary and acquired resistance to therapy, commonly limit clinical applications. We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects, probably due to accelerated receptor degradation. Here, we extend these observations to three-dimensional mammary cell models, and compare the effects of single mAbs with the effects of antibody combinations. Collectively, our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth. Importantly, while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype, combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids. In conclusion, our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells. Hence, combining mAbs offers a therapeutic strategy, potentially able to enhance clinical efficacy of existing antireceptor immunotherapeutics.

[Treatment of breast cancer: from hormones to antibodies]. / Therapie des Mammakarzinoms: Vom Hormon bis zum Antikörper.

Breast cancer, as one of the most frequent tumor entities, is the object of intensive research activity. Clinical research over the last few years has resulted in an increasing differentiation in treatment strategies in the adjuvant setting as well as in metastatic breast cancer. Treatment decision is guided by different risk groups, and relevant changes in clinical practice have arisen in hormonal treatment as well as in chemotherapy. Furthermore, new agents have shown clinical activity, in particular trastuzumab has emerged as standard treatment in HER2 positive breast cancer. It was even licensed in 2006 for adjuvant treatment.

[Causal attributions and coping with illness by breast cancer patients: results of a longitudinal study]. / Kausalattribution und Krankheitsverarbeitung bei Brustkrebspatientinnen: Ergebnisse einer Längsschnittuntersuchung.

The present 3-year longitudinal study investigated the relationship between causal attribution and coping mechanism. Data were collected in a group of 66 breast cancer patients by self-report questionnaires. Three issues were addressed: 1. How do the patients explain the cause of their illness? 2. Do the subjective causes change over the course of three years? 3. What kind of relationship can be found between the causal attributions and the coping mechanism of the patients? Results showed a predominance of psychological attribution. Only little statistical prove could be found for changes between the four ratings. Analysing the individual data of the patients however revealed changing perceptions for about half the patients. A relationship between psychological attribution and depressive coping and problem solving as well were found.

[The co-evolutional focus in individual, couple and family therapy]. / Der koevolutive Fokus in der Einzel-, Paar- und Familientherapie.

A concrete formulation of focus is proposed that in structure and use is suitable for individual as well as couples and family therapy. The concept of coevolution (Willi 1985, 1991) forms a basis for the supposition that important personal developments are realised in human relationships. The development of one person is challenged, taxed, or hindered by the development of other persons. The formulation of a coevolutional focus consists of four steps: 1) The context of the relationship in which the current conflict emerges; 2) The identification of delayed stages of development; 3) The personal and interactional conditions which block this development; 4) Concrete changes which make the progress in the intended development recognizable. The focus in couples and family therapy integrates the impending development of the participants in their collusive interactions.

[People in divorce and their ambivalence: initial use of a newly developed couples inventory]. / Menschen in Trennung und ihre Ambivalenz: Erste Anwendung eines neu entwickelten Paarinventars.

It has been reported that intact internal, external and social accommodation is related to a stable partnership between men and women. Every partnership, however, is also characterized by a certain potential towards separation that may develop despite of the named stabilizing factors. This led to the question of how the accommodation is constituted in men and women during separation. A written questionnaire was, therefore, sent to a total of 35 men and women in separation. The Bradburn inventory was used to define the well-being of the volunteers in relation to a representative sample. Using a newly developed inventory, a number of items had to be rated twice: once to reflect the condition at the beginning of the partnership and once to reflect the situation during the last year. In addition, the relative contribution of a particular item in favor or against separation was asked. The Bradburn inventory shows that the general well-being of the test sample is more impaired than that of the representative sample. The evaluation of the 80% returned questionnaires revealed worsening of all items. Most important reasons to finish the partnership were i) the lack of verbal communication, ii) extramarital affairs, and iii) the impression that the partnership limits the personal development. Reasons to continue the partnership were different between those who initiated the separation and those who were left: The initiators predominantly mentioned structural factors such as financial situation, living conditions and care for children, whereas the non-initiators predominantly mentioned internal qualities of the partnership.(ABSTRACT TRUNCATED AT 250 WORDS)

Coping strategies and course of disease of breast cancer patients. Results of a 3-year longitudinal study.

In a prospective 3-year longitudinal study investigating correlations between coping strategies and course of breast cancer a consecutive series of 107 patients were assessed for biological and psychosocial data. Data analysis indicated no significant correlations between coping strategies and course of cancer. On the other hand, biological parameters such as size of tumor and lymph node stage at time of surgery correlated significantly with the course of disease. It was concluded that the assessed indicators of coping are of little importance in regard to the course of the disease and less predictive compared with somatical parameters of breast cancer.

[Therapy goals from the viewpoint of patients: what is the role of partnership?]. / Therapieziele aus der Sicht von Patienten: Welche Rolle spielt die Partnerschaft?

The topic of this investigation is the significance of the real field of reference of psychosomatic patients in inpatient psychotherapy. Data on expected therapeutic results and changes experienced by patients with a steady partner were submitted to evaluation by content analysis. The greatest importance is attached in each case to individual growth, followed by symptoms and interpersonal relationships. All patients place more emphasis on the actual field of reference at the end than at the beginning of therapy; this difference is more strongly pronounced in patients without couples interviews. Evidently patients with couples interviews assess their partnership more realistically than those without them. Moreover, therapists have presumably developed "an ear for the partner" irrespective of whether or not the partner is included.

[The significance of psychosocial factors for the course of breast cancer--results of a prospective follow-up study]. / Die Bedeutung psychosozialer Faktoren für den Verlauf von Mammakarzinom-Erkrankungen--Ausgangsbefunde einer prospektiven Verlaufsstudie.

The meaning of psychosocial factors for the course of breast cancer--First results of a prospective research project. Studies investigating the meaning of psychosocial factors for the course of cancerous diseases have so far been contradictious. In this paper the basic datas and first results of a prospective research project on this topic covering 107 breast cancer patients are reported. Somatic datas such as stage of lymph-nodes, type of surgery and additional treatments (radiation therapy or chemotherapy), are less important for the coping process 6 months after primary treatment than the cognitive attitudes of the patients toward their disease. About 56 percent of the patients coped quite well with their disease, 44 percent showed difficulties. The group of patients whose somatic and psychosocial prognosis was judged rather unfavorably at the time of the first examination, showed the highest rate of recidivation and progredience in the follow-up of the first 12 months.

[Causal attributions and coping with illness in patients with breast cancer]. / Ursachenattribution und Krankheitsbewältigung bei Patientinnen mit Mammakarzinom.

The aim of the present study was to investigate whether breast cancer patients who attribute their disease to different causes differ in their ability to cope with the disease. A semistructured interview technique was used to question a total of 107 patients, six months after the operation, about the psychological stress involved in their disease and how they coped with it. In addition, two further questionnaires were used: the Freiburg questionnaire concerning adjustment to the disease (FKV) and another questionnaire to register the causes to which the patients attributed their disease (PUK). The results revealed that environmental pollution was the most frequent and important cause of disease mentioned by the patients. This mainly correlated with depressive adjustment to the disease. The same type of adjustment was also frequently seen in patients who attributed their disease to individual psychic problems. Daily stress mentioned as the cause of disease was additionally closely connected with the desire for social support. In accordance with the poor adjustment in connection with internal causes reported in the literature, it was further shown that attribution to psychic causes made psychic adjustment to the disease more difficult, at least within the first six months after the operation.