Evaluation of Potency and Specificity of Cryptophycin-Loaded Antibody-Drug Conjugates.

An enhanced variant of the antimitotic toxin cryptophycin was conjugated to the anti-Her2 monoclonal antibody (mAb) Trastuzumab upon Michael addition. Either antibodies with freed hinge-region cysteines or THIOMAB formats with engineered cysteines in the mAbs light chain were added to a maleimide derivative of cryptophycin. These Antibody-Drug Conjugates (ADCs) showed retained binding to Her2 positive tumor cells and highly efficient cell killing in double-digit pM range on high Her2-expressing SK-BR-3 cells.

Concepts of association between cancer and ionising radiation: accounting for specific biological mechanisms.

The probability that an observed cancer was caused by radiation exposure is usually estimated using cancer rates and risk models from radioepidemiological cohorts and is called assigned share (AS). This definition implicitly assumes that an ongoing carcinogenic process is unaffected by the studied radiation exposure. However, there is strong evidence that radiation can also accelerate an existing clonal development towards cancer.

Estimating long-term health risks after breast cancer radiotherapy: merging evidence from low and high doses.

In breast cancer radiotherapy, substantial radiation exposure of organs other than the treated breast cannot be avoided, potentially inducing second primary cancer or heart disease. While distant organs and large parts of nearby ones receive doses in the mGy-Gy range, small parts of the heart, lung and bone marrow often receive doses as high as 50 Gy. Contemporary treatment planning allows for considerable flexibility in the distribution of this exposure.

Analytical formulas representing track-structure simulations on DNA damage induced by protons and light ions at radiotherapy-relevant energies.

Track structure based simulations valuably complement experimental research on biological effects of ionizing radiation. They provide information at the highest level of detail on initial DNA damage induced by diverse types of radiation. Simulations with the biophysical Monte Carlo code PARTRAC have been used for testing working hypotheses on radiation action mechanisms, for benchmarking other damage codes and as input for modelling subsequent biological processes.

ProZES: the methodology and software tool for assessment of assigned share of radiation in probability of cancer occurrence.

ProZES is a software tool for estimating the probability that a given cancer was caused by preceding exposure to ionising radiation. ProZES calculates this probability, the assigned share, for solid cancers and hematopoietic malignant diseases, in cases of exposures to low-LET radiation, and for lung cancer in cases of exposure to radon. User-specified inputs include birth year, sex, type of diagnosed cancer, age at diagnosis, radiation exposure history and characteristics, and smoking behaviour for lung cancer.

BIOPHYSICAL SIMULATION TOOL PARTRAC: MODELLING PROTON BEAMS AT THERAPY-RELEVANT ENERGIES.

The biophysical simulation tool PARTRAC has been primarily developed to model radiation physics, chemistry and biology on nanometre to micrometre scales. However, the tool can be applied in simulating radiation effects in an event-by-event manner over macroscopic volumes as well. Benchmark simulations are reported showing that PARTRAC does reproduce the macroscopic Bragg peaks of proton beams, although the penetration depths are underestimated by a few per cent for high-energy beams.

Feasibility of reducing differences in estimated doses in nuclear medicine between a patient-specific and a reference phantom.

The feasibility of reducing the differences between patient-specific internal doses and doses estimated using reference phantoms was evaluated. Relatively simple adjustments to a polygon-surface ICRP adult male reference phantom were applied to fit selected individual dimensions using the software Rhinoceros®4.0.

Anthropomorphic dual-lattice voxel models for optimizing image quality and dose.

Using numerical simulations, the influence of various imaging parameters on the resulting image can be determined for various imaging technologies. To achieve this, visualization of fine tissue structures needed to evaluate the image quality with different radiation quality and dose is essential. The present work examines a method that employs simulations of the imaging process using Monte Carlo methods and a combination of a standard and higher resolution voxel models.

An Apoptosis-Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5.

Multivalent ligands of death receptors hold particular promise as tumor cell-specific therapeutic agents because they induce an apoptotic cascade in cancerous cells. Herein, we present a modular approach to generate death receptor 5 (DR5) binding constructs comprising multiple copies of DR5 targeting peptide (DR5TP) covalently bound to biomolecular scaffolds of peptidic nature. This strategy allows for efficient oligomerization of synthetic DR5TP-derived peptides in different spatial orientations using a set of enzyme-promoted conjugations or recombinant production.

A generic approach to engineer antibody pH-switches using combinatorial histidine scanning libraries and yeast display.

There is growing interest in the fast and robust engineering of protein pH-sensitivity that aims to reduce binding at acidic pH, compared to neutral pH. Here, we describe a novel strategy for the incorporation of pH-sensitive antigen binding functions into antibody variable domains using combinatorial histidine scanning libraries and yeast surface display. The strategy allows simultaneous screening for both, high affinity binding at pH 7.

Evaluation of a computer-adaptive test for the assessment of depression (D-CAT) in clinical application.

In the past, a German Computerized Adaptive Test, based on Item Response Theory (IRT), was developed for purposes of assessing the construct depression [Computer-adaptive test for depression (D-CAT)]. This study aims at testing the feasibility and validity of the real computer-adaptive application.The D-CAT, supplied by a bank of 64 items, was administered on personal digital assistants (PDAs) to 423 consecutive patients suffering from psychosomatic and other medical conditions (78 with depression).

Massage therapy reduces physical discomfort and improves mood disturbances in women with breast cancer.

BACKGROUND. A randomized controlled trial was conducted to investigate the efficacy of classical massage treatment in reducing breast cancer-related symptoms and in improving mood disturbances. METHODS.

Functioning and validity of a Computerized Adaptive Test to measure anxiety (A-CAT).

Background: The aim of this study was to evaluate the Computerized Adaptive Test to measure anxiety (A-CAT), a patient-reported outcome questionnaire that uses computerized adaptive testing to measure anxiety.

Methods: The A-CAT builds on an item bank of 50 items that has been built using conventional item analyses and item response theory analyses. The A-CAT was administered on Personal Digital Assistants to n=357 patients diagnosed and treated at the department of Psychosomatic Medicine and Psychotherapy, Charité Berlin, Germany.

An evaluation of patient-reported outcomes found computerized adaptive testing was efficient in assessing stress perception.

Objectives: This study aimed to develop and evaluate a first computerized adaptive test (CAT) for the measurement of stress perception (Stress-CAT), in terms of the two dimensions: exposure to stress and stress reaction.

Study Design And Setting: Item response theory modeling was performed using a two-parameter model (Generalized Partial Credit Model). The evaluation of the Stress-CAT comprised a simulation study and real clinical application.

Evaluation of the Roche cobas s 201 system and cobas TaqScreen multiplex test for blood screening: a European multicenter study.

Background: The Roche cobas TaqScreen test, an automated, multiplex nucleic acid test for blood screening for hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) RNA, human immunodeficiency virus type 1 (HIV-1) groups M and O, and HIV-2 RNA, on the cobas s 201 platform, was evaluated by six European blood screening laboratories.

Study Design And Methods: The 95 percent limit of detection (LOD) of the cobas TaqScreen test for HBV, HCV, and HIV-1, using dilutions of the WHO International Standards, were evaluated. The clinical performance was determined by testing between 2000 to 6000 routine donor samples.

A software tool for modification of human voxel models used for application in radiation protection.

This note describes a new software tool called 'VolumeChange' that was developed to modify the masses and location of organs of virtual human voxel models. A voxel model is a three-dimensional representation of the human body in the form of an array of identification numbers that are arranged in slices, rows and columns. Each entry in this array represents a voxel; organs are represented by those voxels having the same identification number.

Development and evaluation of a computer adaptive test for 'Anxiety' (Anxiety-CAT).

Within the framework of item response theory (IRT), we developed a German version of an item bank, as well as a software application that can be employed to measure anxiety by means of a computer adaptive test (CAT). A sample of n = 2348 psychiatric and psychosomatic patients answered a set of up to 13 standardized questionnaires. 81 items drawn from these questionnaires were considered pertinent to the anxiety construct.

The clinical significance of adaptation to changing health: a meta-analysis of response shift.

Aims: When individuals experience changes in their health states, they may alter their internal standards, values, or conceptualization of quality of life (QOL). Such 'response shifts' can affect or distort QOL outcome measurement, which is of particular concern when evaluating medical or psychosocial interventions. Although clinicians and researchers acknowledge the occurrence of response shifts, little is known about the magnitude and clinical significance of those effects.

[Standardized diagnosing: computer-assisted (CIDI) diagnoses compared to clinically-judged diagnoses in a psychosomatic setting].

Background: Within the past two decades, there has been an increasing trend towards the use of empirically-based, standardized instruments to diagnose mental disorders. The purpose of this study was to investigate the congruence between clinically-derived and standardized computerized diagnoses using the Composite International Diagnostic Interview (CIDI) in a psychosomatic setting.

Patients And Methods: N = 230 inpatients treated at the Department of Psychosomatic Medicine, Charité Berlin, were diagnosed for mental disorders by experienced clinicians and by the CIDI according to the diagnostic criteria of ICD-10 and DSM-IV.

Development of a computer-adaptive test for depression (D-CAT).

Depression is one of the most prevalent mental health problems and measuring depressive symptoms becomes increasingly important in science as well as medical practice. Computer Adaptive Tests (CAT) based on the Item Response Theory (IRT) promise to enhance measurement precision and reduce respondent's burden. Our aim was to develop a CAT application to measure depressive symptoms.

[Disturbed regulation of self-esteem in patients with overt versus covert self-destructive behaviour].

Objectives: According to psychoanalytic models self-harming patients are characterised by an unstable self-system and a disturbed regulation of self-esteem. This is presumed to be denied or dissociated to a greater degree by those who harm themselves secretly (factitious patients) as compared to those who show open self-harm. It is hypothesised and empirically tested that self-destructive patients have more profound disorders of narcissistic self-regulation than patients without self-destruction, and that this should be more evident in patients with overt self-destructive behaviour.