Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax).

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

[Guidelines for social medicine assessment and evaluation of primary fibromyalgia]. / Leitlinien zur sozialmedizinischen Erfassung und Beurteilung der primären Fibromyalgie.

Primary fibromyalgia belongs to the spectrum of rheumatic soft tissue disorders. It is characterized by wide-spread chronic pain and a low pain threshold. The etiology of the disorders is still unknown. Clinical diagnosis requires examination by a rheumatologically trained physician pathognomonic findings are largely lacking. Classification criteria have been published by Wolfe et al. on behalf of the American College of Rheumatology (ACR). The prognosis of FMA is unfavourable and does hardly, respond to therapy. FMA patients' work capacity cannot be established by mere diagnosis; individual impairments have to be taken into account: Clinical, psychosocial and behavioural dimensions have to be considered. Neither inpatient rehabilitation nor early retirement seem to significantly influence the course of FMA. The patient can usually work fulltime in jobs requiring light activities.

Detection and intensity discrimination of a sinusoid.

Intensity discrimination thresholds were measured for gated 100-ms, 1000-Hz tones. Discrimination thresholds were measured at several intensities near absolute threshold as well as at 30, 60, and 90 dB SPL. Psychometric functions were obtained for several of these discrimination conditions, and for detection of the signal in quiet. The results showed that Weber's law is approximately valid for standards as low as 0 dB SL. Small amounts of negative masking were observed even when the data were expressed in terms of increment energy. The psychometric functions for the discrimination conditions had a similar form and were shallower than the psychometric function for the detection of a signal in quiet. A similar set of conditions was run in the presence of a continuous, broadband noise. The results were generally in agreement with those obtained in quiet, but slight differences suggested that the variability which limits performance in the two conditions is different. The results are discussed in terms of the effects of nonlinear transduction, the effects of uncertainty, and contrast mechanisms as proposed by Laming [Sensory Analysis (Academic, London, 1986)].

Absolute intensity discrimination using two responses.

The observer was asked to judge whether a comparison sound was more or less intense than a standard sound of 60 dB SPL. The sounds were broadband noises of 100-ms duration. The independent variables were the range of intensities used in the set of comparison sounds and the presence or absence of feedback. The main dependent variable was the variability of such judgments, which was measured from the psychometric function. The variability, measured in terms of the Weber function, increased from about 1.5 to 4 dB when the stimulus range changed from 10 to 60 dB. Increases in stimulus range increased the variability of the binary judgments in this task, as they had in previous experiments where multiple responses were required. Feedback improved performance primarily at the largest ranges. Only a small fraction of these changes in variability stems from sequential effects.

[Thymomas (author's transl)]. / Thymustumoren. Immunologie und Klinik.

Immunological investigations concerning pathological autoantibodies and defects of humoral immunity were performed in 7 patients with thymomas, 5 of which showed invasive growth. The number of B and T lymphocytes in blood was determined at the same time using membrane markers as well as blood lymphocyte stimulation with phytohaemagglutinine. Two of the 3 patients with auto-antibodies against striated muscles or nuclei showed the clinical signs of accompanying disease (myasthenia gravis, lupus erythematodes). A humoral immunodisturbance with IgM deficiency was demonstrable in one patient and was accompanied by clinical symptoms. Lymphopenia with decreased numbers and functional disturbance of T and B lymphocytes could be shown in the majority of patients. Immunological investigations simplify proof of accompanying diseases in thymomas. These represent an important prognostic criterium in the same way as does invasive growth.