Sarcomas are rare malignant tumors arising from the mesenchymal tissues at all body sites. The inventors show that in a mouse model of p16/p19 deficiency prone to tumor development, the absence of the mouse pantetheinase Vnn1 enhances the frequency of aggressive fibrosarcomas. They also show that reintroduction of a catalytically active form of the Vnn1 pantetheinase limits tumor growth in vivo. Interestingly, VNN1 expression in human sarcomas is associated with reduced aggressiveness and lower risk of metastatic relapse in patients. In conclusion, Vnn1 represents a novel marker of sarcoma and may modulate tumor aggressiveness by sustaining myofibroblast cell differentiation, thereby limiting evolution towards undifferentiated tumors. The present invention relates to the use of Vnn1 as a biomarker and a therapeutic target in sarcomas.

The present invention relates to extended release compositions of an amino-C2-C6-alkyl nitrate and of pharmaceutically acceptable salt thereof, in particular 2-aminoethyl nitrate, and to fixed dose combinations with further pharmaceutically active drug substances. 2-Aminoethyl nitrate does not provoke nitrate tolerance, but has a very short half life in physiological systems.

The present invention relates to extended release compositions of an amino-C2-C6-alkyl nitrate and of pharmaceutically acceptable salt thereof, in particular 2-aminoethyl nitrate, and to fixed dose combinations with further pharmaceutically active drug substances. 2-Aminoethyl nitrate does not provoke nitrate tolerance, but has a very short half life in physiological systems.

Salts of hexylamine, for example, hexylamine succinate and tri-hexylamine citrate and their method of production are described. The disclosure also relates to compositions comprising hexyalmine, for example, for reducing appetite in a human subject, treating obesity in a human subject, preventing obesity in a human subject, preventing weight gain in a human subject, increasing fat loss in a human subject, treating an overweight human subject, increasing athletic performance in a human subject, increasing endurance in a human subject, increasing muscle strength in a human subject, improving cognitive function in a human subject, treating ADHD in a human subject, increasing sweating in a human subject, reducing reaction time of a human subject, increasing psychomotor vigilance of a human subject, enhancing memory in a human subject, increasing central nervous system activity in a human subject, and enhancing alertness, attention, concentration, and/or memory in a human subject.

Salts of hexylamine, for example, hexylamine succinate and tri-hexylamine citrate and their method of production are described. The disclosure also relates to compositions comprising hexyalmine, for example, for reducing appetite in a human subject, treating obesity in a human subject, preventing obesity in a human subject, preventing weight gain in a human subject, increasing fat loss in a human subject, treating an overweight human subject, increasing athletic performance in a human subject, increasing endurance in a human subject, increasing muscle strength in a human subject, improving cognitive function in a human subject, treating ADHD in a human subject, increasing sweating in a human subject, reducing reaction time of a human subject, increasing psychomotor vigilance of a human subject, enhancing memory in a human subject, increasing central nervous system activity in a human subject, and enhancing alertness, attention, concentration, and/or memory in a human subject.

Salts of hexylamine, for example, hexylamine succinate and tri-hexylamine citrate and their method of production are described. The disclosure also relates to compositions comprising hexyalmine, for example, for reducing appetite in a human subject, treating obesity in a human subject, preventing obesity in a human subject, preventing weight gain in a human subject, increasing fat loss in a human subject, treating an overweight human subject, increasing athletic performance in a human subject, increasing endurance in a human subject, increasing muscle strength in a human subject, improving cognitive function in a human subject, treating ADHD in a human subject, increasing sweating in a human subject, reducing reaction time of a human subject, increasing psychomotor vigilance of a human subject, enhancing memory in a human subject, increasing central nervous system activity in a human subject, and enhancing alertness, attention, concentration, and/or memory in a human subject.

The present invention relates to non-naturally occurring antibodies or active antibody fragments specifically binding the calcium-sensing receptor (CaSR), acting as positive allosteric modulators (PAMs) to provide for potent therapeutic agents. More particular, the immunoglobulin single variable domains (ISVDs) identified herein reveal a novel therapeutic strategy to reduce parathyroid hormone release in a subject, and are therefore suitable for treatment of hypercalcemia disorders. Moreover, co-application of such an ISVD and a synthetic PAM or calcimimetic results in a synergistic agonistic CaSR activity providing for pharmaceutical compositions as next generation CaSR drugs.

The present invention relates to non-naturally occurring antibodies or active antibody fragments specifically binding the calcium-sensing receptor (CaSR), acting as positive allosteric modulators (PAMs) to provide for potent therapeutic agents. More particular, the immunoglobulin single variable domains (ISVDs) identified herein reveal a novel therapeutic strategy to reduce parathyroid hormone release in a subject, and are therefore suitable for treatment of hypercalcemia disorders. Moreover, co-application of such an ISVD and a synthetic PAM or calcimimetic results in a synergistic agonistic CaSR activity providing for pharmaceutical compositions as next generation CaSR drugs.

Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

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Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

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