Evaluating sphingosine and its analogues as potential alternatives for aggressive lymphoma treatment.

BACKGROUND: Ceramide (Cer) and sphingosine (Sph) interfere with critical cellular functions relevant for cancer progression and cell survival. While Cer has already been investigated as a potential drug target for lymphoma treatment, information about the potency of sphingosine is scarce. The aim of this study therefore was to evaluate Sph and its synthetic stereoisomer L-threo-sphingosine (Lt-Sph) as potential treatment options for aggressive lymphomas. METHODS: Diffuse large B cell lymphoma (DLBCL) cell lines were incubated with Sph and Lt-Sph and consequently analysed by flow cytometry (FACS), enzyme-linked immunosorbent assay (ELISA), liquid chromatography coupled to triple-quadrupole mass spectrometry (LC/MS/MS), electron microscopy, and Western blot. RESULTS: Sph induced cell death and blocked cell growth independently of S1P receptors in different DLBCL cell lines. Three different modes of Sph-mediated cell death were observed: Apoptosis, autophagy, and protein kinase C (PKC) inhibition. Generation of pro-apoptotic Cer accounted only for a minor portion of the apoptotic rate. CONCLUSION: Sph and its analogues could evolve as alternative treatment options for aggressive lymphomas via PKC inhibition, apoptosis, and autophagy. These physiological responses induced by different intracellular signalling cascades (phosphorylation of JNK, PARP cleavage, LC3-II accumulation) identify Sph and analogues as potent cell death inducing agents.

The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo.

In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity.

Pharmacologic denervation of frown muscles enhances baseline expression of happiness and decreases baseline expression of anger, sadness, and fear.

BACKGROUND: Individuals with intense frowning are commonly perceived as expressing negative emotions. Anger, fear, and sadness are associated with corrugator ("frown") muscle activity. OBJECTIVE: We sought to study how faces were perceived by others after denervation of frown muscles with localized botulinum toxin injections for treatment of facial frown lines. METHODS: Facial photographs were taken from volunteers before and after botulinum toxin injection. These photographs were shown to viewers who were naive to the procedure and asked to rate the expressed intensity of anger, sadness, fear, and happiness. As reference for this task we used a standard set of pictures of facial affect displaying different intensity levels for each emotion tested. RESULTS: Of 40 viewers, 39 were able to discriminate different intensity levels (0%, 25%, 50%, 75%, and 100%) of emotional affect in the control task. According to their ratings faces with denervated frown muscle activity expressed relatively less anger (-40%), fear (-49%), sadness (-10%), and more happiness (+71%). CONCLUSION: Frown muscle activity is essential for both negative and positive emotional expressions. Temporary denervation using botulinum toxin enhances the facial expression of positive emotion resulting in a shift rather than a loss of facial affect.

Amelioration of body odor after intracutaneous axillary injection of botulinum toxin A.

BACKGROUND: Body odor is a ubiquitous phenomenon. It is commonly attributed to sweating and noted explicitly in the axillary area. Botulinum toxin A has recently been shown to be effective for axillary hyperhidrosis. Its effect on axillary odor, however, is unknown. OBSERVATIONS: Sixteen healthy volunteers were injected with botulinum toxin A (Dysport, 100 U dissolved in 0.9% sodium chloride solution) in one axilla and 0.9% sodium chloride solution in the other axilla in a randomized, double-blinded fashion. After 7 days, body odor was assessed by a T-shirt sniff test. A significant reduction of odor intensity was observed for the botulinum toxin A-treated side. The smell was also rated significantly less unpleasant. CONCLUSIONS: These findings suggest that botulinum toxin A can ameliorate or even improve body odor. The underlying mechanisms may include interference with skin microbes and denervation of apoeccrine sweat glands, but this remains to be further investigated.