BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Plasticity in exocytosis revealed through the effects of repetitive stimuli affect the content of nanometer vesicles and the fraction of transmitter released

Electrochemical techniques with disk and nano-tip electrodes, together with calcium imaging, were used to examine the effect of short-interval repetitive stimuli on both exocytosis and vesicular content in a model cell line. We show that the number of events decreases markedly with repeated stimuli suggesting a depletion of exocytosis machinery. However, repetitive stimuli induce a more stable fusion pore, leading to an increased amount of neurotransmitter release. In contrast, the total neurotransmitter content inside the vesicles decreases after repetitive stimuli, resulting in a higher average release fraction from each event. We suggest a possible mechanism regarding a link between activity-induced plasticity and fraction of release.

Uporaba samostoječe usidrane medvretenčne kletke pri operativnem zdravljenju simptomatske vratne spondiloze

Background:One of the most common surgical operations for treatment of cervical spondylosis is anterior cervical discectomy with fusion (ACDF). In order to achieve stable fusion after discectomy and avoid dysphagia the artificial stand-alone zero-profile cages with integrated screws were developed and introduced into clinical practice. Outcome and complications after ACDF with such cages were not adequately assessed yet.Methods:We analyzed 20 consecutive patients with cervical spondylosis treated in our institution with ACDF with stand-alone zero-profile cage Zero-P. Before and after surgery and then 6, 12 and 24 months after surgery we assessed the level of pain with VAS scale, severity of myelopathy with mJOA scale and dysphagia with four level scale. Treatment outcome was assessed after 2 years according to Odom's criteria.Results:No complications occurred during surgery or recovery after surgery. The VAS score after surgery and then after 6, 12 and 24 months was statistically significantly lower than before surgery (p<0.05). The mJOA scores were 6, 12 and 24 months after surgery statistically significantly higher than before surgery (p<0.05). Transient and mild dysphagia was present after surgery in 15% (3/20) of patients and 6, 12 or 24 months after surgery in none. Outcome after 2 years was excellent in 9 patients and good in 11 patients.Conclusions:Operative treatment of symptomatic cervical spondylosis with ACDF using stand-alone zero-profile cage with integrated screws is safe and efficient. Incidence of dysphagia after surgery is low and generally transient.

Charcot Spine and Parkinson’s Disease

Charcot spine is rare condition whose association with Parkinson’s disease (PD) has not been reported yet. The authors reported the cases of two patients with PD who developed Charcot spine. Both patients presented with a history of back pain and bilateral radicular leg pain. They had complete clinical and radiological assessment. Lumbar spine was involved in both patients. Clinical features and response to treatment were described. In the first case, circumferential fusion and stabilization were performed on the dislocated vertebral levels. A solid and stable fusion of the spine was obtained with satisfactory clinical outcome. Surgical treatment has been recommended to the other patient. In both cases, no other neurological etiology was found to account for Charcot spine. In conclusion, Charcot spine is associated with several neurological affections but has not previously been reported in association with Parkinson’s disease.