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Oral decitabine/cedazuridine has been studied in chronic myelomonocytic leukemia (CMML) recently but the molecular changes during this treatment have not been reported so far. We report a CMML patient who was treated with oral decitabine/cedazuridine and showed a stepwise loss of KRAS mutation and trisomy 8 while the TET2 mutated clone gradually increased eventually resulting in clonal hematopoiesis. This case report highlights the disease modifying potential of this treatment in single CMML patients.

This chapter contains sections titled: Introduction Update on Beta‐Amyloid Therapies in Clinical Development Clinical Development of BACE Inhibitors and Other Disease‐Modifying Drugs Final Remarks References

Epilepsy is a common disabling chronic neurological disorder characterized by enduring propensity for generation of seizures which result from abnormal hypersynchronous firing of neurons in the brain. Over 20-30% of epilepsy patients fail to achieve seizure control or soon become resistant to current available therapies. Prolonged seizures or uncontrolled chronic seizures would give rise to neuronal damage or death, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell therapy is potentially a promising novel therapeutic strategy for epilepsy. The regenerative properties of stem cell-based treatment provide an attractive approach for long term seizure control, particularly in drug-resistant epilepsy. Embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs) are capable of differentiating into specialized cell types has been applied for epilepsy treatment in preclinical animal research and clinical trials. In this review, we will focus on the advances of stem cell therapy for epilepsies. The goals of stem cell transplantation, its mechanisms underlying graft effects, the types of grafts and their therapeutic effects. The cell and animal models used for investigating stem cell technology in epilepsy treatment are summarized.

BackgroundHand dexterity impairment is a key feature of disability in people with primary progressive multiple sclerosis (PPMS). So far, ocrelizumab, a recombinant humanized monoclonal antibody that selectively depletes CD20-expressing B cells, is the only therapy approved for PPMS and recent analysis reported its ability to reduce the risk of upper limb disability progression. However, the neural mechanisms underlying hand impairment in PPMS and the brain networks behind the effect of ocrelizumab on manual dexterity are not fully understood.ObjectiveMain aims of our study were: (i) to investigate neurophysiological and behavioural correlates of hand function impairment in subjects with PPMS, and (ii) to use neurophysiologic and behavioural measures to track the effects of ocrelizumab therapy on manual dexterity.MethodsSeventeen PPMS patients and 17 healthy-controls underwent routine neurophysiological protocols assessing the integrity of cortico-spinal and somatosensory pathways and advanced transcranial magnetic stimulation (TMS) protocols evaluating inhibitory (short and long interval intracortical inhibition, short-latency afferent inhibition) and facilitatory (motor thresholds, intracortical facilitation, short-interval intracortical facilitation) circuits in the primary motor cortex. All subjects also underwent behavioural analysis of hand dexterity by means of nine-hole peg test and finger movement analysis, and hand strength with handgrip and three-point pinch test. Neurophysiological and clinical assessments of hand functionality were also performed after 1 year of ocrelizumab therapy.ResultsAt baseline PPMS patients displayed a significant impairment of hand dexterity and strength compared to healthy controls (all p < 0.03). Neurophysiological study disclosed prolonged latencies of standard somatosensory and motor evoked potentials (all p < 0.025) and an overall reduction of intracortical excitability at TMS protocols, involving both excitatory and inhibitory circuits. Importantly, hand dexterity impairment, indexed by delayed 9HPT, correlated with TMS protocols investigating cortical sensorimotor integration (short-latency afferent inhibition, SAI), p = 0.009. Both parameters, 9HPT (p = 0.01) and SAI (p = 0.01), displayed a significant improvement after 1 year of therapy with ocrelizumab.ConclusionIntracortical sensorimotor networks are involved in hand dexterity dysfunction of PPMS. Ocrelizumab therapy displays a beneficial effect on hand dexterity impairment most likely through intracortical networks implicated in fast sensorimotor integration.

Background/Objectives: Pediatric acquired demyelinating syndromes (ADSs) encompass a heterogeneous group of disorders, including multiple sclerosis (MS), MOG antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), with distinct clinical trajectories and prognoses. While analyzed collectively at baseline to reflect real-world diagnostic uncertainty, outcome predictors were also examined according to final diagnosis. Identifying early predictors is crucial for optimizing long-term outcomes. Methods: We retrospectively analyzed 30 pediatric patients (mean onset age: 11.3 years) with ADSs. Clinical, radiological, CSF, antibody, and neurophysiological data were collected and analyzed alongside treatment strategies. Outcomes—EDSS scores, neuroradiological changes, and clinical status—were evaluated over a 3-year period. Results: Final diagnoses included MOGAD (36.6%), MS (33.3%), NMOSD (6.6%), ADEM (10%), and other ADSs (13.3%). At onset, ≥3 brain lesions were present in 76.7% of patients. Disease-modifying therapies (DMTs) were used in 37% and acute immunotherapy in 90%. EDSS progression was significantly associated with DMT use at multiple timepoints, with additional predictors including MRI lesion type, CSF findings, antibody status, and evoked potentials. At 3 years, neurocognitive function predicted clinical outcome. Conclusions: Early immunotherapy and baseline instrumental findings are key predictors of outcome in pediatric ADSs. MOGAD showed a more favorable course, while MS and NMOSD were associated with greater long-term disability. A comprehensive, early diagnostic approach is essential for improving prognosis.

Purpose: Colistin resistance mechanisms involving mutations in chromosomal genes associated with LPS modification are not completely understood. Mutations in genes coding for the MgrB regulator frequently account for colistin resistance in Klebsiella pneumoniae, whereas mutations in genes coding for PhoPQ and PmrAB are frequent in E. coli. Our aim was to perform a genetic analysis of chromosomal mutations in colistin-resistant (MIC [greater than or equal to] 4 [micro]g/mL) clinical isolates of K. pneumoniae (n = 8) and E. coli (n = 7) of different STs. Methods: Isolates were obtained in a 3-year period in a university hospital in Santiago, Chile. Susceptibility to colistin, aminoglycosides, cephalosporins, carbapenems and ciprofloxacin was determined through broth microdilution. Whole genome sequencing was performed for all isolates and chromosomal gene sequences were compared with sequences of colistin-susceptible isolates of the same sequence types. Results: None of the isolates carried mcr genes. Most of the isolates were susceptible to all the antibiotics analyzed. E. coli isolates were ST69, ST127, ST59, ST131 and ST14, and K. pneumoniae isolates were ST454, ST45, ST6293, ST380 and ST25. All the isolates had mutations in chromosomal genes analyzed. K. pneumoniae had mutations mainly in mgrB gene, whereas E. coli had mutations in pmrA, pmrB and pmrE genes. Most of the amino acid changes in LPS- modifying enzymes of colistin- resistant isolates were found in colistin-susceptible isolates of the same and/or different ST. Eleven of them were found only in colistin-resistant isolates. Conclusion: Colistin resistance mechanisms depend on genetic background, and are due to chromosomal mutations, which implies a lower risk of transmission than plasmid-mediated genes. Colistin resistance is not associated with multidrug- resistance, nor to high-risk sequence types. Keywords: sequence type, LPS-modifying enzymes, polymorphism vs potential mutation, MgrB regulator, PmrA-PmrB and PhoP-PhoQ three-component systems

Background: In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS). Objective: To investigate whether simvastatin treatment (80 mg daily for 6 months) in patients with optic neuritis (ON) had a beneficial effect on visual outcome and on brain MRI. Methods: Sixty-four patients with acute ON were randomized to simvastatin treatment (n = 32) or placebo (n = 32) for 6 months. None of the patients had been on immunosuppressive therapy for 6 months prior to inclusion or treated with steroids from symptom onset. Contrast sensitivity (Arden plates), visual acuity, colour perception, visual evoked potentials (VEP) – latency and amplitude, Visual Analogue Scale (VAS) score, and gadolinium enhancing and T2 lesions on brain MRI were evaluated at screening visit, day 14 (except brain MRI), day 90 and day 180. Results: Simvastatin had a beneficial effect on VEP in both latency (p = 0.01) and amplitude (p = 0.01), a borderline effect on the Arden score (p = 0.06) and VAS (p = 0.04), and no effect on brain MRI or on relapse rate between the groups. Conclusion: This study provides Class I evidence that simvastatin 80 mg daily is well tolerated and possibly effective in patients with acute ON.

Background and aims: Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes. Methods: A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated. Results: TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability. Conclusion: TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis.