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Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of

Lysine-specific demethylase 1 (LSD1) inhibitor; Neuroendocrine tumor; Non-Hodgkin lymphoma Tumor neuroendocrino; Linfoma no Hodgkin; Inhibidores de desmetilasa-1 específica a lisina Tumor neuroendocrí; Limfoma no Hodgkin; Inhibidor de la desmetilasa-1 específica a la lisina Background CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. Methods CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation–associated. Conclusions The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies. This study was supported by Bristol Myers Squibb, Princeton, New Jersey, USA. Writing and editorial assistance was provided by Bio Connections, LLC, funded by Bristol Myers Squibb.

SummaryRett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M1, M2, M3, and M5 mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M1 expression demonstrated a linear relationship with MeCP2 expression, such that M1 levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M1 potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2+/- mice. VU595’s efficacy on apneas in Mecp2+/- mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M1 PAMs could represent a new class of RTT therapeutics.

Deep cerebral venous thrombosis is an uncommon condition, which usually produces headache, altered consciousness, and ocular movement abnormality. Parkinsonism occasionally occurs when there is basal ganglia involvement. We report a case of a 78-year-old man who presented with a rapidly progressive parkinsonism with poor response to dopaminergic therapy. The patient had bilateral and symmetrical hypokinesia, rigidity, and marked gait impairment with festination. Brain MRI showed bilateral thalamic hyperintensity on T2-weighted and FLAIR sequences, with right thalamic and intraventricular hemorrhage due to straight sinus thrombosis. Angiography revealed an arteriovenous malformation in the quadrigeminal cistern with afferent supply from the posterior cerebral arteries, as well as partial thrombosis of the vein of Galen and half of the straight sinus. No predisposing factor for thrombosis was found. Given the location and size of the malformation, and the substantial amount of thalamic and intraventricular hemorrhage, conservative management was decided, with slow but progressive gait improvement. The presence of deep cerebral venous thrombosis should be suspected in cases of rapidly progressive parkinsonism with cognitive decline. As in this case, thrombosis may be secondary to a deep arteriovenous malformation, a very rare occurrence that may require specific therapy.

Purpose:Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma.Experimental Design:This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial.Results:The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years.Conclusions:It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.See related commentary by Pawlyn and Davies, p. 2482

Supplementary Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma

Supplementary Figure from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma

Memory bandwidth and latency constitutes a major performance bottleneck for many data-intensive applications. While high-locality access patterns take advantage of the deep cache hierarchies available in modern processors, unpredictable low-locality patterns cause a significant part of the execution time to be wasted waiting for data. An example of those memory bound applications is the exact matching algorithm based on FM-index, used in some well-known sequence alignment applications. Processing-Near-Memory (PNM) has been proposed as a strategy to overcome the memory wall problem, by placing computation close to data, speeding up memory bound workloads by reducing data movements. This paper presents a performance and energy evaluation of two classes of processor architectures when executing the FM-index exact matching algorithm, as a reference algorithm for exact sequence alignment. One architecture class is processor-centric, based on complex cores and DDR3/4 SDRAM memory technology. The other architecture class is memory-centric, based on simple cores and ultra-high-bandwidth hybrid memory cube (HMC) 3D-stacked memory technologies. The results show that the PNM solution improves performance between 1.26 $$\times$$ and 3.7 $$\times$$ and the energy consumption per operation is reduced between 21 $$\times$$ and 40 $$\times$$ . In addition, a synthetic benchmark RANDOM was developed that mimics the memory access pattern of the FM-index exact matching algorithm, but with a user configurable operational intensity. This benchmark allows us to extend the evaluation to the class of algorithms with similar memory behaviour but running over a range of operational intensity values.

The palmar region of the canine carpus is anatomically complex, and the information found in the literature about its anatomy is inconsistent. The aims of this prospective, descriptive, anatomic study were (1) the clarification and (2) the description of the precise anatomic composition of the palmar region of the canine carpus, with special reference to the canalis carpi. For this study, 92 cadaveric specimens were obtained from 46 dogs that had died for reasons unrelated to this study. Of these, 43 medium-to-large-breed dogs were randomly selected for the dissection of transverse slices of the carpus. Samples of the flexor retinaculum and flexor carpi radialis tendon and surrounding tissues were taken for complementary histology. For additional histology of the palmar structures in their anatomical position, three small breed dogs were randomly selected for obtaining transverse slices. The anatomic characteristics of the components of the palmar region of the canine carpus were qualitatively described, with special attention to the following structures: flexor retinaculum, flexor carpi radialis muscle, arteria and vena mediana, nervus medianus, interflexorius muscle, flexor digitorum profundus muscle, canalis carpi, and arteria and nervus ulnaris. The findings from this study provide reference information about the anatomy of the palmar region of the canine carpus.

The first years of life represent a window of opportunity to establish proper dietary patterns and to maintain them over time. Our aim was to describe the diet of a cohort of Spanish children, from 2 to 36 months, and to identify the components that could influence the quality of the diet at 24 and 36 months of age. This was a longitudinal prospective study analyzing information from administered questionnaires about general characteristics and food frequency consumption in 97 full-term babies. At 2–3 months of age, only 53.6% of infants were observed to be breastfed. The intake of animal foodstuffs from 12 to 36 months was higher than national recommendations, and the contrary was true for fruits and vegetables. The intake of vitamin D was below European Food Safety Authority recommendations. Moreover, energy intake at 6 months was inversely associated with Mediterranean Diet Score (MDS) at 24 months, whereas vegetables intake was positively associated with MDS at 36 months. These results could be useful in the creation of future guidelines focused on the promotion of breastfeeding and healthy early-life food habits, This work was financed by PCIN-2015-233 (Project EarlyMicroHealth from the EU Joint Program Initiative HDHL) (MINECO/FEDER, UE) and by the University of Oviedo (Diet, Rhythms and Early Acquisition Microbiota (DREAMS) Project; Reference no. 2017/00001/003/005/013). S.A. was the recipient of a postdoctoral Juan de la Cierva Contract (Reference no. IJCI-2017-32156) funded by MCIU/AEI/10.13039/501100011033. M.G-M. was the recipient of a pre-doctoral FPU contract FPU18/03393) funded by the Spanish Ministry of Science, Innovation, and Universities.