Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders.

Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. Our understanding of the molecular mechanism of action of thalidomide and its derivatives has advanced dramatically since the identification of cereblon (CRBN) as their direct target. The binding of thalidomide derivatives to CRBN, a substrate recognition receptor for Cullin 4 RING E3 ubiquitin ligase (CRL4), induces the recruitment of non-native substrates to CRL4CRBN and their subsequent degradation. This discovery was a breakthrough in the current rapid development of protein-degrading agents because clarification of the mechanism of action of thalidomide derivatives has demonstrated the clinical value of these compounds. This review provides an overview of the mechanism of action of thalidomide and its derivatives and describes perspectives for protein degraders.

ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells.

The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4CRBN. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.

Bioavailability, safety and tolerability of intravenous brivaracetam in healthy Japanese participants.

We characterised the bioavailability, safety, and tolerability of brivaracetam 100 mg intravenous bolus and 15-min infusion versus oral reference tablet in 24 healthy Japanese participants.In this randomised, open-label, three-period crossover study, participants received three 100 mg single doses of brivaracetam, intravenous bolus, infusion, and oral tablets. Maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUCt), and area under the plasma concentration-time curve extrapolated to infinity (AUCinf), were compared using analysis of variance following logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares means ratios (intravenous:oral). Safety and tolerability were monitored throughout the study.The 90% CIs around AUCt and AUCinf ratios were entirely contained within the bioequivalence limits (0.80-1.25), but Cmax was outside the limits (90% CI: 1.77-2.08 and 1.44-1.70 for intravenous bolus and infusion, respectively). All participants completed the study. Brivaracetam was well tolerated.Because response to brivaracetam in epilepsy is related to exposure (AUC), no dose adjustment is warranted when switching from oral to intravenous dosing. However, investigations are needed to assess the safety and tolerability of intravenous administration in Japanese patients with epilepsy.

p63 is a cereblon substrate involved in thalidomide teratogenicity.

Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4CRBN substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4CRBN neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. ∆Np63α is essential for limb development, while TAp63α is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of ∆Np63α and TAp63α, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.

Delayed hypersensitivity reaction to a dural repair substitute.

BACKGROUND: Modern neurosurgeons commonly rely on dural grafts to aid in obtaining watertight closures when the native dura itself cannot be approximated. CASE PRESENTATION: We present a patient who developed a symptomatic, delayed hypersensitivity reaction to a cellulose-based synthetic dural graft, which resolved after reoperation and removal of the graft. DISCUSSION: Dural grafts are a safe and common implant utilized in neurosurgery. Nevertheless, as with all implanted material, there is a chance for symptomatic immune reactions to occur. CONCLUSION: This type of response is exceedingly uncommon, but recognition of this rare presentation may help other providers recognize it in the future.

DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation.

Transcription elongation factor DSIF/Spt4-Spt5 is capable of promoting and inhibiting RNA polymerase II elongation and is involved in the expression of various genes. While it has been known for many years that DSIF inhibits elongation in collaboration with the negative elongation factor NELF, how DSIF promotes elongation is largely unknown. Here, an activity-based biochemical approach was taken to understand the mechanism of elongation activation by DSIF. We show that the Paf1 complex (Paf1C) and Tat-SF1, two factors implicated previously in elongation control, collaborate with DSIF to facilitate efficient elongation. In human cells, these factors are recruited to the FOS gene in a temporally coordinated manner and contribute to its high-level expression. We also show that elongation activation by these factors depends on P-TEFb-mediated phosphorylation of the Spt5 C-terminal region. A clear conclusion emerging from this study is that a set of elongation factors plays nonredundant, cooperative roles in elongation. This study also shows unambiguously that Paf1C, which is generally thought to have chromatin-related functions, is involve directlyd in elongation control.

Safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus: Results from a phase 1/2 randomized study.

OBJECTIVES: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care. METHODS: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed. RESULTS: Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. C(max) and AUC(τ) increased proportionally with dose after first and last infusion, t(1/2) was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19(+)CD22(+)) and unswitched memory B cells (CD19(+)IgD(+)CD27(+)). Small-to-moderate decreases were observed in total B cell (CD20(+)) count. CONCLUSIONS: Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

Clipping of posteriorly projecting large posterior communicating aneurysm via transsylvian anterior temporal approach.

Clipping of a posterior projecting large posterior communicating aneurysm via transsylvian anterior temporal approach is presented. To expose and clip this large aneurysm, retraction of the temporal lobe is required via the conventional pterional approach. In this video, we demonstrate microsurgical techniques as to how to dissect and mobilize the sylvian veins as well as a bridging vein to the sphenoparietal sinus, and the middle cerebral artery branches to the frontal lobe side. After the microsurgical dissection, a wide anteriolateral temporal space is obtained without significant temporal lobe retraction. The aneurysm was completely obliterated via this approach. The video can be found here: http://youtu.be/vU9Nxm7Yn-A.

"Mom called me!" Behavioral and prefrontal responses of infants to self-names spoken by their mothers.

Development of a sense of self is a fundamental process needed for human social interaction. Although functional neuroimaging studies have revealed the importance of medial prefrontal cortex (mPFC) in self-referencing, how this function develops in infancy remains poorly understood. To determine the cerebral basis underlying processing of self-related stimuli, we used behavioral measures and functional multi-channel near-infrared spectroscopy (fNIRS) to measure prefrontal cortical responses in 6-month-old infants hearing their own names. We also investigated the influence of a mother's voice on name perception in infants - an ability that plays a crucial role in the recognition of social signals. Experiment 1 measured the behavioral preferences of infants for their own names and for other names, spoken either by their mothers or by strangers. Results showed that infants significantly preferred their own name to other names, regardless of speaker type. Experiment 2 examined hemodynamic responses to the same four conditions in the prefrontal cortex. Compared with other names, hearing their own names, especially when spoken by their mother, elicited greater activity in the infant's dorsal mPFC. Furthermore, the magnitude of the cerebral response correlated with the degree of behavioral preference only when involving their mother's voice. These findings suggest that, particularly in the context of their mothers' voice, the dorsal mPFC of infants is already sensitive to social signals related to self at 6 months. At the same time, familiarity and affection related processing are also discussed as possible factors modulating dorsal mPFC activation at this age.

Exploring factors of successful transition to elementary school among children with autism spectrum disorder in Japan: a focus group study.

Introduction: Children with autism spectrum disorder (ASD) face numerous challenges in transitioning to elementary school, which can cause confusion for the children and concern among their parents. Aims: This study aimed to identify the process of school transition from kindergarten to elementary school for children with autism spectrum disorder in Japan, by evaluating the effectiveness of a school transition program. Methods: A focus group interview was conducted with seven parents who participated in a transition program. They were asked about communication with the teachers, support obtained from the school, and their experiences after their children entered elementary school. After the group interview was recorded and transcribed, the data were analyzed using inductive content analysis to determine the parents' experiences of the school transition process. Findings: Six main themes emerged from the focus group interview: acquisition of prerequisite skills, adjustment in dealing with children with ASD, communication between school and home, communication between peers and children with autism spectrum disorder, collaboration with special needs education teachers, and the principal's understanding of special needs education. Conclusion: These findings provide an overview of the challenges and possible solutions to support school transitions for children with autism spectrum disorder in inclusive educational environments.

Complete sequencing and characterization of 21,243 full-length human cDNAs.

As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

Reliability and validity of eye-hand coordination pointing tests for older adults.

To examine the reliability and validity of eye-hand coordination pointing with pencil test (EHCPPT), which evaluates the spatial and temporal displacement of rhythmic movements. One hundred and thirty-five older adults participated in our study. Reproducibility of the EHCPPT was assessed by the participants tapping on the center of the circles using a tablet pen in response to 2 types of stimulus sound sequences (Test A and B) across 2 separate trials, the first and second half. Construct validity was assessed by comparison in the distances between ultimate and current processing abilities, based on the spatial and temporal displacement relationship across Test A and Test B. Concurrent validity was assessed by examining the relationship between the distances between ultimate and current processing abilities and the motor and cognitive functions. Spatial and temporal displacements showed an excellent intraclass correlation coefficient in both Tests A and B of EHCPPT. The distance between ultimate and current processing ability, based on the relationship of spatial and temporal displacement, was significantly shorter in Test A compared to Test B. Spatial and temporal displacements were correlated with motor and cognitive functions. The spatial and temporal displacements of EHCPPT indicated reproducibility and validity in older adults. The EHCPPT may serve as a rhythmic movement reflecting motor and cognitive functions.

Baseline Variability Affects N-of-1 Intervention Effect: Simulation and Field Studies.

The simulation study investigated the relationship between the local linear trend model's data-comparison accuracy, baseline-data variability, and changes in level and slope after introducing the N-of-1 intervention. Contour maps were constructed, which included baseline-data variability, change in level or slope, and percentage of non-overlapping data between the state and forecast values by the local linear trend model. Simulation results showed that baseline-data variability and changes in level and slope after intervention affect the data-comparison accuracy based on the local linear trend model. The field study investigated the intervention effects for actual field data using the local linear trend model, which confirmed 100% effectiveness of previous N-of-1 studies. These results imply that baseline-data variability affects the data-comparison accuracy using a local linear trend model, which could accurately predict the intervention effects. The local linear trend model may help assess the intervention effects of effective personalized interventions in precision rehabilitation.

Effects of Paired Associative Stimulation on Cortical Plasticity in Agonist-Antagonist Muscle Representations.

Paired associative stimulation (PAS) increases and decreases cortical excitability in primary motor cortex (M1) neurons, depending on the spike timing-dependent plasticity, i.e., long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity, respectively. However, how PAS affects the cortical circuits for the agonist and antagonist muscles of M1 is unclear. Here, we investigated the changes in the LTP- and LTD-like plasticity for agonist and antagonist muscles during PAS: 200 pairs of 0.25-Hz peripheral electric stimulation of the right median nerve at the wrist, followed by a transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 ms (PAS-25 ms) and 10 ms (PAS-10 ms). The unconditioned motor evoked potential amplitudes of the agonist muscles were larger after PAS-25 ms than after PAS-10 ms, while those of the antagonist muscles were smaller after PAS-25 ms than after PAS-10 ms. The γ-aminobutyric acid A (GABAA)- and GABAB-mediated cortical inhibition for the agonist and antagonist muscles were higher after PAS-25 ms than after PAS-10 ms. The cortical excitability for the agonist and antagonist muscles reciprocally and topographically increased and decreased after PAS, respectively; however, GABAA and GABAB-mediated cortical inhibitory functions for the agonist and antagonist muscles were less topographically decreased after PAS-10 ms. Thus, PAS-25 ms and PAS-10 ms differentially affect the LTP- and LTD-like plasticity in agonist and antagonist muscles.

Use of intravenous cangrelor in the treatment of ruptured and unruptured cerebral aneurysms: an updated single-center analysis and pooled analysis of current studies.

BACKGROUND: Intracranial stent placement for the treatment of cerebral aneurysms is increasingly utilized in both ruptured and unruptured scenarios. Intravenous (IV) cangrelor is a relatively new antiplatelet agent that was initially approved for coronary interventions. In addition to our institution, five other centers have published their results using IV cangrelor in neurointerventional procedures. This article combines the aneurysm treatment data from all prior studies to provide insight into the safety and efficacy of cangrelor for intracranial aneurysm treatment. METHODS: A prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during aneurysm embolization. 20 additional patients were identified who had not been previously published. In addition, a literature search was performed to identify prior publications regarding cangrelor in neurointervention. The data from these were combined with our institutional results in a pooled-analysis. RESULTS: Overall, 85 patients who received IV cangrelor during aneurysm embolization were identified, including 46 ruptured and 39 unruptured cases. The asymptomatic and symptomatic intracranial hemorrhage rates were 4% (2/46) for ruptured cases and 2.6% (1/39) for unruptured cases. The rate of retroperitoneal hematoma and gastrointestinal bleeding was 0%. There were no incidents of intraprocedural thromboembolic complication or intraprocedural in-stent thrombosis in either cohort. One subject suffered an ischemic stroke at 24 hours secondary to in-stent thrombosis in a ruptured case. CONCLUSIONS: IV cangrelor during aneurysm embolization appears to be safe, with a symptomatic intracranial hemorrhage rate of 4% in ruptured cases and 2.6% in unruptured cases. More research is needed to determine the ideal dosing regimen.

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

Cerebral responses to infant-directed speech and the effect of talker familiarity.

A number of behavioral studies suggest that infant-directed speech (IDS) plays a more important role in facilitating both: a) speech perception, and b) adult-infant social interactions than does adult-directed speech (ADS), and hence that IDS contributes to subsequent social and language development. However neural substrates that may underlie these IDS functions have not been examined. The present study examined cerebral hemodynamic responses to IDS in 48 infants (4-13 months of age) using near-infrared spectroscopy (NIRS). Japanese sentences uttered by the infants' own mothers and by unfamiliar mothers were used to record activations in temporal and frontal area separately. Increased activations were observed predominantly in infants' left and right temporal areas when they listened to IDS rather than to ADS when both involved voices of their own and unfamiliar mothers. In contrast, significantly greater activations were observed in the frontal area when infants listened to IDS produced by their own mothers, not when IDS arose from unfamiliar mothers. Furthermore, the present results indicate that responses to IDS do vary as a function of the infant's age and the talker familiarity. These findings suggest a differential function for frontal and temporal areas in processing infant-directed speech by the different speakers.

Segment-Unit Reading Comprehension Training for Japanese Students with Autism Spectrum Disorder and Learning Disabilities.

Students with autism spectrum disorder (ASD) and learning disabilities (LDs) often experience reading difficulties. In particular, reading long passages can cause comprehension problems. We examined whether 8 Japanese students with ASD, 7 students with LDs, and 13 typically developing (TD) students improved their reading comprehension through two types of repeated reading training: whole-sentence-unit reading (WSUR) training and segment-unit reading (SUR) training. Participants undergoing WSUR training read whole sentences repeatedly. In SUR training, they repeatedly read a segment of a sentence in its correct spatial location. Results indicated that students with ASD and LDs showed greater improvement in reading comprehension after SUR training than after WSUR training, whereas both procedures were equally effective for TD students. Moreover, students with ASD showed only negligible reading comprehension improvements, whereas students with LDs showed intermediate improvements after WSUR training. These results suggest that sequentially presenting word segments can improve the reading comprehension of students with ASD and specific LDs.

Evaluation of a Telehealth Parent-Training Program in Japan: Collaboration with Parents to Teach Novel Mand Skills to Children Diagnosed with Autism Spectrum Disorder.

This study developed a telehealth parent-training program to teach parents of children with autism spectrum disorder the process of mand-training implementation in Japan, and to further the international dissemination of evidence-based training strategies. Parent-training sessions were based on a behavioral skills training (BST) model, combined with weekly graphic and video feedback. The sessions were conducted by a board-certified behavior analyst-doctoral residing in Japan. Four parents with children with autism spectrum disorder participated in this study. The results preliminarily support the effectiveness and social validity of the program. This study extends previous parent-training research conducted in Japan by comprising all of the following features: (1) online program design; (2) mand training; (3) BST model; (4) session-by-session data on children's behavioral changes and procedural integrity; (5) within-subject experimental design; and (6) social validity evaluation.

Infants' Prefrontal Hemodynamic Responses and Functional Connectivity During Joint Attention in an Interactive-Live Setting.

The present study examined cerebral hemodynamic responses and functional connectivity during joint attention either initiated by infants (Initiating Joint Attention, IJA condition) or by their partner (Responding to Joint Attention, RJA condition). To capture responses to natural social cues in infants aged 7-12 months using functional near-infrared spectroscopy (fNIRS), we employed an interactive-live paradigm for IJA and RJA. During the measurement, an adult sat facing an infant, and objects, such as small stuffed animals, paired with sound toys were presented to the right or left side of the screen. In the RJA condition, the adult gazed at the infants' eyes and then to the objects to encourage the infants to follow the adult's gaze. On the other hand, in the IJA condition, the adult followed the infant's gaze as it shifted to the presented object. Our results indicate that the concentration of oxy-Hb in the bilateral ventral prefrontal region had significantly decreased, then followed by an increase in the right dorsal prefrontal region in the RJA. In addition, a selective activation in the bilateral dorsal prefrontal region was seen in the IJA condition. Moreover, the infants exhibited increased functional connectivity especially within the right ventral prefrontal region during RJA condition when compared with IJA conditions. These findings suggest that RJA and IJA recruit specific brain networks localized in the prefrontal cortex of infants.