An alternative method to evaluate lumbar interbody fusion status focusing on position change of screw-rod constructs.

OBJECTIVES: The evaluation of lumbar interbody fusion status is generally subjective and may differ among raters. The authors examined whether the assessment of position change of screw-rod constructs could be an alternative method for the evaluation of fusion status. METHODS: Sixty-three patients undergoing lumbar interbody single-level fusion were retrospectively reviewed. Three-dimensional images of screw-rod constructs were created from baseline CT examination on the day after surgery and follow-up CT examinations (3-5 months, 6-11 months, and ≥ 12 months) and superposed, with position change of screw-rod constructs being evaluated by the distance between the 3-dimensional images at baseline and follow-up. The evaluation was repeated twice to confirm the reproducibility. Fusion status on follow-up CT examinations was assessed by three raters, where inter-rater reliability was evaluated with Fleiss' kappa. The results of the fusion status were classified into fusion and incomplete fusion groups in each timing of follow-up CT examinations, where the amount of position change was compared between the two groups. RESULTS: The evaluation of position change was completely reproducible. The Fleiss' kappa (agreements) was 0.481 (69.4%). The medians of the amount of position change in fusion and incomplete fusion groups were 0.134 mm and 0.158 mm at 3-5 months (p = 0.21), 0.160 mm and 0.190 mm at 6-11 months (p = 0.02), and 0.156 mm and 0.314 mm at ≥ 12 months (p = 0.004). CONCLUSIONS: The assessment of position change of screw-rod constructs at 6 months or more after surgery can be an alternative method for evaluating lumbar interbody fusion status. KEY POINTS: • Lumbar interbody fusion status (satisfactory, incomplete, or failed) is associated with the quantification of position change of screw-rod in this study. • Reference values for the evaluation of position change in identifying interbody fusion status are provided. • Position change of screw-rod could be a supportive method for evaluating interbody fusion status.

Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents.

OBJECTIVE: Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. METHODS: Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. RESULTS: NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. CONCLUSIONS: NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids.

Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish.

The heart is an endocrine organ, as cardiomyocytes (CMs) secrete natriuretic peptide (NP) hormones. Since the discovery of NPs, no other peptide hormones that affect remote organs have been identified from the heart. We identified osteocrin (Ostn) as an osteogenesis/chondrogenesis regulatory hormone secreted from CMs in zebrafish. ostn mutant larvae exhibit impaired membranous and chondral bone formation. The impaired bones were recovered by CM-specific overexpression of OSTN. We analyzed the parasphenoid (ps) as a representative of membranous bones. In the shortened ps of ostn morphants, nuclear Yap1/Wwtr1-dependent transcription was increased, suggesting that Ostn might induce the nuclear export of Yap1/Wwtr1 in osteoblasts. Although OSTN is proposed to bind to NPR3 (clearance receptor for NPs) to enhance the binding of NPs to NPR1 or NPR2, OSTN enhanced C-type NP (CNP)-dependent nuclear export of YAP1/WWTR1 of cultured mouse osteoblasts stimulated with saturable CNP. OSTN might therefore activate unidentified receptors that augment protein kinase G signaling mediated by a CNP-NPR2 signaling axis. These data demonstrate that Ostn secreted from the heart contributes to bone formation as an endocrine hormone.

Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

A New Secretory Peptide of Natriuretic Peptide Family, Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction.

RATIONALE: An increase of severe ischemic heart diseases results in an increase of the patients with congestive heart failure (CHF). Therefore, new therapies are expected in addition to recanalization of coronary arteries. Previous clinical trials using natriuretic peptides (NPs) prove the improvement of CHF by NPs. OBJECTIVE: We aimed at investigating whether OSTN (osteocrin) peptide potentially functioning as an NPR (NP clearance receptor) 3-blocking peptide can be used as a new therapeutic peptide for treating CHF after myocardial infarction (MI) using animal models. METHODS AND RESULTS: We examined the effect of OSTN on circulation using 2 mouse models; the continuous intravenous infusion of OSTN after MI and the OSTN-transgenic (Tg) mice with MI. In vitro studies revealed that OSTN competitively bound to NPR3 with atrial NP. In both OSTN-continuous intravenous infusion model and OSTN-Tg model, acute inflammation within the first week after MI was reduced. Moreover, both models showed the improvement of prognosis at 28 days after MI by OSTN. Consistent with the in vitro study binding of OSTN to NPR3, the OSTN-Tg exhibited an increased plasma atrial NP and C-type NP, which might result in the improvement of CHF after MI as indicated by the reduced weight of hearts and lungs and by the reduced fibrosis. CONCLUSIONS: OSTN might suppress the worsening of CHF after MI by inhibiting clearance of NP family peptides.

Cardiomyokines from the heart.

The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions.

Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.

We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.

Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjögren's syndrome.

OBJECTIVES: Multiomics study was conducted to elucidate the crucial molecular mechanisms of primary Sjögren's syndrome (SS) pathology. METHODS: We generated multiple data set from well-defined patients with SS, which includes whole-blood transcriptomes, serum proteomes and peripheral immunophenotyping. Based on our newly generated data, we performed an extensive bioinformatic investigation. RESULTS: Our integrative analysis identified SS gene signatures (SGS) dysregulated in widespread omics layers, including epigenomes, mRNAs and proteins. SGS predominantly involved the interferon signature and ADAMs substrates. Besides, SGS was significantly overlapped with SS-causing genes indicated by a genome-wide association study and expression trait loci analyses. Combining the molecular signatures with immunophenotypic profiles revealed that cytotoxic CD8 -T cells- were associated with SGS. Further, we observed the activation of SGS in cytotoxic CD8 T cells isolated from patients with SS. CONCLUSIONS: Our multiomics investigation identified gene signatures deeply associated with SS pathology and showed the involvement of cytotoxic CD8 T cells. These integrative relations across multiple layers will facilitate our understanding of SS at the system level.

Indium-Catalyzed Reductive Dithioacetalization of Carboxylic Acids with Dithiols: Scope, Limitations, and Application to Oxidative Desulfurization.

In this study an InI3-TMDS (1,1,3,3-tetramethyldisiloxane) reducing system effectively catalyzed the reductive dithioacetalization of a variety of aromatic and aliphatic carboxylic acids with 1,2-ethanedithiol or 1,3-propanedithiol leading to the one-pot preparation of either 1,3-dithiolane derivatives or a 1,3-dithiane derivative. Also, the intact indium catalyst continuously catalyzed the subsequent oxidative desulfurization of an in situ formed 1,3-dithiolane derivative, which led to the preparation of the corresponding aldehydes.

Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis.

OBJECTIVES: To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). METHODS: Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan™ assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12weeks after treatment with methotrexate (MTX) for MTX-naïve RA patients (n=28) or with the biologics tocilizumab (TCZ) (n=7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method. RESULTS: Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (ρ=0.51, p<0.01) and were significantly increased in patients with untreated active RA compared to HCs (p<0.01) or those with pSS (p<0.01). IL-16 levels decreased following treatment in both the MTX-naïve and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (ρ=0.89, p<0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. CONCLUSIONS: IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients.

Polarization diversity of human CD4+ stem cell memory T cells.

T cells are considered to develop through three stages, from naïve T (Tn) into central memory T (Tcm) and finally into effector memory T (Tem). Among the subsets of Tn, stem cell memory T (Tscm) were recently found to be the least developed memory subset. While this subset was revealed to possess self-reproducibility and multipotentiality, little is known about the relationship between development and polarity. We conducted transcriptome analysis of human CD4(+) T subsets and found that Tscm was a clearly distinct subset, located between Tn and Tcm. Surface antigen analysis and differentiation assay showed that the flexibility of polarity and the cytokine production progressively changed as the differentiation of CD4(+) T cells advanced. Interestingly, we found that most cells of the CD45RO(-)CCR7(+)CCR6(+) subset, hitherto considered the naïve precursor of Th17, were in fact Tscm. These findings may advance our understanding of the highly heterogeneous human helper T cells.

Human cortical responses to slow and fast binaural beats reveal multiple mechanisms of binaural hearing.

When two tones with slightly different frequencies are presented to both ears, they interact in the central auditory system and induce the sensation of a beating sound. At low difference frequencies, we perceive a single sound, which is moving across the head between the left and right ears. The percept changes to loudness fluctuation, roughness, and pitch with increasing beat rate. To examine the neural representations underlying these different perceptions, we recorded neuromagnetic cortical responses while participants listened to binaural beats at a continuously varying rate between 3 Hz and 60 Hz. Binaural beat responses were analyzed as neuromagnetic oscillations following the trajectory of the stimulus rate. Responses were largest in the 40-Hz gamma range and at low frequencies. Binaural beat responses at 3 Hz showed opposite polarity in the left and right auditory cortices. We suggest that this difference in polarity reflects the opponent neural population code for representing sound location. Binaural beats at any rate induced gamma oscillations. However, the responses were largest at 40-Hz stimulation. We propose that the neuromagnetic gamma oscillations reflect postsynaptic modulation that allows for precise timing of cortical neural firing. Systematic phase differences between bilateral responses suggest that separate sound representations of a sound object exist in the left and right auditory cortices. We conclude that binaural processing at the cortical level occurs with the same temporal acuity as monaural processing whereas the identification of sound location requires further interpretation and is limited by the rate of object representations.

A novel approach to evaluation of lumbar bone density using Hounsfield units in volume of interest on computed tomography imaging.

OBJECTIVE: The purpose of this retrospective study was to evaluate the relationship between bone mineral density (BMD), as assessed with dual-energy x-ray absorptiometry (DEXA), and Hounsfield units (HU) measured in volumes of interest (VOIs) and regions of interest (ROIs) on lumbar spine CT. METHODS: A retrospective analysis was performed on data of lumbar vertebrae obtained from patients who underwent both DEXA and lumbar spine CT scan within a 6-month period. Vertebrae with a history of compression fracture, infectious spondylitis, cement reinforcement, or lumbar surgery were excluded. HU measurements were performed in the VOI and ROI (midaxial, midcoronal, and midsagittal sections) with CT, whereas BMD was assessed with DEXA. Statistical analyses, including correlation assessments and receiver operating characteristic (ROC) curve analyses, were performed. RESULTS: This analysis included 712 lumbar vertebrae, with a median patient age of 72.0 years. BMD values and HU measurements in the VOI increased sequentially from L1 to L4, whereas HU values in the ROI did not show a consistent pattern. HU values in the VOI consistently showed a stronger correlation with BMD than those in the ROI. ROC analysis revealed patient-level cutoff values for the diagnosis of osteoporosis at different lumbar vertebral levels with high sensitivity and specificity, as well as an excellent area under the curve. CONCLUSIONS: This is the first study to introduce a novel approach using the HU value in the VOI to assess bone health at the lumbar spine. There is a strong correlation between the HU value in the VOI and BMD, and the HU value in the VOI can be used to predict osteoporosis.

Temporal Shape Changes of Pedicle screw-rod Constructs After Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: To examine the shape change of screw-rod constructs over time following short-segment lumbar interbody fusion and to clarify its relationship to clinical characteristics. SUMMARY OF BACKGROUND DATA: No study has focused on the shape change of screw-rod constructs after short-segment fusion and its clinical implications. METHODS: One hundred and eight patients who had single-level lumbar interbody fusion with pedicle screws and cages were enrolled. Three-dimensional (3D) images of screw-rod constructs were generated from baseline CT on the day after surgery and follow-up CT, and were superposed on the right and left side, respectively, using the iterative closest point algorithm. The shape change was quantitatively assessed by computing the median distance between the 3D images, which was defined as the shape change value. Among the five time-course categories of follow-up CT (≤1 month, 2-3 months, 4-6 months, 7-12 months, ≥13 months), the shape change values were compared. The relationships between the shape change values and clinical characteristics, such as age, CT-derived vertebral bone mineral density, screw and rod materials, and postoperative interbody fusion status, cage subsidence, and screw loosening, were evaluated. RESULTS: A total of 237 follow-up CTs were included (≤1 month [34 scans], 2-3 months [33 scans], 4-6 months [80 scans], 7-12 months [48 scans], ≥13 months [42 scans]) because many patients underwent multiple follow-up CTs. There were significant differences in shape change values among the time-course categories (P<0.001 in Kruskal-Wallis test). Most shape changes occurred within 6 months postoperatively, with no significant changes observed at 7 months or more. There were no significant relationships between the shape change values and each clinical characteristic. CONCLUSION: The temporal shape changes of screw-rod constructs following short-segment lumbar interbody fusion progressed up to 6 months after surgery but not significantly thereafter.

Three-dimensional Images Fusion Method Useful for Preoperative Simulation of Clipping Surgery for Cerebral Aneurysms.

This study aimed to introduce a three-dimensional (3D) images fusion method for preoperative simulation of aneurysm clipping. Consecutive unruptured aneurysm cases treated with surgical clipping from March 2021 to October 2023 were included. In all cases, preoperative images of plain computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) 3D fluid-attenuated inversion recovery, 3D heavily T2-weighted images, and 3D rotational angiography were acquired and transported into a commercial software (Ziostation2 Plus, Ziosoft, Inc. Tokyo, Japan). The software provided 3D images of skull, arteries including aneurysms, veins, and brain tissue that were freely rotated, magnified, trimmed, and superimposed. Using the 3D images fusion method, two operators predicted clips to be used in the following surgery. The predicted clips and actually used ones were compared to give agreement scores for the following factors: (1) type of clips (simple or fenestrated), (2) shape of clips (straight, curved, angled, or bayonet), and (3) clipping strategy (single or multiple). The agreement score ranged from 0 to 3 because a score of 1 or 0 was given for agreement or disagreement on each factor. Interoperator reproducibility was also evaluated. During the study period, 44 aneurysms from 37 patients were clipped. All procedures were successfully completed, thanks to the precisely reproduced surgical corridors with the 3D images fusion method. Agreement in clip prediction was good with mean agreement score of 2.4. Interobserver reproducibility was also high with the kappa value of 0.79. The 3D images fusion method was useful for preoperative simulation of aneurysm clipping.

Aberrant heartbeat-evoked potential in schizophrenia.

Self-disturbance is considered a core feature underlying the psychopathology of schizophrenia. Interoception has an important role in the development of a sense of self, leading to increased interest in the potential contribution of abnormal interoception to self-disturbances in schizophrenia. Several neuropsychological studies have demonstrated aberrant interoception in schizophrenia. However, cortical interoceptive processing has not yet been thoroughly investigated. Thus, we sought to examine resting-state heartbeat-evoked potential (HEP) in this population. We hypothesized that patients with schizophrenia would exhibit significant alterations in HEP compared to healthy controls (HCs). In this cross-sectional electroencephalogram (EEG) study, we compared the HEPs between age- and sex-matched groups of patients with schizophrenia and HCs. A 10-min resting-state EEG with eyes closed and an electrocardiogram (ECG) were recorded and analyzed for the time window of 450 ms to 500 ms after an ECG R peak. A positive HEP shift was observed in the frontal-central regions (F [1, 82] = 7.402, p = 0.008, partial η2 = 0.009) in patients with schizophrenia (n = 61) when compared with HCs (n = 31) after adjusting for confounders such as age, sex, and heart rate. A cluster-based correction analysis revealed that the HEP around the right frontal area (Fp2, F4, and F8) showed the most significant group differences (F [1, 82] = 10.079, p = 0.002, partial η2 = 0.021), with a peak at the F4 electrode site (F [1, 82] = 12.646, p < 0.001, partial η2 = 0.069). We observed no correlation between HEP and symptoms in patients with schizophrenia. A positive shift of HEP during the late component could reflect a trait abnormality in schizophrenia. Further research is required to determine the association between the altered cortical interoceptive processing indexed with HEP and self-disturbances in schizophrenia.

Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix.

Hsp47 (heat shock protein 47), a collagen-specific molecular chaperone, is essential for the maturation of various types of procollagens. Previous studies have suggested that Hsp47 may preferentially recognize the triple-helix form of procollagen rather than unfolded procollagen chains in the endoplasmic reticulum. However, the underlying mechanism has remained unclear because of limitations in the available methods for detecting in vitro and in vivo interactions between Hsp47 and collagen. In this study, we established novel methods for this purpose by adopting a time-resolved FRET technique in vitro and a bimolecular fluorescence complementation technique in vivo. Using these methods, we provide direct evidence that Hsp47 binds to collagen triple helices but not to the monomer form in vitro. We also demonstrate that Hsp47 binds a collagen model peptide in the trimer conformation in vivo. Hsp47 did not bind collagen peptides that had been modified to block their ability to form triple helices in vivo. These results conclusively indicate that Hsp47 recognizes the triple-helix form of procollagen in vitro and in vivo.

Effects of New-Generation Antiepileptic Drug Prophylaxis on Delayed Neurovascular Events After Aneurysmal Subarachnoid Hemorrhage.

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72 h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR T-cell immunotherapy.

Chimeric antigen receptor (CAR)-modified T-cell therapies targeting CD19 represent a new treatment option for patients with relapsed/refractory (R/R) B-cell malignancies. However, CAR T-cell therapy fails to elicit durable responses in a significant fraction of patients. Limited in vivo proliferation and survival of infused CAR T cells are key causes of failure. In a phase 1/2 clinical trial of CD19 CAR T cells for B-cell malignancies (#NCT01865617), low serum interleukin 15 (IL-15) concentration after CAR T-cell infusion was associated with inferior CAR T-cell kinetics. IL-15 supports T-cell proliferation and survival, and therefore, supplementation with IL-15 may enhance CAR T-cell therapy. However, the clinical use of native IL-15 is challenging because of its unfavorable pharmacokinetic (PK) and toxicity. NKTR-255 is a polymer-conjugated IL-15 that engages the entire IL-15 receptor complex (IL-15Rα/IL-2Rßγ) and exhibits reduced clearance, providing sustained pharmacodynamic (PD) responses. We investigated the PK and immune cell PDs in nonhuman primates treated with NKTR-255 and found that NKTR-255 enhanced the in vivo proliferation of T cells and natural killer cells. In vitro, NKTR-255 induced dose-dependent proliferation and accumulation of human CD19 CAR T cells, especially at low target cell abundance. In vivo studies in lymphoma-bearing immunodeficient mice demonstrated enhanced antitumor efficacy of human CD19 CAR T cells. In contrast to mice treated with CAR T cells alone, those that received CAR T cells and NKTR-255 had markedly higher CAR T-cell counts in the blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation/exhaustion as assessed by Ki-67 and inhibitory receptor coexpression. These data support an ongoing phase 1 clinical trial of combined therapy with CD19 CAR T cells and NKTR-255 for R/R B-cell malignancies.