Safety and efficacy of Cesium-131 brachytherapy for brain tumors.

BACKGROUND: The introduction of Cesium-131 (Cs-131) as a radiation source has led to a resurgence of brachytherapy for central nervous system (CNS) tumors. The aim of this study was to evaluate the safety and efficacy of the largest cohort of Cs-131 patients to-date. METHODS: A retrospective review of all CNS tumors treated with resection and adjuvant Cs-131 brachytherapy at New York-Presbyterian/Weill Cornell from 2010 to 2021 was performed. Overall survival (OS) and local control (LC) were assessed with Kaplan-Meier methodology. Univariable analysis was conducted to identify patient factors associated with local recurrence or radiation necrosis. RESULTS: Adjuvant Cs-131 brachytherapy following resection was performed in 119 patients with a median follow-up time of 11.8 (IQR 4.7-23.6) months and a mean of 22.3 +/-30.3 months. 1-year survival rates were 53.3% (95%CI 41.9-64.6%) for brain metastases (BrM), 45.9% (95%CI 24.8-67.0%) for gliomas, and 73.3% (95%CI 50.9-95.7%) for meningiomas. 1-year local control rates were 84.7% for BrM, 34.1% for gliomas, and 83.3% for meningiomas (p < 0.001). For BrM, local control was superior in NSCLC relative to other BrM pathologies (90.8% versus 76.5%, p = 0.039). Radiographic radiation necrosis (RN) was identified in 10 (8.4%) cases and demonstrated an association with smaller median tumor size (2.4 [IQR 1.8-2.7 cm] versus 3.1 [IQR 2.4-3.8 cm], p = 0.034). Wound complications occurred in 14 (11.8%) patients. CONCLUSIONS: Cs-131 brachytherapy demonstrated a favorable safety and efficacy profile characterized by high rates of local control for all treated pathologies. The concept of brachytherapy has seen a resurgence given the excellent results when Cs-131 is used as a source.

Depression rates among African American inflammatory bowel disease patients at a large safety net hospital.

AIM: Major depressive disorder is a prominent psychiatric illness in the United States. It has been found to be higher among patients with inflammatory bowel disease. However, few studies have focused on depression among minority populations with inflammatory bowel disease. Our study determined the prevalence of depression in minority patients with inflammatory bowel disease at our safety-net hospital, which serves a predominantly African American patient population. METHODS: We conducted a single centre retrospective cohort study at a large, urban outpatient centre. We retrieved the electronic medical records of patients with inflammatory bowel disease who were seen in the gastroenterology clinic from December 2018-December 2019. Data on the severity of depression within the minority population, using the nine-question Patient Health Questionnaire, was obtained. The effects of age, sex, inflammatory bowel disease diagnosis, and comorbidities were analysed. A p-value <0.05 was considered statistically significant. RESULTS: A total of IBD patients were included in the study, of which 46.7% were female and 53.3% were male. Mean age was 44 years. With regard to race, 88.4% were African American, 5.3% Asian, 2.1% Hispanic, 1.1% American Indian/Alaskan Native, and 3.2% multiracial. A total of 71.6% had Crohn's disease and 28.4% had ulcerative colitis. Overall prevalence of major depressive disorder was 25.3%; 45.8% had minimal, 8.3% mild, 33.3% moderate, and 12.5% severe depression. A total of 34.7% of patients were never screened for depression, and 13.8% had other psychiatric conditions. There was a difference in depression rates based on psychiatric conditions (p = 0.00), but no difference based on sex (p = 0.37), IBD subtype (p = 0.34), or medical conditions (p = 0.84). CONCLUSIONS: Rates of depression among minority patients, predominantly African American, with inflammatory bowel disease were higher than previously reported for all patients with inflammatory bowel disease. Over 40% experienced moderate to severe depression. There was a low screening rate for depression. This data will be used to improve depression screening, especially among minorities.

Pediatric pituitary adenomas are more aggressive, more likely to be hormone producing and are more difficult to cure than adult pituitary adenomas: case series and systematic literature review.

PURPOSE: Pediatric pituitary adenomas (pPAs) are uncommon. Thus, their presentation and outcomes after treatment are less well-understood than those of pituitary adenomas in adulthood (aPAs). METHODS: A retrospective chart review was conducted for all patients who underwent endoscopic endonasal transsphenoidal surgery (EETS) for pPA at NewYork-Presbyterian Hospital/Weill Cornell Medicine (NYP/WCM) from 2005-2020. Eleven patients were identified, and information pertaining to age, sex, adenoma characteristics, procedural details, and outcomes was reviewed. A systematic review of the literature was also performed to compare outcomes of EETS versus microscopic endonasal transsphenoidal surgery (METS) for pPA. RESULTS: From 2005-2020, 11 patients underwent EETS for pPA at NYP/WCM. Mean age at operation was 14.9 ± 2.7 years, and 5 patients (45.5%) were male. 10 adenomas (90.9%) were hormone-producing. Of the functional adenomas, 8 (80.0%) were PRL-secreting and 2 (20.0%) were GH-secreting. Maximum adenoma diameter (MAD) ranged from 1.2-5.1 cm, with a median of 1.55 cm. Cavernous sinus invasion (CSI) occurred in 2 patients with macroprolactinoma. Gross total resection (GTR) was achieved in 10 (90.9%). Biochemical remission occurred in 5/10 (50.0%). Post-operative complications were documented in 8 cases (72.7%) and included diabetes insipidus, hypopituitarism, sinusitis, weight gain, cerebrospinal fluid leak, meningitis, and hydrocephalus. Systematic literature review of 105 microscopic and 175 endoscopic cases revealed high frequency of hormone-producing tumors (83.6%) and similar rates of GTR (82.4% vs 85.1%) and biochemical cure (75.8% vs 64.3%). CONCLUSIONS: pPAs are more likely to be hormone producing and may be more aggressive and difficult to cure than aPAs. EETS is an effective treatment, although complication rates may be higher than in adult populations.

Normal Humeral Head Ossification in Pediatric and Adolescent Shoulders Can Mimic Hill-Sachs Lesions: A Magnetic Resonance Imaging-based Study.

BACKGROUND: The sequential maturation of the humeral head (HH) as viewed on magnetic resonance imaging (MRI) has not been described to date. Proper assessment may be complicated by the presence of physeal tissue in pediatric patients. Past studies suggest that skeletally immature patients may also have a higher risk of a false-positive diagnosis of Hill-Sachs lesion on MRI. The purpose of this study was to define pediatric HH developmental patterns using MRI and to investigate for any associations with findings of known false-positive Hill-Sachs. METHODS: Picture Archiving and Communication System (PACS) records at an urban academic tertiary care musculoskeletal facility from 2014 to 2020 were queried for shoulder MRI in patients aged 0 to 15 years. Patients were excluded if they had a history of glenohumeral instability, fracture, growth arrest, brachial plexus injury, surgery, or infection. All images were independently evaluated by a musculoskeletal fellowship-trained radiologist. Each HH was staged based on skeletal maturity. RESULTS: For both sexes, HHs matured in a predictable manner with increasing chronological age associated with a higher ossification stage. False Hill-Sachs lesions were observed in girls aged 4 to 7 and boys aged 5 to 14, exclusively during stage I to II ossification. CONCLUSIONS: False Hill-Sachs lesions were visualized on MRI in stage I to II proximal humerus ossification. Due to differential timing of skeletal maturation, males present with false Hill-Sachs lesions at a later age than females on average. When interpreting shoulder MRI for glenohumeral instability, clinicians should be cautious of false Hill-Sachs lesions, especially in younger patients with distinct greater tuberosity and HH ossification centers (stage I to II ossification). LEVEL OF EVIDENCE: Level III.

Information Transmission through Biotic-Abiotic Interfaces to Restore or Enhance Human Function.

Advancements in reliable information transfer across biotic-abiotic interfaces have enabled the restoration of lost human function. For example, communication between neuronal cells and electrical devices restores the ability to walk to a tetraplegic patient and vision to patients blinded by retinal disease. These impactful medical achievements are aided by tailored biotic-abiotic interfaces that maximize information transfer fidelity by considering the physical properties of the underlying biological and synthetic components. This Review develops a modular framework to define and describe the engineering of biotic and abiotic components as well as the design of interfaces to facilitate biotic-abiotic information transfer using light or electricity. Delineating the properties of the biotic, interface, and abiotic components that enable communication can serve as a guide for future research in this highly interdisciplinary field. Application of synthetic biology to engineer light-sensitive proteins has facilitated the control of neural signaling and the restoration of rudimentary vision after retinal blindness. Electrophysiological methodologies that use brain-computer interfaces and stimulating implants to bypass spinal column injuries have led to the rehabilitation of limb movement and walking ability. Cellular interfacing methodologies and on-chip learning capability have been made possible by organic transistors that mimic the information processing capacity of neurons. The collaboration of molecular biologists, material scientists, and electrical engineers in the emerging field of biotic-abiotic interfacing will lead to the development of prosthetics capable of responding to thought and experiencing touch sensation via direct integration into the human nervous system. Further interdisciplinary research will improve electrical and optical interfacing technologies for the restoration of vision, offering greater visual acuity and potentially color vision in the near future.

Feasibility of virtual low-cost quantitative continuous measurement of movements in the extremities of people with Parkinson's disease.

A low-cost quantitative continuous measurement of movements in the extremities of people with Parkinson's disease, a structured motor assessment administered by a trained examiner to a patient physically present in the same room, utilizes sensors to generate output to facilitate the evaluation of the patient. However, motor assessments with the patient and the examiner in the same room may not be feasible due to distances between the patient and the examiner and the risk of transmission of infections between the patient and the examiner. Therefore, we propose a protocol for the remote assessment by examiners in different locations of both (A) videos of patients recorded during in-person motor assessments and (B) live virtual assessments of patients in different locations from examiners. The proposed procedure provides a framework for providers, investigators, and patients in vastly diverse locations to conduct optimal motor assessments required to develop treatment plans utilizing precision medicine tailored to the specific needs of each individual patient. The proposed protocol generates the foundation for providers to remotely perform structured motor assessments necessary for optimal diagnosis and treatment of people with Parkinson's disease and related conditions.

Corrigendum to "Feasibility of virtual low-cost quantitative continuous measurement of movements in the extremities of people with Parkinson's disease" [MethodsX 11 (2023) 102230].

[This corrects the article DOI: 10.1016/j.mex.2023.102230.].

Dataset of quality assurance measurements of rhythmic movements.

A low-cost quantitative structured office measurement of movements in the extremities of people with Parkinson's disease [1,2] was performed on participants with Parkinson's disease and multiple system atrophy as well as age- and sex-matched healthy participants with typical development. Participants underwent twelve videotaped procedures rated by a trained examiner while connected to four accelerometers [1,2] generating a trace of the three location dimensions expressed as spreadsheets [3,4]. The signals of the five repetitive motion items (3.4 Finger tapping, 3.5 Hand movements, 3.6 Pronation-supination movements of hands, 3.7 Toe tapping, and 3.8 Leg agility) [1] underwent processing to fast Fourier [5] and amor and bump continuous wavelet transforms [6], [7], [8], [9], [10], [11], [12], [13]. Images of the signals and their transforms [4], [5], [6] of the five repetitive tasks of each participant were randomly expressed as panels on an electronic framework for rating by 35 trained examiners who did not know the source of the original output [14]. The team of international raters completed ratings of the signals and their transforms independently using criteria like the scoring systems for live assessments of movements in human participants [1,2]. The raters scored signals and transforms for deficits in the sustained performance of rhythmic movements (interruptions, slowing, and amplitude decrements) often observed in people with Parkinson's disease [15], [16], [17], [18], [19], [20]. Raters were first presented the images of the signals and transforms of a man with multiple system atrophy as a test and a retest in a different random order. After the raters completed the assessments of the man with multiple system atrophy, they were presented random test and retest panels of the images of signals and transforms of ten participants with Parkinson's disease who completed a single rating session. After the raters completed the assessments of the participants with Parkinson's disease who completed one set of ratings, they were presented random test and retest panels of the images of signals and transforms of (A) ten participants with Parkinson's disease and (B) eight age- and sex-match healthy participants with typical development who completed two rating session separated by a month or more [15], [16], [17], [18], [19], [20]. The data provide a framework for further analysis of the acquired information. Additionally, the data provide a template for the construction of electronic frameworks for the remote analysis by trained raters of signals and transforms of rhythmic processes to verify that the systems are operating smoothly without interruptions or changes in frequency and amplitude. Thus, the data provide the foundations to construct electronic frameworks for the virtual quality assurance of a vast spectrum of rhythmic processes. The dataset is a suitable template for solving unsupervised and supervised machine learning algorithms. Readers may utilize this procedure to assure the quality of rhythmic processes by confirming the absence of deviations in rate and rhythm. Thus, this procedure provides the means to confirm the quality of the vast spectrum of rhythmic processes.

Chromosomal enrichment and activation of the aurora B pathway are coupled to spatially regulate spindle assembly.

Chromatin-induced spindle assembly depends on regulation of microtubule-depolymerizing proteins by the chromosomal passenger complex (CPC), consisting of Incenp, Survivin, Dasra (Borealin), and the kinase Aurora B, but the mechanism and significance of the spatial regulation of Aurora B activity remain unclear. Here, we show that the Aurora B pathway is suppressed in the cytoplasm of Xenopus egg extract by phosphatases, but that it becomes activated by chromatin via a Ran-independent mechanism. While spindle microtubule assembly normally requires Dasra-dependent chromatin binding of the CPC, this function of Dasra can be bypassed by clustering Aurora B-Incenp by using anti-Incenp antibodies, which stimulate autoactivation among bound complexes. However, such chromatin-independent Aurora B pathway activation promotes centrosomal microtubule assembly and produces aberrant achromosomal spindle-like structures. We propose that chromosomal enrichment of the CPC results in local kinase autoactivation, a mechanism that contributes to the spatial regulation of spindle assembly and possibly to other mitotic processes.

The TFIIH complex is required to establish and maintain mitotic chromosome structure.

Condensins compact chromosomes to promote their equal segregation during mitosis, but the mechanism of condensin engagement with and action on chromatin is incompletely understood. Here, we show that the general transcription factor TFIIH complex is continuously required to establish and maintain a compacted chromosome structure in transcriptionally silent Xenopus egg extracts. Inhibiting the DNA-dependent ATPase activity of the TFIIH complex subunit XPB rapidly and reversibly induces a complete loss of chromosome structure and prevents the enrichment of condensins I and II, but not topoisomerase II, on chromatin. In addition, inhibiting TFIIH prevents condensation of both mouse and Xenopus nuclei in Xenopus egg extracts, which suggests an evolutionarily conserved mechanism of TFIIH action. Reducing nucleosome density through partial histone depletion restores chromosome structure and condensin enrichment in the absence of TFIIH activity. We propose that the TFIIH complex promotes mitotic chromosome condensation by dynamically altering the chromatin environment to facilitate condensin loading and condensin-dependent loop extrusion.

Classification of extremity movements by visual observation of signals and their transforms.

A low-cost quantitative continuous measurement of movements utilizes accelerometers to generate signal outputs to precisely record the positions of extremities during the performance of movements. This procedure can readily be accomplished with inexpensive materials constructed indivisuals throughout the world. The proposed protocol provides the framework for trained raters to assess the signal outputs by visual observation to generate objective measurements like the measurements of the actual movements. Expert raters can then remotely give quantitative suggestions for providers in underserved regions to utilize precision medicine to develop optimal treatment plans tailored to the specific needs of each individual. The proposed protocol lays the foundations for experts located in tertiary centers to provide optimal assessments of signal outputs generated remotely in underserved regions. This protocol provides the means to address gaps in current research including the dearth of objective measurements of movements utilizing automatic intelligence and machine learning to accurately and precisely analyze movement assessments. Future research will include the development of robotic tools to perform assessments and analyses of the movements of human beings to enhance the conduct of movement evaluations of people with Parkinson's disease and related conditions to apply precision medicine for optimal diagnostic and therapeutic interventions.

What's left in the tank? Identification of non-ascribed aquarium's coral collections with DNA barcodes as part of an integrated diagnostic approach.

The unprecedented threats to coral reef ecosystems from global climate change require an urgent response from the aquarium community, which is becoming an increasingly vital coral conservation resource. Unfortunately, many hermatypic corals in aquaria are not identified to species level, which hinders assessment of their conservation significance. Traditional methods of species identification using morphology can be challenging, especially to non-taxonomists. DNA barcoding is an option for species identification of Scleractinian corals, especially when used in concert with morphology-based assessment. This study uses DNA barcodes to try to identify aquarium specimens of the diverse reef-forming genus Acropora from 127 samples. We identified to our best current knowledge, to species name 44% of the analysed samples and provided provisional identification for 80% of them (101/127, in the form of a list of species names with associate confidence values). We highlighted a sampling bias in public nucleotide sequences repertories (e.g. GenBank) towards more charismatic and more studied species, even inside a well-studied genus like Acropora. In addition, we showed a potential "single observer" effect with over a quarter of the reference sequences used for these identifications coming from the same study. We propose the use of barcoding and query matching as an additional tool for taxonomic experts and general aquarists, as an additional tool to increase their chances of making high confidence species-level identifications. We produce a standardised and easily repeatable methodology to increase the capacity of aquariums and other facilities to assess non-ascribed species, emphasising the value of integrating this approach with morphological identification optimising usage of authoritative identification guides and expert opinion. Supplementary Information: The online version contains supplementary material available at 10.1007/s12686-021-01250-3.

Influenza, PCV13, and PPSV23 Vaccination Rates Among Inflammatory Bowel Disease Patients With Additional Co-Morbidities as per CDC Recommendations.

Background Inflammatory bowel disease (IBD) and its immunosuppressive therapy alter the body's immune response, predisposing patients to higher infection risk preventable with vaccination. The CDC recommends every adult receive the annual influenza vaccine and patients with certain comorbidities receive the pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23). However, vaccination rates among IBD patients remain unacceptably low. The aim of our study is to present influenza and pneumococcal vaccinations rates of IBD patients at our center. Methods We hypothesized that vaccination rates will be suboptimal at our outpatient center and that patients are not being vaccinated based on comorbid conditions in accordance with guidelines. We retrieved electronic medical records from the gastroenterology clinic between December 2018 and December 2019. Data regarding influenza and pneumococcal vaccines, immunosuppressive drugs, and comorbidities were obtained. Microsoft Excel and SPSS Statistics (IBM Corp., Armonk, NY) were used for data analyses. A p-value < 0.05 was considered statistically significant. Results In total, 109 IBD patients were identified, 46.8% female and 53.2% male. The majority were African American (77.06%). The mean age was 45 years. Around 26.61% of the patients were on immunosuppressive therapy. Around 28.7% received the annual influenza vaccine, 42.2% PPSV23 alone, 19.27% PCV13 alone, and 16.5% received both. Patients >50 years were more likely to receive the influenza vaccine (P = 0.0122). Patients on immunosuppressive therapy were not more likely to be vaccinated with both PCV13 and PPSV23 (P = 0.1848, P = 0.7382). Active smokers were not more likely to be vaccinated with PPSV23 (P = 0.695). Patients with human immunodeficiency virus (HIV), chronic kidney disease (CKD), and sickle-cell disease were more likely to be vaccinated with both PCV13 and PPSV23 (P = 0.02, P = 0.02). Patients with other chronic medical conditions were more likely to be vaccinated with PPSV23 (P = 0.0201). Conclusion Our study revealed suboptimal influenza and pneumococcal vaccination rates among IBD patients at our facility. We also found that patients were not consistently vaccinated based on qualifying co-morbid conditions. Age plays a role in whether patients received the influenza vaccine contrary to guidelines. We urge clinicians to examine IBD patient vaccination rates at their facilities.

3D printing of high-strength, porous, elastomeric structures to promote tissue integration of implants.

Despite advances in biomaterials research, there is no ideal device for replacing weight-bearing soft tissues like menisci or intervertebral discs due to poor integration with tissues and mechanical property mismatch. Designing an implant with a soft and porous tissue-contacting structure using a material conducive to cell attachment and growth could potentially address these limitations. Polycarbonate urethane (PCU) is a soft and tough biocompatible material that can be 3D printed into porous structures with controlled pore sizes. Porous biomaterials of appropriate chemistries can support cell proliferation and tissue ingrowth, but their optimal design parameters remain unclear. To investigate this, porous PCU structures were 3D-printed in a crosshatch pattern with a range of in-plane pore sizes (0 to 800 µm) forming fully interconnected porous networks. Printed porous structures had ultimate tensile strengths ranging from 1.9 to 11.6 MPa, strains to failure ranging from 300 to 486%, Young's moduli ranging from 0.85 to 12.42 MPa, and porosity ranging from 13 to 71%. These porous networks can be loaded with hydrogels, such as collagen gels, to provide additional biological support for cells. Bare PCU structures and collagen-hydrogel-filled porous PCU support robust NIH/3T3 fibroblast cell line proliferation over 14 days for all pore sizes. Results highlight PCU's potential in the development of tissue-integrating medical implants.

Ventral Tonsillar Herniation Predicts Headaches in Adults With Chiari Malformation.

BACKGROUND: Radiographic characterization of Chiari malformation (CM) has historically focused on caudal tonsillar herniation (CH) below the foramen magnum. Previously, we published evidence linking ventral tonsillar herniation (VH) and medullary symptoms in very young children. We sought to extend that investigation by studying the radiographic and clinical significance of VH in adults diagnosed with CM. METHODS: We retrospectively reviewed adults with cerebellar ectopia who underwent posterior fossa decompression with or without duraplasty (PFD/D) at our institution. VH was defined as tonsils crossing a line bisecting the caudal medulla at the level of the foramen magnum on axial MRI. Degree of VH was measured as distance between this bisecting line and the ventral tip of the herniated tonsil. Dorsal brainstem compression was qualitatively determined by assessing for obliteration of CSF space between the dorsal brainstem and the tonsils. RESULTS: Out of 89 cases reviewed, 54 had some degree of VH. Compared with those without VH, the VH group was significantly older in age and more likely to also present with dorsal brainstem compression and headaches. No correlation was observed between degrees of CH and VH in the VH group. The degree of VH significantly decreased 3 months after PFD/D. CONCLUSIONS: VH is relatively common in CM patients and might be an important independent radiographic metric to evaluate and consider as part of the decision-making process, especially in those presenting with Chiari-like symptomatology referable to the medulla but who do not meet the traditional criteria of cerebellar ectopia greater than 5 mm.

Effect of surface topography on in vitro osteoblast function and mechanical performance of 3D printed titanium.

Critical-sized defects remain a significant challenge in orthopaedics. 3D printed scaffolds are a promising treatment but are still limited due to inconsistent osseous integration. The goal of the study is to understand how changing the surface roughness of 3D printed titanium either by surface treatment or artificially printing rough topography impacts the mechanical and biological properties of 3D printed titanium. Titanium tensile samples and discs were printed via laser powder bed fusion. Roughness was manipulated by post-processing printed samples or by directly printing rough features. Experimental groups in order of increasing surface roughness were Polished, Blasted, As Built, Sprouts, and Rough Sprouts. Tensile behavior of samples showed reduced strength with increasing surface roughness. MC3T3 pre-osteoblasts were seeded on discs and analyzed for cellular proliferation, differentiation, and matrix deposition at 0, 2, and 4 weeks. Printing roughness diminished mechanical properties such as tensile strength and ductility without clear benefit to cell growth. Roughness features were printed on mesoscale, unlike samples in literature in which roughness on microscale demonstrated an increase in cell activity. The data suggest that printing artificial roughness on titanium scaffold is not an effective strategy to promote osseous integration.

Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma.

Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NBs) have a poor prognosis despite multimodality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small-molecule rigosertib inhibits the growth of RMS and NB cell lines by arresting cells in mitosis, which leads to cell death. Our data indicate that rigosertib, like the vinca alkaloids, exerts its effects mainly by interfering with mitotic spindle assembly. Although rigosertib has the ability to inhibit oncogenic RAS signaling, we provide evidence that rigosertib does not induce cell death through inhibition of the RAS pathway in RAS-mutated RMS and NB cells. However, the combination of rigosertib and the MEK inhibitor trametinib, which has efficacy in RAS-mutated tumors, synergistically inhibits the growth of an RMS cell line, suggesting a new avenue for combination therapy. Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS.

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors.

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model.

The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term "immune education." These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8-/- mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.

The Borealin dimerization domain interacts with Sgo1 to drive Aurora B-mediated spindle assembly.

The chromosomal passenger complex (CPC), which includes the kinase Aurora B, is a master regulator of meiotic and mitotic processes that ensure the equal segregation of chromosomes. Sgo1 is thought to play a major role in the recruitment of the CPC to chromosomes, but the molecular mechanism and contribution of Sgo1-dependent CPC recruitment is currently unclear. Using Xenopus egg extracts and biochemical reconstitution, we found that Sgo1 interacts directly with the dimerization domain of the CPC subunit Borealin. Borealin and the PP2A phosphatase complex can bind simultaneously to the coiled-coil domain of Sgo1, suggesting that Sgo1 can integrate Aurora B and PP2A activities to modulate Aurora B substrate phosphorylation. A Borealin mutant that specifically disrupts the Sgo1-Borealin interaction results in defects in CPC chromosomal recruitment and Aurora B-dependent spindle assembly, but not in spindle assembly checkpoint signaling at unattached kinetochores. These findings establish a direct molecular connection between Sgo1 and the CPC and have major implications for the different functions of Aurora B, which promote the proper interaction between spindle microtubules and chromosomes.