PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

Using an Intraoperative Stress Exam to Direct Treatment in Posterior Femoral Head Fracture-Dislocations.

OBJECTIVE: To examine the results of a treatment algorithm incorporating an EUA performed intraoperatively after fixation of the femoral head through a Smith Petersen approach to determine need for posterior wall or capsule repair. METHODS: Design: Retrospective review. SETTING: Two Level 1 trauma centers. PATIENT SELECTION CRITERIA: All acute, traumatic femoral head fractures from posterior hip dislocations treated at participating centers over a 5-year period from 2017-2022. Injuries were classified according to the Pipkin system. OUTCOME MEASURES AND COMPARISONS: The primary outcome was the result of intraoperative EUA performed after femoral head fixation to determine the need for Kocher-Langenbeck exposure for posterior wall and/or capsule fixation. The secondary outcomes included rates of avascular necrosis, heterotopic bone formation, late instability, and conversion to total hip arthroplasty. RESULTS: Studied were 63 males and 22 females with mean age 32.5 (range 18-71). 79 of 85 (92.9%) patients had a stable EUA after fixation of the femoral head through a Smith-Petersen approach. Six (6/85, 7.1%) underwent an additional Kocher-Langenbeck approach for posterior wall or capsule fixation. This included 1 Pipkin I, 1 Pipkin II, and 4 Pipkin IV injuries. Of the Pipkin IV injuries, 51/55 (92.7%) had stable EUA and did not require fixation of their posterior wall. This included 7 patients with wall involvement >20%. Five patients were excluded because of planned fixation of their posterior wall based on preoperative imaging. Of patients with at least 6 months follow up, 16 of 65 (26.4%) developed radiographic evidence of AVN and 21 of 65 (32.3%) evidence of heterotopic bone formation. Seven out of 65 (10.8%) were converted to total hip arthroplasty over the study period. When comparing patients with a single exposure with those with additional KL exposure, they did not vary in their rate of AVN (27.1% vs. 0.0%, P=0.3228), HO formation (30.5% vs. 50.0%, P=0.3788), or conversion to total hip arthroplasty (10.2% vs. 16.7%, P=0.510). CONCLUSIONS: This study found residual posterior hip instability after femoral head fixation in patients with and without posterior wall fractures after posterior dislocations. The results of this study support use of an EUA after femoral head fixation to identify residual posterior hip instability in all femoral head fractures from posterior hip dislocations, regardless of Pipkin type. Use of the Smith-Petersen exposure remains a viable surgical option and may be improved with incorporation of an EUA after femoral head fixation. For Pipkin IV injuries with posterior wall fractures with indeterminate stability, an EUA accurately identifies residual instability. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation.

The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) is a ligand-regulated transcription factor and validated drug target for several human diseases. LRH-1 activation is regulated by small molecule ligands, which bind to the ligand binding domain (LBD) within the full-length LRH-1. We recently identified 57 compounds that bind LRH-1, and unexpectedly found these compounds regulated either the isolated LBD, or the full-length LRH-1 in cells, with little overlap. Here, we correlated compound binding energy from a single rigid-body scoring function with full-length LRH-1 activity in cells. Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "ΔΔG". Initial regressions, correlations and contingency analyses all suggest compounds with high ΔΔG values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 separate crystal structures of LRH-1 to obtain averaged ΔΔG values for each compound, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low ΔΔG values, identifying a structural relationship between ΔΔG and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest rigid-body computational docking can be used to quickly calculate ΔΔG, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose ΔΔG as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for resource-intense secondary screening.

Does Local Aqueous Tobramycin Injection Reduce Open Fracture-Related Infection Rates?

OBJECTIVES: To examine the effect of local aqueous tobramycin injection adjunct to perioperative intravenous (IV) antibiotic prophylaxis in reducing fracture-related infections (FRIs) following reduction and internal fixation of open fractures. DESIGN: Retrospective cohort study. SETTING: Single academic Level I trauma center. PATIENTS SELECTION CRITERIA: Patients with open extremity fractures treated with reduction and internal fixation with (intervention group) or without (control group) 80 mg of local aqueous (2 mg/mL) tobramycin injected during closure at the time of definitive fixation were identified from December 2018 to August 2021 based on population-matched demographic and injury characteristics. OUTCOME MEASURES AND COMPARISONS: The primary outcome was FRI within 6 months of definitive fixation. Secondary outcomes consisted of fracture nonunion and bacterial speciation. Differences in outcomes between the 2 groups were assessed and logistic regression models were created to assess the difference in infection rates between groups, with and without controlling for potential confounding variables, such as sex, fracture location, and Gustilo-Anderson classification. RESULTS: An analysis of 157 patients was performed with 78 patients in the intervention group and 79 patients in the control group. In the intervention group, 30 (38.5%) patients were women with a mean age of 47.1 years. In the control group, 42 (53.2%) patients were women with a mean age of 46.4 years. The FRI rate was 11.5% in the intervention group compared with 25.3% in the control group ( P = 0.026). After controlling for sex, Gustilo-Anderson classification, and fracture location, the difference in FRI rates between groups remained significantly different ( P = 0.014). CONCLUSIONS: Local aqueous tobramycin injection at the time of definitive internal fixation of open extremity fractures was associated with a significant reduction in FRI rates when administered as an adjunct to intravenous antibiotics, even after controlling for potential confounding variables. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Bilirubin is a new ligand for nuclear receptor Liver Receptor Homolog-1.

The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2 ) binds to phospholipids that regulate important LRH-1 functions in the liver. A recent compound screen unexpectedly identified bilirubin, the product of liver heme metabolism, as a possible ligand for LRH-1. Here, we show unconjugated bilirubin directly binds LRH-1 with apparent K d =9.3uM, altering LRH-1 interaction with all transcriptional coregulator peptides tested. Bilirubin decreased LRH-1 protease sensitivity, consistent with MD simulations predicting bilirubin stably binds LRH-1 within the canonical ligand binding site. Bilirubin activated a luciferase reporter specific for LRH-1, dependent on co-expression with the bilirubin membrane transporter SLCO1B1 , but bilirubin failed to activate ligand-binding genetic mutants of LRH-1. Gene profiling in HepG2 cells shows bilirubin selectively regulated transcripts from endogenous LRH-1 ChIP-seq target genes, which was significantly attenuated by either genetic knockdown of LRH-1, or by a specific chemical competitor of LRH-1. Gene set enrichment suggests bilirubin and LRH-1 share roles in cholesterol metabolism and lipid efflux, thus we propose a new role for LRH-1 in directly sensing intracellular levels of bilirubin.

Cost-Outcome Descriptive Study for Mobile App (UPSCALER) in the Rehabilitation of Anterior Cruciate Ligament (ACL) Injuries After Reconstructive Surgery.

Anterior cruciate ligament (ACL) injuries are a significant concern in athletes, often leading to long-term complications and reduced quality of life. Despite advancements in surgical techniques, outcomes following ACL reconstruction remain suboptimal, largely due to poor adherence to postoperative rehabilitation. This study introduces a novel postoperative rehabilitation approach utilizing a smartphone application, UPSCALER, developed by the Universiti Putra Malaysia Sports Injury and Arthroscopic Surgery Center of Excellence. The application delivers a validated accelerated rehabilitation protocol through instructional videos tailored to each patient's recovery phase. Results from the study demonstrate promising outcomes, including improvements in Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales post-rehabilitation, potentially attributed to increased adherence facilitated by the application's accessibility. Furthermore, the study explores the cost-effectiveness of this approach compared to conventional methods. In conclusion, smartphone application-guided rehabilitation shows promise in improving ACL reconstruction outcomes, warranting further research to validate its effectiveness and long-term impact on patient recovery and healthcare costs.

Multiple inositol phosphate species enhance stability of active mTOR.

Mechanistic Target of Rapamycin (mTOR) binds the small metabolite inositol hexakisphosphate (IP6) as shown in structures of mTOR, however it remains unclear if IP6, or any other inositol phosphate species, can activate mTOR kinase activity. Here, we show that multiple, exogenously added inositol phosphate species (IP6, IP5, IP4 and IP3) can all enhance the ability of mTOR and mTORC1 to auto-phosphorylate and incorporate radiolabeled phosphate into peptide substrates in in vitro kinase reactions. Although IP6 did not affect the apparent KM of mTORC1 for ATP, monitoring kinase activity over longer reaction times showed increased product formation, suggesting inositol phosphates stabilize an active form of mTORC1 in vitro. The effects of IP6 on mTOR were reversible, suggesting IP6 bound to mTOR can be exchanged dynamically with the free solvent. Interestingly, we also observed that IP6 could alter mTOR solubility and electrophoretic mobility in SDS-PAGE in the presence of manganese, suggesting divalent cations may play a role in inositol phosphate regulation of mTOR. Together, these data suggest for the first time that multiple inositol phosphate species (IP4, IP5 and IP6) can dynamically regulate mTOR and mTORC1 by promoting a stable, active state of the kinase. Our data suggest that studies of the dynamics of inositol phosphate regulation of mTOR are well justified.

IPMK regulates HDAC3 activity and histone H4 acetylation in human cells.

Histone deacetylases (HDACs) repress transcription by catalyzing the removal of acetyl groups from histones. Class 1 HDACs are activated by inositol phosphate signaling molecules in vitro , but it is unclear if this regulation occurs in human cells. Inositol Polyphosphate Multikinase (IPMK) is required for production of inositol hexakisphosphate (IP6), pentakisphosphate (IP5) and certain tetrakisphosphate (IP4) species, all known activators of Class 1 HDACs in vitro . Here, we generated IPMK knockout (IKO) human U251 glioblastoma cells, which decreased cellular inositol phosphate levels and increased histone H4-acetylation by mass spectrometry. ChIP-seq showed IKO increased H4-acetylation at IKO-upregulated genes, but H4-acetylation was unchanged at IKO-downregulated genes, suggesting gene-specific responses to IPMK knockout. HDAC deacetylase enzyme activity was decreased in HDAC3 immunoprecipitates from IKO vs . wild-type cells, while deacetylase activity of other Class 1 HDACs had no detectable changes in activity. Wild-type IPMK expression in IKO cells fully rescued HDAC3 deacetylase activity, while kinase-dead IPMK expression had no effect. Further, the deficiency in HDAC3 activity in immunoprecipitates from IKO cells could be fully rescued by addition of synthesized IP4 (Ins(1,4,5,6)P4) to the enzyme assay, while control inositol had no effect. These data suggest that cellular IPMK-dependent inositol phosphates are required for full HDAC3 enzyme activity and proper histone H4-acetylation. Implications for targeting IPMK in HDAC3-dependent diseases are discussed.

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

X-ray crystallographic analyses of 14 IPMK inhibitor complexes.

Inositol polyphosphate multikinase (IPMK) is a ubiquitously expressed kinase that has been linked to several cancers. Here, we report 14 new co-crystal structures (1.7Å - 2.0Å resolution) of human IPMK complexed with various IPMK inhibitors developed by another group. The new structures reveal two ordered water molecules that participate in hydrogen-bonding networks, and an unoccupied pocket in the ATP-binding site of human IPMK. New Protein Data Bank (PDB) codes of these IPMK crystal structures are: 8V6W (1.95Å), 8V6X (1.75Å), 8V6Y (1.70Å), 8V6Z (1.85Å), 8V70 (1.85Å), 8V71 (1.70Å), 8V72 (2.0Å), 8V73 (1.90Å), 8V74 (1.85Å), 8V75 (1.85Å), 8V76 (1.95Å), 8V77 (1.95Å), 8V78 (1.95Å), 8V79 (1.95Å).

Design, synthesis and cellular characterization of a new class of IPMK kinase inhibitors.

Many genetic studies have established the kinase activity of inositol phosphate multikinase (IPMK) is required for the synthesis of higher-order inositol phosphate signaling molecules, the regulation of gene expression and control of the cell cycle. These genetic studies await orthogonal validation by specific IPMK inhibitors, but no such inhibitors have been synthesized. Here, we report complete chemical synthesis, cellular characterization, structure-activity relationships and rodent pharmacokinetics of a novel series of highly potent IPMK inhibitors. The first-generation compound 1 (UNC7437) decreased cellular proliferation and tritiated inositol phosphate levels in metabolically labeled human U251-MG glioblastoma cells. Compound 1 also regulated the transcriptome of these cells, selectively regulating genes that are enriched in cancer, inflammatory and viral infection pathways. Further optimization of compound 1 eventually led to compound 15 (UNC9750), which showed improved potency and pharmacokinetics in rodents. Compound 15 specifically inhibited cellular accumulation of InsP 5 , a direct product of IPMK kinase activity, while having no effect on InsP 6 levels, revealing a novel metabolic signature detected for the first time by rapid chemical attenuation of cellular IPMK activity. These studies designed, optimized and synthesized a new series of IPMK inhibitors, which reduces glioblastoma cell growth, induces a novel InsP 5 metabolic signature, and reveals novel aspects inositol phosphate cellular metabolism and signaling.

The Feel of Speech: Multisystem and Polymodal Somatosensation in Speech Production.

PURPOSE: The oral structures such as the tongue and lips have remarkable somatosensory capacities, but understanding the roles of somatosensation in speech production requires a more comprehensive knowledge of somatosensation in the speech production system in its entirety, including the respiratory, laryngeal, and supralaryngeal subsystems. This review was conducted to summarize the system-wide somatosensory information available for speech production. METHOD: The search was conducted with PubMed/Medline and Google Scholar for articles published until November 2023. Numerous search terms were used in conducting the review, which covered the topics of psychophysics, basic and clinical behavioral research, neuroanatomy, and neuroscience. RESULTS AND CONCLUSIONS: The current understanding of speech somatosensation rests primarily on the two pillars of psychophysics and neuroscience. The confluence of polymodal afferent streams supports the development, maintenance, and refinement of speech production. Receptors are both canonical and noncanonical, with the latter occurring especially in the muscles innervated by the facial nerve. Somatosensory representation in the cortex is disproportionately large and provides for sensory interactions. Speech somatosensory function is robust over the lifespan, with possible declines in advanced aging. The understanding of somatosensation in speech disorders is largely disconnected from research and theory on speech production. A speech somatoscape is proposed as the generalized, system-wide sensation of speech production, with implications for speech development, speech motor control, and speech disorders.

Biomedicines in Longevity and Aging the Quest to Resist Biological Decline.

Aging is considered part of the natural process of life, however in recent years medical literature has started to show that specific facets of aging are beginning to be understood and those factors may even be considered preventable with various measures. Aging is also considered the number one cause of poor quality of life, disease, disability, and death, so the importance of understanding the aging process and how to control certain aspects of it cannot be underestimated when age related suffering is factored in. The causes of aging are now becoming well understood, and in recent years many therapies have already become available to the public to attenuate specific corridors of aging. The heterogeneity of the aging process and the biological drivers involved is examined here in parallel with various compounds and therapies to combat biological decline. The benefits for governments in keeping their populations healthy and vibrant are vast, and at the same time offer a great incentive to invest into newly emerging technologies that may prevent the onset of preventable disease. Whilst this paper only discusses nine pathways to the aging process, many more exist.

Nonoperative Treatment of Humeral Shaft Fractures With Immediate Functional Bracing Versus Coaptation Splinting and Delayed Functional Bracing: A Retrospective Study.

OBJECTIVES: To compare radiographic and clinical outcomes in nonoperative management of humeral shaft fractures treated initially with coaptation splinting (CS) followed by delayed functional bracing (FB) versus treatment with immediate FB. DESIGN: Retrospective cohort study. SETTING: Academic Level 1 Trauma Center. PATIENT SELECTION CRITERIA: Patients with closed humeral shaft fractures managed nonoperatively with initial CS followed by delayed FB or with immediate FB from 2016 to 2022. Patients younger than 18 years and/or with less than 3 months of follow-up were excluded. OUTCOME MEASURES AND COMPARISONS: The primary outcome was coronal and sagittal radiographic alignment assessed at the final follow-up. Secondary outcomes included rate of failure of nonoperative management (defined as surgical conversion and/or fracture nonunion), fracture union, and skin complications secondary to splint/brace wear. RESULTS: Ninety-seven patients were managed nonoperatively with delayed FB (n = 58) or immediate FB (n = 39). Overall, the mean age was 49.9 years (range 18-94 years), and 64 (66%) patients were female. The immediate FB group had less smokers ( P = 0.003) and lower incidence of radial nerve palsy ( P = 0.025), with more proximal third humeral shaft fractures ( P = 0.001). There were no other significant differences in demographic or clinical characteristics ( P > 0.05). There were no significant differences in coronal ( P = 0.144) or sagittal ( P = 0.763) radiographic alignment between the groups. In total, 33 (34.0%) humeral shaft fractures failed nonoperative management, with 11 (28.2%) in the immediate FB group and 22 (37.9%) in the delayed FB group ( P = 0.322). There were no significant differences in fracture union ( P = 0.074) or skin complications ( P = 0.259) between the groups. CONCLUSIONS: This study demonstrated that nonoperative treatment of humeral shaft fractures with immediate functional bracing did not result in significantly different radiographic or clinical outcomes compared to treatment with CS followed by delayed functional bracing. Future prospective studies assessing patient-reported outcomes will further guide clinical decision making. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Acute prevention of a heart attack : Early identification of prodromal symptoms as the Rosetta Stone in decoding the heart attack problem.

Chest discomfort before severe chest pain represents a marker of clinical ischemia and indicates live myocardium in jeopardy and often precedes cardiac arrest or acute myocardial infarction (MI). The intermittent or "stuttering" symptoms that precede MI are referred to as "prodromal symptoms." These symptoms have been shown to correlate with cyclic ST changes and repeated episodes of spontaneous reperfusion and occlusion, occurring during a period of hours or days before the acute ischemia proceeds to death or heart damage. These symptoms of premonitory angina have been associated with improved outcomes due to ischemic pre-conditioning or opening of collateral vascular channels around the area of ischemia. Acute prevention of an MI through recognition of prodromal symptoms represents an opportunity to significantly reduce heart attack deaths. The Early Heart Attack Care (EHAC) program puts emphasis on prodromal symptom recognition and allows for a shift in time backward to prevent the ischemic process from proceeding to MI. This strategy has been shown to detect the 15% of patients with ischemia in the low-probability group and to reduce inappropriate admissions to hospital as well as to reduce the number of patients with missed MI being sent home from the emergency department.

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

Evaluation of effectiveness and safety of the CorPath GRX robotic system in endovascular embolization procedures of cerebral aneurysms.

BACKGROUND: Robotic-assisted neurointervention was recently introduced, with implications that it could be used to treat neurovascular diseases. OBJECTIVE: To evaluate the effectiveness and safety of the robotic-assisted platform CorPath GRX for treating cerebral aneurysms. METHODS: This prospective, international, multicenter study enrolled patients with brain aneurysms that required endovascular coiling and/or stent-assisted coiling. The primary effectiveness endpoint was defined as successful completion of the robotic-assisted endovascular procedure without any unplanned conversion to manual treatment with guidewire or microcatheter navigation, embolization coil(s) or intracranial stent(s) deployment, or an inability to navigate vessel anatomy. The primary safety endpoint included intraprocedural and periprocedural events. RESULTS: The study enrolled 117 patients (74.4% female) with mean age of 56.6 years from 10 international sites,. Headache was the most common presenting symptom in 40/117 (34.2%) subjects. Internal carotid artery was the most common location (34/122, 27.9%), and the mean aneurysm height and neck width were 5.7±2.6 mm and 3.5±1.4 mm, respectively. The overall procedure time was 117.3±47.3 min with 59.4±32.6 min robotic procedure time. Primary effectiveness was achieved in 110/117 (94%) subjects with seven subjects requiring conversion to manual for procedure completion. Only four primary safety events were recorded with two intraprocedural aneurysm ruptures and two strokes. A Raymond-Roy Classification Scale score of 1 was achieved in 71/110 (64.5%) subjects, and all subjects were discharged with a modified Rankin Scale score of ≤2. CONCLUSIONS: This first-of-its-kind robotic-assisted neurovascular trial demonstrates the effectiveness and safety of the CorPath GRX System for endovascular embolization of cerebral aneurysm procedures. TRIAL REGISTRATION NUMBER: NCT04236856.

Steroidogenic Factor-1 form and function: From phospholipids to physiology.

Steroidogenic Factor-1 (SF-1, NR5A1) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors, consisting of a DNA-binding domain (DBD) connected to a transcriptional regulatory ligand binding domain (LBD) via an unstructured hinge domain. SF-1 is a master regulator of development and adult function along the hypothalamic pituitary adrenal and gonadal axes, with strong pathophysiological association with endometriosis and adrenocortical carcinoma. SF-1 was shown to bind and be regulated by phospholipids, one of the most interesting aspects of SF-1 regulation is the manner in which SF-1 interacts with phospholipids: SF-1 buries the phospholipid acyl chains deep in the hydrophobic core of the SF-1 protein, while the lipid headgroups remain solvent-exposed on the exterior of the SF-1 protein surface. Here, we have reviewed several aspects of SF-1 structure, function and physiology, touching on other transcription factors that help regulate SF-1 target genes, non-canonical functions of SF-1, the DNA-binding properties of SF-1, the use of mass spectrometry to identify lipids that associate with SF-1, how protein phosphorylation regulates SF-1 and the structural biology of the phospholipid-ligand binding domain. Together this review summarizes the form and function of Steroidogenic Factor-1 in physiology and in human disease, with particular emphasis on adrenal cancer.

Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

BACKGROUND & AIMS: Metoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared with placebo in reducing symptoms of diabetic gastroparesis in women. METHODS: This US multicenter, randomized, double-blind, parallel group study enrolled women aged 18-75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy end point was change in mean daily Gastroparesis Symptom Assessment total score from baseline to Week 4. The Gastroparesis Symptom Assessment daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a 5-point ordinal scale. RESULTS: Two hundred and five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared with the placebo group from baseline to Week 4 (P = .881). However, subjects with moderate-to-severe symptoms at baseline had a significant treatment effect from Weeks 1 to 3 (P < .05) and experienced a significant reduction in nausea and upper abdominal pain for all 4 weeks versus placebo (P < .05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. CONCLUSIONS: Although the primary end point was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate-to-severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. (ClinicalTrials.gov identifier: NCT02025725.).