eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity.

Dystonia is the 3 rd most common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular mechanisms. Eukaryotic initiation factor alpha (eIF2α) controls cell state including neuronal plasticity via protein translation control and expression of ATF4. Dysregulated eIF2α phosphorylation (eIF2α-P) occurs in dystonia patients and models including DYT1, but the consequences are unknown. We increased/decreased eIF2α-P and tested motor control and neuronal properties in a Drosophila model. Bidirectionally altering eIF2α-P produced dystonia-like abnormal posturing and dyskinetic movements in flies. These movements were also observed with expression of the DYT1 risk allele. We identified cholinergic and D2-receptor neuroanatomical origins of these dyskinetic movements caused by genetic manipulations to dystonia molecular candidates eIF2α-P, ATF4, or DYT1, with evidence for decreased cholinergic release. In vivo , increased and decreased eIF2α-P increase synaptic connectivity at the NMJ with increased terminal size and bouton synaptic release sites. Long-term treatment of elevated eIF2α-P with ISRIB restored adult longevity, but not performance in a motor assay. Disrupted eIF2α-P signaling may alter neuronal connectivity, change synaptic release, and drive motor circuit changes in dystonia.

Maternal nano-titanium dioxide inhalation exposure alters placental cyclooxygenase and oxidant balance in a sexually dimorphic manner.

The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulation, and thus impacts fetal growth and development. We have previously shown that nano-titanium dioxide (nano-TiO2) inhalation exposure during gestation decreased fetal female pup and placenta mass [1], which persists in the following generation [2]. In utero exposed females, once mated, their offspring's placentas had increased capacity for H2O2 production. Generation of oxidants such as hydrogen peroxide (H2O2), have been shown to impact cyclooxygenase activity, specifically metabolites such as prostacyclin (PGI2) or thromboxane (TXA2). Therefore, we hypothesized that maternal nano-TiO2 inhalation exposure during gestation results in alterations in placental production of prostacyclin and thromboxane mediated by enhanced H2O2 production in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed to nano-TiO2 aerosols or filtered air (sham--control) from gestational day (GD) 10-19. Dams were euthanized on GD 20, and fetal serum and placental tissue were collected based on fetal sex. Fetal placental zones (junctional zone (JZ) and labyrinth zone (LZ)) were assessed for xanthine oxidoreductase (XOR) activity, H2O2, and catalase activity, as well as 6-keto-PGF1α and TXB2 levels. Nano-TiO2 exposed fetal female LZ demonstrated significantly greater XOR activity compared to exposed males. Exposed fetal female LZ also demonstrated significantly diminished catalase activity compared to sham-control females. Exposed fetal female LZ had significantly increased abundance of 6-keto-PGF1α compared to sham-control females and increased TXB2 compared to exposed males. In the aggregate these data indicate that maternal nano-TiO2 inhalation exposure has a greater impact on redox homeostasis and PGI2/TXA2 balance in the fetal female LZ. Future studies need to address if treatment with an XO inhibitor during gestation can prevent diminished fetal female growth during maternal nano-TiO2 inhalation exposure.

Characterization of renal masses with MRI-based radiomics: assessment of inter-package and inter-observer reproducibility in a prospective pilot study.

OBJECTIVES: To evaluate radiomics features' reproducibility using inter-package/inter-observer measurement analysis in renal masses (RMs) based on MRI and to employ machine learning (ML) models for RM characterization. METHODS: 32 Patients (23M/9F; age 61.8 ± 10.6 years) with RMs (25 renal cell carcinomas (RCC)/7 benign masses; mean size, 3.43 ± 1.73 cm) undergoing resection were prospectively recruited. All patients underwent 1.5 T MRI with T2-weighted (T2-WI), diffusion-weighted (DWI)/apparent diffusion coefficient (ADC), and pre-/post-contrast-enhanced T1-weighted imaging (T1-WI). RMs were manually segmented using volume of interest (VOI) on T2-WI, DWI/ADC, and T1-WI pre-/post-contrast imaging (1-min, 3-min post-injection) by two independent observers using two radiomics software packages for inter-package and inter-observer assessments of shape/histogram/texture features common to both packages (104 features; n = 26 patients). Intra-class correlation coefficients (ICCs) were calculated to assess inter-observer and inter-package reproducibility of radiomics measurements [good (ICC ≥ 0.8)/moderate (ICC = 0.5-0.8)/poor (ICC < 0.5)]. ML models were employed using reproducible features (between observers and packages, ICC > 0.8) to distinguish RCC from benign RM. RESULTS: Inter-package comparisons demonstrated that radiomics features from T1-WI-post-contrast had the highest proportion of good/moderate ICCs (54.8-58.6% for T1-WI-1 min), while most features extracted from T2-WI, T1-WI-pre-contrast, and ADC exhibited poor ICCs. Inter-observer comparisons found that radiomics measurements from T1-WI pre/post-contrast and T2-WI had the greatest proportion of features with good/moderate ICCs (95.3-99.1% T1-WI-post-contrast 1-min), while ADC measurements yielded mostly poor ICCs. ML models generated an AUC of 0.71 [95% confidence interval = 0.67-0.75] for diagnosis of RCC vs. benign RM. CONCLUSION: Radiomics features extracted from T1-WI-post-contrast demonstrated greater inter-package and inter-observer reproducibility compared to ADC, with fair accuracy for distinguishing RCC from benign RM. CLINICAL RELEVANCE: Knowledge of reproducibility of MRI radiomics features obtained on renal masses will aid in future study design and may enhance the diagnostic utility of radiomics models for renal mass characterization.

Genomes for Nurses: Understanding and Overcoming Barriers to Nurses Utilizing Genomics.

Background: Genomic testing is an increasingly important technology within pediatric oncology that aids in cancer diagnosis, provides prognostic information, identifies therapeutic targets, and reveals underlying cancer predisposition. However, nurses lack basic knowledge of genomics and have limited self-assurance in using genomic information in their daily practice. This single-institution project was carried out at an academic pediatric cancer hospital in the United States with the aim to explore the barriers to achieving genomics literacy for pediatric oncology nurses. Method: This project assessed barriers to genomic education and preferences for receiving genomics education among pediatric oncology nurses, nurse practitioners, and physician assistants. An electronic survey with demographic questions and 15 genetics-focused questions was developed. The final survey instrument consisted of nine sections and was pilot-tested prior to administration. Data were analyzed using a ranking strategy, and five focus groups were conducted to capture more-nuanced information. The focus group sessions lasted 40 min to 1 hour and were recorded and transcribed. Results: Over 50% of respondents were uncomfortable with or felt unprepared to answer questions from patients and/or family members about genomics. This unease ranked as the top barrier to using genomic information in clinical practice. Discussion: These results reveal that most nurses require additional education to facilitate an understanding of genomics. This project lays the foundation to guide the development of a pediatric cancer genomics curriculum, which will enable the incorporation of genomics into nursing practice.

Illuminating Firefly Diversity: Trends, Threats and Conservation Strategies.

Fireflies are a diverse group of bioluminescent beetles belonging to the family Lampyridae. Recent research on their diversity, evolution, behavior and conservation has greatly advanced our scientific understanding of these charismatic insects. In this review, we first summarize new discoveries about their taxonomic and ecological diversity, then focus on recent endeavors to identify and protect threatened fireflies around the world. We outline the main threats linked to recent population declines (habitat loss and degradation, light pollution, pesticide overuse, climate change and tourism) and describe relevant risk factors that predict which species will be particularly vulnerable to these threats. Although global coordination of firefly conservation efforts has begun only recently, considerable progress has already been made. We describe work by the IUCN SSC Firefly Specialist Group to identify species currently facing elevated extinction risks and to devise conservation strategies to protect them. To date, IUCN Red List assessments have been completed for 150 firefly taxa, about 20% of which face heightened extinction risks. The conservation status for many species has yet to be determined due to insufficient information, although targeted surveys and community science projects have contributed valuable new data. Finally, we highlight some examples of successful firefly habitat protection and restoration efforts, and we use the framework of the IUCN SSC Species Conservation Cycle to point out high-priority actions for future firefly conservation efforts.

Clinical utility of a genetic diagnosis in individuals with cerebral palsy and related motor disorders.

OBJECTIVE: Evaluation of the clinical utility of a genetic diagnosis in CP remains limited. We aimed to characterize the clinical utility of a genetic diagnosis by exome sequencing (ES) in patients with CP and related motor disorders. METHODS: We enrolled participants with CP and "CP masquerading" conditions in an institutional ES initiative. In those with genetic diagnoses who had clinical visits to discuss results, we retrospectively reviewed medical charts, evaluating recommendations based on the genetic diagnosis pertaining to medication intervention, surveillance initiation, variant-specific testing, and patient education. RESULTS: We included 30 individuals with a molecular diagnosis and clinical follow-up. Nearly all (28 out of 30) had clinical impact resulting from the genetic diagnosis. Medication interventions included recommendation of mitochondrial multivitamin supplementation (6.67%, n = 2), ketogenic diet (3.33%, n = 1), and fasting avoidance (3.33%, n = 1). Surveillance-related actions included recommendations for investigating systemic complications (40%, n = 12); referral to new specialists to screen for systemic manifestations (33%, n = 10); continued follow-up with established specialists to focus on specific manifestations (16.67%, n = 5); referral to clinical genetics (16.67%, n = 5) to oversee surveillance recommendations. Variant-specific actions included carrier testing (10%, n = 3) and testing of potentially affected relatives (3.33%, n = 1). Patient education-specific actions included referral to experts in the genetic disorder (30%, n = 9); and counseling about possible changes in prognosis, including recognition of disease progression and early mortality (36.67%, n = 11). INTERPRETATION: This study highlights the clinical utility of a genetic diagnosis for CP and "CP masquerading" conditions, evident by medication interventions, surveillance impact, family member testing, and patient education, including possible prognostic changes.

Utility of nifedipine use for Doppler ultrasound early after liver transplantation to predict short-term complications and long-term outcomes.

PURPOSE: To evaluate the response to nifedipine administration measured by changes in hepatic arterial (HA) flow on post-operative Doppler ultrasound (US) to predict short-term complications and long-term outcomes in liver transplant (LT) patients. METHODS: Patients who underwent LT with post-operative Doppler US within 3 days between 1 January 2005 and 31 December 2015 were included in this retrospective single center study. The patients who received and did not receive nifedipine during the Doppler US comprised the study and control groups, respectively. A positive response to nifedipine was defined as the detection of HA flow when none was present initially or a reduction in HA resistive index (RI) ≥ 0.1 after nifedipine administration. The rates of re-transplantation, re-operation, percutaneous intervention (PCI), and overall survival (OS) were recorded. Cox proportional hazards regression was used to evaluate the association of clinic-demographic variables and Doppler findings with the outcome measures. RESULTS: 444 LT patients (305 M/139F, mean age 51.7 ± 17.4 years, mean interval between LT-Doppler US 1.12 ± 0.9 days) are presented. 220 patients comprised the nifedipine study group [n = 157/220 (71.4%) responder, n = 63/220 (28.6%) nonresponder] and 224 patients comprised the control group. There was no difference in re-transplantation or PCI rates between the groups (all p-values ≥ 0.2 and ≥ 0.08, respectively). The responder group had a lower rate of re-operation vs. the control group (15.9% vs. 24.1%, p = 0.03) and nonresponder group (15.9% vs. 31.8%, p = 0.004). 1-year and 2-year OS were similar between the groups (all p-values > 0.37). CONCLUSION: Short-term complication rates and long-term outcomes for patients with liver transplant who responded to nifedipine administration on Doppler US are similar to those who did not require nifedipine administration. A lack of response to nifedipine was associated with a higher re-operation rate.

Contemporary and Emerging MRI Strategies for Assessing Kidney Allograft Complications: Arterial Stenosis and Parenchymal Injury, From the AJR Special Series on Imaging of Fibrosis.

MRI plays an important role in the evaluation of kidney allografts for vascular complications as well as parenchymal insults. Transplant renal artery stenosis, the most common vascular complication of kidney transplant, can be evaluated by MRA using gadolinium and nongadolinium contrast agents as well as by unenhanced MRA techniques. Parenchymal injury occurs through a variety of pathways, including graft rejection, acute tubular injury, BK polyomavirus infection, drug-induced interstitial nephritis, and pyelonephritis. Investigational MRI techniques have sought to differentiate among these causes of dysfunction as well as to assess the degree of interstitial fibrosis or tubular atrophy (IFTA)-the common end pathway for all of these processes-which is currently evaluated by invasively obtained core biopsies. Some of these MRI sequences have shown promise in not only assessing the cause of parenchymal injury but also assessing IFTA noninvasively. This review describes current clinically used MRI techniques and previews promising investigational MRI techniques for assessing complications of kidney grafts.

TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial.

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or

Clinical actionability of genetic findings in cerebral palsy.

Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety/practicality of the intervention, and anticipated intervention efficacy . Results: We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as actionable , defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the primary disease mechanism , 16 had specific prevention strategies , and 26 had specific symptom management recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have clinical utility with 97% of outcomes being moderate-high severity if left untreated and 62% of interventions predicted to be of moderate-high efficacy . Most interventions (71%) were considered moderate-high safety/practicality . Discussion: Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy , outcome severity , and intervention safety / practicality indicates moderate-high clinical utility of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

Magnetic resonance elastography for noninvasive detection of liver fibrosis: is there an added value of 3D acquisition?

PURPOSE: (1) Assess the diagnostic performance of liver 3D magnetic resonance elastography (MRE) parameters (including stiffness, storage/loss modulus and damping ratio) compared to liver stiffness measured with 2D MRE for noninvasive detection of advanced liver fibrosis (F3-F4) and cirrhosis (F4) in patients with chronic liver disease. (2) Assess the value of serum markers (FIB-4) in detecting advanced liver fibrosis and cirrhosis in the same patients. METHODS: This was a single center, prospective IRB-approved cross-sectional study that included 49 patients (M/F: 23/26, mean age 50.8 y) with chronic liver disease and concomitant liver biopsy. MRE was acquired at 1.5T using a spin echo-EPI sequence. The following parameters were measured: liver stiffness using 2D MRE (LS-2D) and 3D MRE parameters (LS-3D, liver storage, loss modulus and damping ratio). The Mann-Whitney U test, ROC curve analysis, Spearman correlation and logistic regression were performed to evaluate diagnostic performance of MRE parameters and FIB-4. RESULTS: LS-2D and LS-3D had similar diagnostic performance for diagnosis of F3-F4, with AUCs of 0.87 and 0.88, sensitivity of 0.71 and 0.81, specificity of 0.89 for both. For diagnosis of F4, LS-2D and LS-3D had similar performance with AUCs of 0.81 for both, sensitivity of 0.75 and 0.83, and specificity of 0.84 and 0.73, respectively. Additional 3D parameters (storage modulus, loss modulus, damping ratio) had variable performance, with AUC range of 0.59-0.78 for F3-F4; and 0.52-0.70 for F4. FIB-4 had lower diagnostic performance, with AUCs of 0.66 for F3-F4, and 0.68 for F4. CONCLUSION: Our study shows no added value of 3D MRE compared to 2D MRE for detection of advanced fibrosis and cirrhosis, while FIB-4 had lower diagnostic performance.

Hemin and iron increase synthesis and trigger export of xanthine oxidoreductase from hepatocytes to the circulation.

We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the cellular signaling and export mechanisms underpinning this process were not identified. Here, we present novel data showing hepatocytes upregulate XOR expression/protein abundance and actively release it to the extracellular compartment following exposure to hemopexin-bound hemin, hemin or free iron. For example, murine (AML-12 cells) hepatocytes treated with hemin (10 µM) exported XOR to the medium in the absence of cell death or loss of membrane integrity (2.0 ± 1.0 vs 16 ± 9 µU/mL p < 0.0001). The path of exocytosis was found to be noncanonical as pretreatment of the hepatocytes with Vaculin-1, a lysosomal trafficking inhibitor, and not Brefeldin A inhibited XOR release and promoted intracellular XOR accumulation (84 ± 17 vs 24 ± 8 hemin vs 5 ± 3 control µU/mg). Interestingly, free iron (Fe2+ and Fe3+) induced similar upregulation and release of XOR compared to hemin. Conversely, concomitant treatment with hemin and the classic transition metal chelator DTPA (20 µM) or uric acid completely blocked XOR release (p < 0.01). Our previously published time course showed XOR release from hepatocytes likely required transcriptional upregulation. As such, we determined that both Sp1 and NF-kB were acutely activated by hemin treatment (∼2-fold > controls for both, p < 0.05) and that silencing either or TLR4 with siRNA prevented hemin-induced XOR upregulation (p < 0.01). Finally, to confirm direct action of these transcription factors on the Xdh gene, chromatin immunoprecipitation was performed indicating that hemin significantly enriched (∼5-fold) both Sp1 and NF-kB near the transcription start site. In summary, our study identified a previously unknown pathway by which XOR is upregulated via SP1/NF-kB and subsequently exported to the extracellular environment. This is, to our knowledge, the very first study to demonstrate mechanistically that XOR can be specifically targeted for export as the seminal step in a compensatory response to heme/Fe overload.

Longitudinal assessment of hepatocellular carcinoma response to stereotactic body radiation using gadoxetate-enhanced MRI: A case series.

PURPOSE: To describe the longitudinal response in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) and who underwent liver transplant (LT) using gadoxetate-enhanced MRI. METHODS: Five men (median age 61y, range 57-64y) with 6 HCCs treated with SBRT (median dose 50 Gy) who subsequently underwent LT were included in this retrospective study. Patients underwent gadoxetate-enhanced MRI before and after SBRT over a period of 3-18 months. Response was assessed using RECIST1.1, mRECIST, LI-RADS and image subtraction, by 2 observers in consensus. Percentage of pathologic tumor necrosis was evaluated. RESULTS: LT was performed 278 days (IQR, 148-418d) after completion of SBRT and 48d after the last MRI. Histopathology demonstrated tumor necrosis of 48 ± 42% (range, 10-100%). Mean tumor size at baseline and last post-treatment MRIs pre-LT were 2.6 ± 0.8 cm and 2.4 ± 0.9 cm. Enhancing tumor component size at baseline MRI and last post-treatment MRI pre-LT were 1.6 ± 0.8 cm and 0.9 ± 1.0 cm. Responses assessed at the last LRI pre-LT were: partial response (PR, n = 3), stable disease (SD, n = 3) using RECIST1.1; complete response (CR, n = 2), partial response (PR, n = 2), stable disease (SD, n = 2) using mRECIST; and LR-TR viable (n = 4), LR-TR non-viable (n = 2) using LI-RADS. At the last MRI pre-LT, per-lesion features of arterial phase hyperenhancement (APHE, 4/6), portal venous washout (3/6) and capsule (3/6) were observed. 5/6 lesions displayed a hypointense perilesional halo on hepatobiliary phase with a mean delay of 3.1 months post-SBRT. CONCLUSIONS: This case-series showed decreased size, persistent APHE, and incomplete pathologic necrosis in most HCCs treated with SBRT undergoing transplant.

Society of abdominal radiology survey of practice patterns in using LI-RADS treatment response criteria in the evaluation of hepatocellular carcinoma post-locoregional treatment.

PURPOSE: To examine national trends in the adoption and use of the LI-RADS Treatment Response Algorithm. METHODS: Members of the Society of Abdominal Radiology (SAR) Disease-Focused Panel (DFP) on LI-RADS Treatment Response (LR-TR) of hepatocellular carcinoma (HCC) developed a 15-question survey which was distributed to radiologists at academic and private practice institutions around the USA and Canada. The survey focused on HCC-related practice patterns as well as the adoption and use of the LR-TR algorithm. RESULTS: Of 122 surveys distributed, a total of 76 radiologists responded (62%). Responders were predominantly from academic centers (85%). Nearly all (96%) participate in multidisciplinary hepatic tumor boards and most (67%) have an active liver transplant program. All responders' institutions perform locoregional therapy for HCC, including radiation-based therapy (TARE and SBRT). There was a preference for use of MRI over CT for follow-up after locoregional therapy. All responders were aware of the LR-TR algorithm and nearly all (92%) used the system in routine practice. Radiologists expressed a need for more visual aids related to the LR-TR system. Multiple respondents requested additional clarity within the LR-TR algorithm regarding the evolution of post-treatment radiation changes over time. CONCLUSION: Most survey participants use the LR-TR algorithm after locoregional therapy for HCC. Future iterations of the algorithm may benefit from increased clarity regarding response after radiation-based therapies. Educational materials should include more visual aids to improve reader understanding.

Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental disorders.

AGAP1 is an Arf1 GTPase-activating protein that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report three new cases in which individuals had microdeletion variants in AGAP1. The affected individuals had intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlying AGAP1 variant-mediated neurodevelopmental impairments using the Drosophila ortholog CenG1a. We discovered reduced axon terminal size, increased neuronal endosome abundance and elevated autophagy compared to those in controls. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in the phosphorylation of the integrated stress-response protein eIF2α (or eIF2A) and inability to further increase eIF2α phosphorylation with subsequent cytotoxic stressors. CenG1a-mutant flies had increased lethality from exposure to environmental insults. We propose a model wherein disruption of AGAP1 function impairs endolysosomal trafficking, chronically activating the integrated stress response and leaving AGAP1-deficient cells susceptible to a variety of second-hit cytotoxic stressors. This model may have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders.