Citations

Management of patients with advanced sarcoma has been evolving in recent decades, from a one-fit-all perspective to a more refined, personalized, and multidisciplinary approach. In parallel, the evolution of local therapies (radiotherapy, surgical and interventional radiology techniques) has contributed to the improvement of survival of patients with advanced sarcoma. In this article, we review the evidence regarding local treatments in advanced sarcoma, as well as its integration with systemic therapies, to provide the reader a wider and deeper perspective on the management of patients with metastatic sarcoma.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Abstract Context Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. Objective (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Design Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). Results We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Conclusions Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. Clinical Trial number NCT04969926

An imbalance in goal-directed and habitual behavioral control is a hallmark of decision-making–related disorders, including addiction. Although external globus pallidus (GPe) is critical for action selection, which harbors enriched astrocytes, the role of GPe astrocytes involved in action-selection strategies remained unknown. Using in vivo calcium signaling with fiber photometry, we found substantially attenuated GPe astrocytic activity during habitual learning compared to goal-directed learning. The support vector machine analysis predicted the behavioral outcomes. Chemogenetic activation of the astrocytes or inhibition of GPe pan-neuronal activities facilitates the transition from habit to goal-directed reward-seeking behavior. Next, we found increased astrocyte-specific GABA (γ-aminobutyric acid) transporter type 3 (GAT3) messenger RNA expression during habit learning. Notably, the pharmacological inhibition of GAT3 occluded astrocyte activation–induced transition from habitual to goal-directed behavior. On the other hand, attentional stimuli shifted the habit to goal-directed behaviors. Our findings suggest that the GPe astrocytes regulate the action selection strategy and behavioral flexibility.

Introduction: The role of hypertriglyceridemia (HTG) in cardiovascular disease (CVD) remains controversial, especially in persons with well-controlled low-density lipoprotein cholesterol (LDL-C). Hypothesis: We aimed to evaluate the association between triglyceride (TG) levels and CVD mortality according to LDL-C and age in a general population. Methods: From the Korean National Health Insurance Service database, 15,672,028 participants aged 18-99 who underwent routine health examinations were followed up for CVD mortality. Hazard ratios (HRs) for CVD mortality were calculated using Cox models after adjusting for various confounders. Results: During a mean 8.8 years of follow-up, 105,174 individuals died from CVD. There was a clear log-linear association between TG and overall CVD mortality down to 50 mg/dL. Each two-fold increase in TG was associated with 1.10-fold (overall CVD), 1.22-fold (ischemic heart disease [IHD]), 1.24-fold (acute myocardial infarction [AMI]), and 1.10-fold (ischemic stroke) higher CVD mortality. Hemorrhagic stroke and heart failure were not associated with TG levels. The impact of HTG on CVD weakened but remained present in persons with LDL-C <100 mg/dL, in whom each two-fold higher TG was associated with 1.05-fold (overall CVD), 1.12-fold (IHD), 1.15-fold (AMI), and 1.05-fold (ischemic stroke) higher CVD mortality. The younger population (18 to 44 years) had stronger associations between TG levels and mortality from overall CVD, IHD, and AMI than the older population. Conclusions: HTG independently increases CVD mortality. There are residual risks of HTG in both young and older individuals with a low level of LDL-C. HTG management might be beneficial in individuals with well-controlled LDL-C.

Background: Aesthetic soft-tissue filler injections for lip enhancement are popular and performed throughout the world. When injecting lips with a cannula, as the cannula is advanced, resistance is perceived in consistent locations, potentially indicating boundaries between intralabial compartments. Objective: We aimed to investigate whether intralabial compartments exist and, if so, to describe their volumes, location, boundaries, and dimensions. Methods: This cadaveric study investigated a total of 20 human body donors (13 male, seven female) with a mean (SD) age at death of 61.9 years (23.9) and body mass index of 24.3 kg/m2 (3.7). The investigated cohort included 11 White donors, eight Asian donors, and one Black donor. Dye injections simulating minimally invasive lip treatments were conducted. Results: Independent of sex or race, six anterior and six posterior compartments in the upper and lower lip were identified, for a total of 24 lip compartments. Compartment boundaries were formed by vertically oriented septations that were found in consistent locations. The anterior compartments had volumes ranging from 0.30 to 0.39 cc; the posterior compartment volume ranged from 0.44 to 0.52 cc. The compartment volumes were larger centrally and decreased gradually toward the oral commissure. Conclusions: The volume and size of each of 24 compartments contribute to the overall appearance and shape of the lips. To achieve a natural lip shape preserving aesthetic outcome it may be preferable to administer the volumizing product using a compartment-respecting injection approach.

Abstract Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.