Molecular insights into the unique properties of the blood-circulating proteasome.

Proteasomes are essential for protein degradation and maintaining cellular balance, yet their roles in extracellular fluids are not well understood. Our study investigates the freely circulating proteasome in blood, to uncover its unique molecular characteristics, compared to its intracellular counterparts. Using a transgenic mouse model, mass spectrometry, and biochemical tools, we show that the predominant proteasome in serum is the free uncapped 20S particle, which seems to assemble intracellularly before entering the bloodstream.

Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma.

Investigating the Potential of Haptic Props for 3D Object Manipulation in Handheld AR.

The manipulation of virtual 3D objects is essential for a variety of handheld AR scenarios. However, the mapping of commonly supported 2D touch gestures to manipulations in 3D space is not trivial. As an alternative, our work explores the use of haptic props that facilitate direct manipulation of virtual 3D objects with 6 degrees of freedom.

Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial.

Importance: The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines.

Objective: To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma.

Design, Setting, And Participants: The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America.

Lexicon for blood-based early detection and screening: BLOODPAC consensus document.

In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success.

Egr1 regulates regenerative senescence and cardiac repair.

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice.

A label-free quantification method for assessing sex from modern and ancient bovine tooth enamel.

Identification of the sex of modern, fossil and archaeological animal remains offers many insights into their demography, mortality profiles and domestication pathways. However, due to many-factors, sex determination of osteological remains is often problematic. To overcome this, we have developed an innovative protocol to determine an animal's sex from tooth enamel, by applying label-free quantification (LFQ) of two unique AmelY peptides 'LRYPYP' (AmelY;[M+2] 404.

Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.

Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane.

A new biomarker panel for differential diagnosis of cholangiocarcinoma: Results from an exploratory analysis.

Introduction: Diagnosis of cholangiocarcinoma (CCA) can be challenging due to unclear imaging criteria and difficulty obtaining adequate tissue biopsy. Although serum cancer antigen 19-9 and carcinoembryonic antigen have been proposed as potential diagnostic aids, their use remains limited by insufficient sensitivity and specificity. This exploratory analysis aimed to identify individual- and combinations of serum biomarkers to distinguish CCA from hepatocellular carcinoma (HCC) and chronic liver disease (CLD) controls using samples from a published study.

Using Constellation Pharmacology to Characterize a Novel α-Conotoxin from .

The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function of the various nAChR subtypes. By studying how conotoxins interact with nAChRs, we can improve our understanding of these receptors, leading to new insights into neurological diseases associated with nAChRs.

Glycoproteome-Wide Discovery of Cortical Glycoproteins That May Provide Cognitive Resilience in Older Adults.

Background And Objectives: Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience.

Upward Lightning at Wind Turbines: Risk Assessment From Larger-Scale Meteorology.

Upward lightning (UL) has become a major threat to the growing number of wind turbines producing renewable electricity. It can be much more destructive than downward lightning due to the large charge transfer involved in the discharge process. Ground-truth lightning current measurements indicate that less than 50% of UL could be detected by lightning location systems (LLS).

Upward Lightning at the Gaisberg Tower: The Larger-Scale Meteorological Influence on the Triggering Mode and Flash Type.

Upward lightning is rarer than downward lightning and requires tall (100+ m) structures to initiate. It may be either self-initiated or triggered by other lightning discharges. While conventional lightning location systems (LLSs) detect most of the upward lightning flashes superimposed by pulses or return strokes, they miss a specific flash type that consists only of a continuous current.

Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

Background: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020.

Methods: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics.

VWD domain stabilization by autocatalytic Asp-Pro cleavage.

Domains known as von Willebrand factor type D (VWD) are found in extracellular and cell-surface proteins including von Willebrand factor, mucins, and various signaling molecules and receptors. Many VWD domains have a glycine-aspartate-proline-histidine (GDPH) amino-acid sequence motif, which is hydrolytically cleaved post-translationally between the aspartate (Asp) and proline (Pro). The Fc IgG binding protein (FCGBP), found in intestinal mucus secretions and other extracellular environments, contains 13 VWD domains, 11 of which have a GDPH cleavage site.

Cross-cultural adaptation, validation and psychometric evaluation of the International Hip Outcome Tool 12 (iHOT) to Hebrew.

Background: The "International Hip Outcome Tool 12" (iHOT) is a self-administered patient-reported outcome tool for measuring health-related quality of life and physical functioning in young and active patients with hip pathology. Since the iHOT has become widely used, we sought to translate and validate it for Hebrew-speaking populations. The aims of this study were: (1) To translate and culturally adapt the iHOT into Hebrew using established guidelines.

Synchronous T-lymphoblastic lymphoma and neuroblastoma in a 3-yr-old with novel germline and variants.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses.

Amplification of annual and diurnal cycles of alpine lightning.

The response of lightning to a changing climate is not fully understood. Historic trends of proxies known for fostering convective environments suggest an increase of lightning over large parts of Europe. Since lightning results from the interaction of processes on many scales, as many of these processes as possible must be considered for a comprehensive answer.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Unlabelled: Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.

Thyroglobulin Cutoff Values for Detecting Excellent Response to Therapy in Patients With Differentiated Thyroid Cancer.

Context: Serum thyroglobulin (Tg) is a biochemical marker for detecting persistent or recurrent differentiated thyroid carcinoma (DTC) post-thyroidectomy. Tg can indicate DTC before structural disease (SD) is visible with imaging procedures.

Objective: This work aimed to evaluate the clinical performance of the Elecsys Tg II assay at a Tg cutoff of 0.

Precision oncology for children: A primer for paediatricians.

Cancer is the leading cause of disease-related death in children, adolescents, and young adults beyond the newborn period in North America. Improving survival rates for patients with hard-to-cure cancer remains a challenge. One approach that has gained particular traction is 'precision oncology', whereby next-generation sequencing is used to identify genomic or transcriptomic changes that can help clarify the diagnosis, refine prognosis, define an underlying genetic cause, or identify a unique treatment target for a patient's cancer.

Renal Implications of Long-Term Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

Background: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA).

Case-diagnosis/treatment: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon).

Deciphering the involvement of the Hippo pathway co-regulators, YAP/TAZ in invadopodia formation and matrix degradation.

Invadopodia are adhesive, actin-rich protrusions formed by metastatic cancer cells that degrade the extracellular matrix and facilitate invasion. They support the metastatic cascade by a spatially and temporally coordinated process whereby invading cells bind to the matrix, degrade it by specific metalloproteinases, and mechanically penetrate diverse tissue barriers by forming actin-rich extensions. However, despite the apparent involvement of invadopodia in the metastatic process, the molecular mechanisms that regulate invadopodia formation and function are still largely unclear.