MDM2 functions as a timer reporting the length of mitosis.

Delays in mitosis trigger p53-dependent arrest in G1 of the next cell cycle, thus preventing repeated cycles of chromosome instability and aneuploidy. Here we show that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises due to the attenuation of protein synthesis in mitosis.

Aging Selectively Alters PRR and ISG Expression in Endo- and Ecto-Cervical Stromal Fibroblasts From the Human Female Reproductive Tract.

Problem: Aging alters immune function in women and can lead increased risk of infections, particularly in the female reproductive tract (FRT).

Method Of Study: To determine how aging affects innate immune responses in the cervical stroma of the FRT, we isolated endocervical (CX) and ectocervical (ECX) stromal fibroblasts and determine if their expression of multiple pattern recognition receptors (PRRs) and responses to viral stimulation varied with menopause and age.

Results: Constitutive expression of most PRRs did not vary with age or menopausal status in either cell type.

Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of "Fusion-Positive" Cases.

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Here, we report 2 cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children's Oncology Group staging system).

Physician Specialty Differences in Unprofessional Behaviors Observed and Reported by Coworkers.

Importance: Because unprofessional behaviors are associated with patient complications, malpractice claims, and well-being concerns, monitoring concerns requiring investigation and individuals identified in multiple reports may provide important opportunities for health care leaders to support all team members.

Objective: To examine the distribution of physicians by specialty who demonstrate unprofessional behaviors measured through safety reports submitted by coworkers.

Design, Setting, And Participants: This retrospective cohort study was conducted among physicians who practiced at the 193 hospitals in the Coworker Concern Observation Reporting System (CORS), administered by the Vanderbilt Center for Patient and Professional Advocacy.

Molecular basis for pH sensing in the KDEL trafficking receptor.

Trafficking receptors control protein localization through the recognition of specific signal sequences that specify unique cellular locations. Differences in luminal pH are important for the vectorial trafficking of cargo receptors. The KDEL receptor is responsible for maintaining the integrity of the ER by retrieving luminally localized folding chaperones in a pH-dependent mechanism.

The PAX Genes: Roles in Development, Cancer, and Other Diseases.

Since their 1986 discovery in , Paired box (PAX) genes have been shown to play major roles in the early development of the eye, muscle, skeleton, kidney, and other organs. Consistent with their roles as master regulators of tissue formation, the PAX family members are evolutionarily conserved, regulate large transcriptional networks, and in turn can be regulated by a variety of mechanisms. Losses or mutations in these genes can result in developmental disorders or cancers.

Piperacetazine Directly Binds to the PAX3::FOXO1 Fusion Protein and Inhibits Its Transcriptional Activity.

Unlabelled: The tumor-specific chromosomal translocation product, PAX3::FOXO1, is an aberrant fusion protein that plays a key role for oncogenesis in the alveolar subtype of rhabdomyosarcoma (RMS). PAX3::FOXO1 represents a validated molecular target for alveolar RMS and successful inhibition of its oncogenic activity is likely to have significant clinical applications. Even though several PAX3::FOXO1 function-based screening studies have been successfully completed, a directly binding small-molecule inhibitor of PAX3::FOXO1 has not been reported.

Rhabdomyosarcomas are oncogene addicted to the activation of AVIL.

Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS.

PP6 regulation of Aurora A-TPX2 limits NDC80 phosphorylation and mitotic spindle size.

Amplification of the mitotic kinase Aurora A or loss of its regulator protein phosphatase 6 (PP6) have emerged as drivers of genome instability. Cells lacking PPP6C, the catalytic subunit of PP6, have amplified Aurora A activity, and as we show here, enlarged mitotic spindles which fail to hold chromosomes tightly together in anaphase, causing defective nuclear structure. Using functional genomics to shed light on the processes underpinning these changes, we discover synthetic lethality between PPP6C and the kinetochore protein NDC80.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

Purpose: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS.

Novel GLCCI1-BRAF fusion drives kinase signaling in a case of pheochromocytomatosis.

Introduction: Recurrent and metastatic pheochromocytoma (PCC) are rare advanced endocrine neoplasms with limited treatment options. Insight into the pathogenic molecular alterations in patients with advanced PCC can provide therapeutic options for precisely targeting dysregulated pathways.

Objective: We report the discovery and characterization of a novel BRAF-containing fusion transcript and its downstream molecular alterations in a patient with recurrent PCC with peritoneal seeding (pheochromocytomatosis).

NanoString Digital Molecular Profiling of Protein and microRNA in Rhabdomyosarcoma.

Purpose: Rhabdomyosarcoma (RMS) exhibits a complex prognostic algorithm based on histologic, biologic and clinical parameters. The embryonal (ERMS) and spindle cell-sclerosing RMS (SRMS) histologic subtypes warrant further studies due to their heterogenous genetic background and variable clinical behavior. NanoString digital profiling methods have been previously highlighted as robust novel methods to detect protein and microRNA expression in several cancers but not in RMS.

Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.

Background: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.

Patients And Methods: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment.

Characteristics and Clinical Outcomes of Children and Adolescents Aged <18 Years Hospitalized with COVID-19 - Six Hospitals, United States, July-August 2021.

During June 2021, the highly transmissible B.1.617.

Sex Hormones and Aging Modulate Interferon Lambda 1 Production and Signaling by Human Uterine Epithelial Cells and Fibroblasts.

Estradiol (E) and progesterone (P) have potent effects on immune function in the human uterine endometrium which is essential for creating an environment conducive for successful reproduction. Type III/lambda (λ) interferons (IFN) are implicated in immune defense of the placenta against viral pathogens, which occurs against the backdrop of high E and P levels. However, the effect of E and P in modulating the expression and function of IFNλ1 in the non-pregnant human uterine endometrium is unknown.

Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification.

The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.

A signal capture and proofreading mechanism for the KDEL-receptor explains selectivity and dynamic range in ER retrieval.

ER proteins of widely differing abundance are retrieved from the Golgi by the KDEL-receptor. Abundant ER proteins tend to have KDEL rather than HDEL signals, whereas ADEL and DDEL are not used in most organisms. Here, we explore the mechanism of selective retrieval signal capture by the KDEL-receptor and how HDEL binds with 10-fold higher affinity than KDEL.

MYOD1 as a prognostic indicator in rhabdomyosarcoma.

Background/objectives: Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis.

A Fusion Transcription Factor-Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target.

Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1-induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein.

Molecular basis for KDEL-mediated retrieval of escaped ER-resident proteins - SWEET talking the COPs.

Protein localisation in the cell is controlled through the function of trafficking receptors, which recognise specific signal sequences and direct cargo proteins to different locations. The KDEL receptor (KDELR) was one of the first intracellular trafficking receptors identified and plays an essential role in maintaining the integrity of the early secretory pathway. The receptor recognises variants of a canonical C-terminal Lys-Asp-Glu-Leu (KDEL) signal sequence on ER-resident proteins when these escape to the Golgi, and targets these proteins to COPI- coated vesicles for retrograde transport back to the ER.