Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex.

The Pro/N-degron recognizing C-terminal to LisH (CTLH) complex is an E3 ligase of emerging interest in the developmental biology field and for targeted protein degradation (TPD) modalities. The human CTLH complex forms distinct supramolecular ring-shaped structures dependent on the multimerization of WDR26 or muskelin β-propeller proteins. Here, we find that, in HeLa cells, CTLH complex E3 ligase activity is dictated by an interplay between WDR26 and muskelin in tandem with muskelin autoregulation.

Recruitment of FBXO22 for targeted degradation of NSD2.

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.

A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.

Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor.

Patients And Methods: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors.

CRISPR-Cas9 In Vivo Gene Editing of for Hereditary Angioedema.

Background: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (), with the goal of lifelong control of angioedema attacks after a single dose.

Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit.

Noncanonical functions of Ku may underlie essentiality in human cells.

The Ku70/80 heterodimer is a key player in non-homologous end-joining DNA repair but is involved in other cellular functions like telomere regulation and maintenance, in which Ku's role is not fully characterized. It was previously reported that knockout of Ku80 in a human cell line results in lethality, but the underlying cause of Ku essentiality in human cells has yet to be fully explored. Here, we established conditional Ku70 knockout cells using CRISPR/Cas9 editing to study the essentiality of Ku70 function.

Model-based approach to identify predictors of paclitaxel-induced myelosuppression in "real-world" administration.

Taxanes are currently the most frequently used chemotherapeutic agents in cancer care, where real-world use has focused on minimizing adverse events and standardizing the delivery. Myelosuppression is a well-characterized, adverse pharmacodynamic effect of taxanes. Electronic health records (EHRs) comprise data collected during routine clinical care that include patients with heterogeneous demographic, clinical, and treatment characteristics.

Pertuzumab Plus Trastuzumab in Patients With Endometrial Cancer With Amplification, Overexpression, or Mutation: Results From the TAPUR Study.

Purpose: The TAPUR Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with endometrial cancer (EC) with or amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab (P + T) are reported.

Methods: Eligible patients had advanced EC, no standard treatment options, measurable disease (RECIST v1.

Physical Therapists Use of Diagnostic Ultrasound Imaging in Clinical Practice: A Review of Case Reports.

Objective: Ultrasound diagnostic imaging (USI) is widely utilized in sports medicine, orthopaedics, and rehabilitation. Its use in physical therapy clinical practice is increasing. This review summarizes published patient case reports describing USI in physical therapist practice.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

Purpose: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy.

Patients And Methods: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer.

Exploring the integration of diagnostic musculoskeletal ultrasound imaging into clinical practice by physical therapists.

Background: Musculoskeletal ultrasound (MSK-US) use for diagnostic purposes is expanding in physical therapy practice. Identifying and describing physical therapy-specific approaches to incorporating MSK-US into the evaluation process is needed. Musculoskeletal ultrasound extends the physical exam to allow clinicians to visualize anatomy and pathophysiology both statically and dynamically.

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo.

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding.

Mechanical testing of frontal plane adaptability of commercially available prosthetic feet.

Introduction: Prosthetic feet have limited adaptability in the frontal plane. Research shows walking on uneven terrain is difficult for many prosthesis users. A new prosthetic foot, the META Arc, was designed with a polycentric ankle joint that allows relatively free movement in the frontal plane to address this limitation.

Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome.

Distinct nuclear and cytoplasmic assemblies and interactomes of the mammalian CTLH E3 ligase complex.

The C-terminal to LisH (CTLH) complex is a newly discovered multi-subunit E3 ubiquitin ligase and its cellular functions are poorly characterized. Although some CTLH subunits have been found to localize in both the nucleus and cytoplasm of mammalian cells, differences between the compartment-specific complexes have not been explored. Here, we show that the CTLH complex forms different molecular mass complexes in nuclear and cytoplasmic fractions.

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

Objective: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity.

Methods: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies.

Early Readout on Overall Survival of Patients With Melanoma Treated With Immunotherapy Using a Novel Imaging Analysis.

Importance: Existing criteria to estimate the benefit of a therapy in patients with cancer rely almost exclusively on tumor size, an approach that was not designed to estimate survival benefit and is challenged by the unique properties of immunotherapy. More accurate prediction of survival by treatment could enhance treatment decisions.

Objective: To validate, using radiomics and machine learning, the performance of a signature of quantitative computed tomography (CT) imaging features for estimating overall survival (OS) in patients with advanced melanoma treated with immunotherapy.

An imaging signature to predict outcome in metastatic colorectal cancer using routine computed tomography scans.

Background & Aims: Quantitative analysis of computed tomography (CT) scans of patients with metastatic colorectal cancer (mCRC) can identify imaging signatures that predict overall survival (OS).

Methods: We retrospectively analysed CT images from 1584 mCRC patients on two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466). In the training set (n = 720), an algorithm was trained to predict OS landmarked from month 2; the output was a signature value on a scale from 0 to 1 (most to least favourable predicted OS).