Discovery and Development of Cyclic Peptide Proteasome Stimulators.

The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins.

Antenatal risk score for prediction of shoulder dystocia with focus on fetal ultrasound data.

Background: Shoulder dystocia is one of the most threatening complications during delivery, and although it is difficult to predict, individual risk should be considered when counseling for mode of delivery.

Objective: This study aimed to develop and validate a risk score for shoulder dystocia based on fetal ultrasound and maternal data from 15,000 deliveries.

Study Design: Data were retrospectively obtained of deliveries in 3 tertiary centers between 2014 and 2017 for the derivation cohort and between 2018 and 2020 for the validation cohort.

Identification of a covalent binder to the oncoprotein gankyrin using a NIR-Based OBOC screening method.

Despite huge advancements in the process of synthesizing small molecules as part of one-bead-one-compound (OBOC) libraries, progress lags in the ability to screen these libraries against proteins of interest. Recently, we developed a method to screen OBOC libraries in which a target protein is labeled with a near-infrared (NIR) range fluorophore. The labeled protein incubates with beads of a library in a 96-well plate, then the plate is imaged for fluorescence.

Associations of glycemia and lipid levels in pregnancy with dyslipidemia 10-14 years later: The HAPO follow-up study.

Aims: To examine associations of pregnancy glycemia with future dyslipidemia.

Methods: We analyzed data from Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study participants. We examined associations of gestational diabetes (GDM), sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24-32 weeks' gestation with dyslipidemia 10-14 years postpartum.

Solid-Phase Synthesis and Application of a Clickable Version of Epoxomicin for Proteasome Activity Analysis.

Degradation of proteins by the proteasome is an essential cellular process and one that many wish to study in a variety of disease types. There are commercially available probes that can monitor proteasome activity in cells, but they typically contain common fluorophores that limit their simultaneous use with other activity-based probes. In order to exchange the fluorophore or incorporate an enrichment tag, the proteasome probe likely has to be synthesized which can be cumbersome.

Validation of genetic classifiers derived from mouse and human tumors to identify molecular subtypes of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Standard treatment for advanced-stage CRC for decades has included 5-fluorouracil-based chemotherapy. More recently, targeted therapies for metastatic CRC are being used based on the individual cancer's molecular profile.

Antenatal risk prediction of shoulder dystocia: influence of diabetes and obesity: a multicenter study.

Purpose: To estimate the risk of shoulder dystocia (SD) in pregnancies with/without maternal diabetes or obesity; to identify antenatal maternal and fetal ultrasound-derived risk factors and calculate their contributions.

Methods: A multicenter retrospective analysis of 13,428 deliveries in three tertiary hospitals (2014-2017) with fetal ultrasound data ≤ 14 days prior to delivery (n = 7396).

Inclusion Criteria: singleton pregnancies in women ≥ 18 years old; vertex presentation; vaginal delivery at ≥ 37 weeks of gestation.

Protein-creatinine ratio and albumin-creatinine ratio for the diagnosis of significant proteinuria in pregnant women with hypertension: Systematic review and meta-analysis of diagnostic test accuracy.

Background: The gold standard for assessment and diagnosis of significant proteinuria in pregnancy has been by 24-hour urine collection and analysis. Determining fast, accurate methods to identify clinically significant proteinuria would aid diagnosis of pre-eclampsia. The objective of this study was to determine the accuracy of spot protein-creatinine ratio (PCR) and albumin-creatinine ratio (ACR) measurements compared with 24-hour urine collection for the identification of clinically significant proteinuria in women with hypertensive disorders of pregnancy.

A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study.

Objective: To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM).

Design: A consensus developmental study.

Setting: International.

Resolving the Gestational Diabetes Diagnosis Conundrum: The Need for a Randomized Controlled Trial of Treatment.

The diagnosis of and criteria for gestational diabetes mellitus (GDM) continue to divide the scientific and medical community, both between and within countries. Many argue for universal adoption of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria and feel that further clinical trials are unjustified and even unethical. However, there are concerns about the large increase in number of women who would be diagnosed with GDM using these criteria and the subsequent impact on health care resources and the individual.

Approaches to Evaluate the Impact of a Small-Molecule Binder to a Noncatalytic Site of the Proteasome.

Proteasome activity is crucial for cell survival and proliferation. In recent years, small molecules have been discovered that can affect the catalytic activity of the proteasome. Rather than targeting the active sites of the proteasome, it might be possible to affect ubiquitin-dependent degradation of proteins by limiting the association of the 19S regulatory particle (19S RP) with the 20S core particle (20S CP) of the proteasome.

Association of glucose metabolism and blood pressure during pregnancy with subsequent maternal blood pressure.

The goal of this study was to examine associations of measures of maternal glucose metabolism and blood pressure during pregnancy with blood pressure at follow-up in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. The HAPO Follow-Up Study included 4747 women who had a 75-g oral glucose tolerance test (OGTT) at ~28 weeks' gestation. Of these, 4572 women who did not have chronic hypertension during their pregnancy or other excluding factors, had blood pressure evaluation 10-14 years after the birth of their HAPO child.

Methods for the discovery of small molecules to monitor and perturb the activity of the human proteasome.

Regulating protein production and degradation is critical to maintaining cellular homeostasis. The proteasome is a key player in keeping proteins at the proper levels. However, proteasome activity can be altered in certain disease states, such as blood cancers and neurodegenerative diseases.

Febuxostat mitigates concanavalin A-induced acute liver injury via modulation of MCP-1, IL-1β, TNF-α, neutrophil infiltration, and apoptosis in mice.

Aim: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied.

A core outcome set for studies of gestational diabetes mellitus prevention and treatment.

Aims/hypothesis: The aim of this systematic review was to develop core outcome sets (COSs) for trials evaluating interventions for the prevention or treatment of gestational diabetes mellitus (GDM).

Methods: We identified previously reported outcomes through a systematic review of the literature. These outcomes were presented to key stakeholders (including patient representatives, researchers and clinicians) for prioritisation using a three-round, e-Delphi study.

The Immunoproteasome: An Emerging Target in Cancer and Autoimmune and Neurological Disorders.

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed when cells are stressed or receive an inflammatory signal. The primary role of the iCP is to hydrolyze proteins into peptides that are compatible with being loaded into a MHC-I complex. When the activity of the iCP is dysregulated or highly expressed, it can lead to unwanted cell death.

Follow-up at 1 year and beyond of women with gestational diabetes treated with insulin and/or oral glucose-lowering agents: a core outcome set using a Delphi survey.

Aims/hypothesis: Gestational diabetes mellitus (GDM) is linked with a higher lifetime risk for the development of impaired fasting glucose, impaired glucose tolerance, type 2 diabetes, the metabolic syndrome, cardiovascular disease, postpartum depression and tumours. Despite this, there is no consistency in the long-term follow-up of women with a previous diagnosis of GDM. Further, the outcomes selected and reported in the research involving this population are heterogeneous and lack standardisation.

Fisetin and 5-fluorouracil: Effective combination for PIK3CA-mutant colorectal cancer.

The normal colon epithelium is transformed into its neoplastic counterpart through a series of genetic alterations in driver genes including activating mutations in PIK3CA. Treatment often involves surgery followed by 5-fluorouracil (5-FU) based therapy, which has limited efficiency and serious side effects. We sought to determine whether fisetin, a dietary flavonoid, alone or in combination with 5-FU affected tumorigenesis in the mammalian intestine.

Development of a Method To Prioritize Protein-Ligand Pairs on Beads Using Protein Conjugated to a Near-IR Dye.

The development of techniques to screen one-bead-one-compound (OBOC) libraries remains a critical step in identifying small molecules that bind target proteins. While great strides have been made, there remains a need to continue to develop OBOC screening techniques that not only reliably identify hit molecules but also can distinguish poor from excellent binders in a single screen. Similarly, relatively strong binding between a small molecule and protein target is required to be considered a hit from the initial pool of screened molecules.

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear.

Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum.

Design, Setting, And Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016).

A cost-effectiveness comparison of the NICE 2015 and WHO 2013 diagnostic criteria for women with gestational diabetes with and without risk factors.

Objectives: To compare the cost-effectiveness (CE) of the National Institute for Health and Care Excellence (NICE) 2015 and the WHO 2013 diagnostic thresholds for gestational diabetes mellitus (GDM).

Setting: The analysis was from the perspective of the National Health Service in England and Wales.

Participants: 6221 patients from four of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study centres (two UK, two Australian), 6308 patients from the Atlantic Diabetes in Pregnancy study and 12 755 patients from UK clinical practice.

Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study.

Aims/hypothesis: The aim of this prospective nationwide study was to examine antenatal pregnancy care and pregnancy outcomes in women with type 1 and type 2 diabetes, and to describe changes since 2002/2003.

Methods: This national population-based cohort included 3036 pregnant women with diabetes from 155 maternity clinics in England and Wales who delivered during 2015. The main outcome measures were maternal glycaemic control, preterm delivery (before 37 weeks), infant large for gestational age (LGA), and rates of congenital anomaly, stillbirth and neonatal death.