Utility of Hook Sign in the Diagnosis of Median Arcuate Ligament Syndrome.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a clinical syndrome caused by compression of the celiac artery by the median arcuate ligament that often manifests with nonspecific abdominal pain. Identification of this syndrome is often dependent on imaging of compression and upward bending of the celiac artery by lateral computed tomography angiography, the so-called "hook sign." The purpose of this study was to assess the relationship of radiologic characteristics of the celiac artery to clinically relevant MALS. METHODS: An institutional review board-approved retrospective chart review from 2,000 to 2,021 of 293 patients at a tertiary academic center diagnosed with celiac artery compression (CAC) was performed. Patient demographics and symptoms of 69 patients who were diagnosed with symptomatic MALS were compared to 224 patients without MALS (but with CAC) per electronic medical record review. Computed tomography angiography images were reviewed and the fold angle (FA) was measured. The presence of a hook sign (defined as a visual FA < 135°), as well as stenosis (defined as >50% of luminal narrowing on imaging) were recorded. Wilcoxon rank-sum test and Chi-squared test were used for comparative analysis. Logistic model was run to relate the presence of MALS with comorbidities and radiographic findings. RESULTS: Imaging was available in 59 patients (25 males, 34 females) and 157 patients (60 males, 97 females) with and without MALS, respectively. Patients with MALS were more likely to have a more severe FA (120.7 ± 33.6 vs. 134.8 ± 27.9, P = 0.002). Males with MALS were also more likely to have a more severe FA compared with males without MALS (111.1 ± 33.7 vs. 130.4 ± 30.4, P = 0.015). In patients with body mass index (BMI) >25, MALS patients also had narrower FA compared with patients without MALS (112.6 ± 30.5 vs. 131.7 ± 30.3, P = 0.001). The FA was negatively correlated with BMI in patients with CAC. The hook sign and stenosis were associated with diagnosis of MALS (59.3% vs. 28.7%, P < 0.001, and 75.7% vs. 45.2%, P < 0.001, respectively). In logistic regression, pain, stenosis, and a narrow FA were statistically significant predictors of the presence of MALS. CONCLUSIONS: The upward deflection of the celiac artery in patients with MALS is more severe compared with patients without MALS. Consistent with prior literature, this bending of the celiac artery is negatively correlated with BMI in patients with and without MALS. When demographic variables and comorbidities are considered, a narrow FA is a statistically significant predictor of MALS. Regardless of MALS diagnosis, a hook sign was associated with narrower FA. While demographics and imaging findings may inform MALS diagnosis, clinicians should not rely on a visual assessment of a hook sign but should quantitatively measure the anatomic bending angle of the celiac artery to assist with the diagnosis and understand the outcomes.

EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling.

We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase-based TPDephos and the effective epidermal growth factor receptor (EGFR) tyrosine dephosphorylation. We also used phosphoproteomic approaches to study the signaling transductions affected by PhosTAC-related molecules at the proteome-wide level. This work demonstrated the differential signaling pathways inhibited by PhosTAC compared with the TKI, gefitinib. Moreover, a covalent PhosTAC selective for mutated EGFR was developed and showed its inhibitory potential for dysregulated EGFR. Last, EGFR PhosTACs, consistent with EGFR dephosphorylation profiles, induced apoptosis and inhibited cancer cell viability during prolonged PhosTAC treatment. PhosTACs showcased their potential of modulating RTKs activity, expanding the scope of bifunctional molecule utility.

Prevalence and Characteristics of Patients with Median Arcuate Ligament Syndrome in a Cohort Diagnosed with Celiac Artery Compression.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a frequent differential diagnosis in patients with postprandial abdominal symptoms, but diagnosis remains challenging. The aim of this study was to identify characteristics of patients who had MALS compared with non-MALS patients among a cohort of patients diagnosed with celiac artery compression (CAC). STUDY DESIGN: An IRB-approved retrospective chart review (2000 to 2021) of patients at our institution with a discharge diagnosis of CAC was performed. Medical record review for clinical symptoms and findings consistent with MALS was performed. RESULTS: Two hundred ninety-three patients with a diagnosis of CAC were identified; 59.7% were women, and average age was 63.9 ± 20.2 years. Sixty-nine (23.5%) patients with CAC had MALS. There were no significant differences in sex or race between MALS and non-MALS patients, but MALS patients were younger (55.7 vs 68.1, p < 0.001). There was no significant difference in gastrointestinal comorbidities between the 2 groups. Patients with MALS were less likely to have diabetes (12.5% vs 26.9%), renal disease (4.6% vs 8.2%), hypertension (41.5% vs 70.3%), mesenteric atherosclerotic disease (14% vs 61.9%), and peripheral artery disease (15.0% vs 39.7%). CONCLUSIONS: We demonstrate a novel observation that MALS patients tend to have fewer atherosclerotic characteristics than non-MALS patients with CAC. Patients in our study with MALS were more likely to be younger, women, and presenting with epigastric pain. MALS patients had a significantly lower incidence of diabetes, hypertension, renal disease, mesenteric artery disease, and peripheral arterial disease compared with the non-MALS group. An important clinically relevant feature of MALS patients may be their lack of atherosclerotic phenotype compared with non- MALS patients with CAC.

Pregnancy in physicians: A scoping review.

BACKGROUND: The personal health and professional impact of physician pregnancy requires further study. We performed a comprehensive scoping review of physician pregnancy to synthesize and assess the evidence to aid decision-making for relevant stakeholders. METHODS: A search of 7 databases resulted in 3733 citations. 407 manuscripts were included and scored for evidence level. Data were extracted into themes using template analysis. RESULTS: Physician pregnancy impacted colleagues through perceived increased workload and resulted in persistent stigmatization and discrimination despite work productivity and academic metrics being independent of pregnancy events. Maternity leave policies were inconsistent and largely unsatisfactory. Women physicians incurred occupational hazard risk and had high rates of childbearing delay, abortion, and fertility treatment; obstetric and fetal complication rates compared to controls are conflicting. CONCLUSIONS: Comprehensive literature review found that physician pregnancy impacts colleagues, elicits negative perceptions of productivity, and is inadequately addressed by current parental leave policies. Data are poor and insufficient to definitively determine the impact of physician pregnancy on maternal and fetal health. Prospective risk-matched observational studies of physician pregnancy should be pursued.

The Medical Community's Evolving Focus on Physician and Surgeon Pregnancy: Thematic Trends From a Scoping Review.

PURPOSE: The authors aimed to chronicle the evolution of the medical community's study of physician and surgeon pregnancy by investigating thematic trends in the literature in the context of pertinent sociopolitical events. METHOD: A scoping review was conducted in Cochrane Library, Google Scholar, Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science Core Collection from inception through August 11, 2020, using vocabulary and terms for physicians (including surgeons), pregnancy, and family leave. Study populations were categorized by all physician specialties or exclusively surgical specialties as well as by all career levels or exclusively trainees. Subthemes and themes were based on a priori assumptions of physician pregnancy and extrapolated from previously published reviews, respectively. Thematic trends were analyzed by plotting the total number of publications and the frequency of themes and subthemes by publication year. RESULTS: After title and abstract and full-text reviews, 407 manuscripts met inclusion criteria. Publications on physician pregnancy first emerged in the 1960s and surged from 1988 to 1996 and again from 2010 to 2019. The first known manuscript exclusively on surgeon pregnancy was published in 1991; subsequent publication frequency trends for surgeon pregnancy generally paralleled those for all physician pregnancy publications albeit in reduced quantities. Four major themes were found: impact of pregnancy on the physician and her colleagues, pregnant physician work productivity, physician maternity leave policies, and physician maternal-fetal health outcomes. CONCLUSIONS: As the number of women physicians increased and the sociopolitical environment progressed, the thematic focus of the literature on physician pregnancy evolved. Multi-institutional prospective observational studies are needed to develop definitive evidence-based recommendations that will positively impact physician pregnancy.

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study of phosphorylation targeting chimeras (PhosTACs). Similar to PROTACs in their ability to induce ternary complexes, PhosTACs focus on recruiting a Ser/Thr phosphatase to a phosphosubstrate to mediate its dephosphorylation. However, distinct from PROTACs, PhosTACs can uniquely provide target gain-of-function opportunities to manipulate protein activity. In this study, we applied a chemical biology approach to evaluate the feasibility of PhosTACs by recruiting the scaffold and catalytic subunits of the PP2A holoenzyme to protein substrates such as PDCD4 and FOXO3a for targeted protein dephosphorylation. For FOXO3a, this dephosphorylation resulted in the transcriptional activation of a FOXO3a-responsive reporter gene.

A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.

An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.