Citations

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer‐related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small‐molecule YAP‐TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient‐derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild‐type models. CA3 was associated with on‐target decreases in YAP‐TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor–mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP‐TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis. However, evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. We conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer, to understand their perceptions of their familial risk of HBOC and interest in genetic testing. In phase 1 of this study, participants were recruited from the networks of patient support organizations and historically Black sororities representing mostly highly educated and well insured patients. In phase 2, participants were recruited from a family medicine safety net clinic in Jacksonville, FL for socioeconomic diversity. Participants in both cohorts frequently expressed a lack of awareness about their family cancer history and identified many barriers to family disclosure of a cancer diagnosis. These include a culture of silence around medical issues and a belief that personal difficulties should be kept to oneself. Practical and cultural barriers to family history sharing were magnified among those with lower socioeconomic status. Many participants in both cohorts indicated a strong desire to understand their own risk of HBOC. They also expressed interested in genetic testing to proactively mitigate risk to themselves and future generations. Understanding of the potential relevance of HBOC testing to one’s personal health and post-test actionability was variable across both groups, although perceptions of genetic testing were generally favorable. These findings suggest that culturally tailored educational materials and alternative clinical modalities to collect family health history may be beneficial to improve timely identification of Black women who meet NCCN Guidelines for HBOC testing. Specifically, greater attention should be given to addressing barriers that led to underestimation of HBOC risk among patients experiencing disparities driven by adverse social determinants of health. Citation Format: Kirsten Riggan, Jane Yap, Ewan Cobran, Michele Halyard, Sarah James, Marion Kelly, Daphne Phillips, Megan Allyse. Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-08.

AbstractPulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell‐specific approach. Our previous work demonstrated that targeting non‐canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non‐canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH‐associated PASMC remodeling, with longer‐lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non‐canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.

AbstractObjectivesThirty‐five states, including Florida, now cover cell‐free DNA (cfDNA) screening of fetuses for all pregnant patients enrolled in state public insurance programs. We interviewed Black and Hispanic obstetric patients at a safety net clinic in Florida shortly after the state rolled out cfDNA as a first‐tier screening method for publicly insured patients.MethodsBlack and Hispanic patients receiving prenatal care from a prenatal or maternal fetal medicine clinic at a federally qualified health center in Jacksonville, FL were invited to participate in a qualitative interview in English or Spanish to explore experiences and perceptions of prenatal cfDNA screening. Participants were recruited following their first prenatal visit when cfDNA is typically introduced. Interview transcripts were qualitatively analyzed for iterative themes based on principles of grounded theory.ResultsOne hundred Black and Hispanic patients (n = 51 non‐Hispanic Black, n = 43 Hispanic, n = 3 Hispanic Black, n = 3 Not Reported/Other) completed an interview. Participants described minimal opportunity for pre‐screening counseling and limited health literacy about cfDNA or its uses. Some believed that cfDNA could positively impact pregnancy health. Many were unsure if they had received cfDNA even though they were aware of the information provided by it. Most participants expressed an interest in cfDNA as a means for early detection of fetal sex and as an additional indication of general fetal health.ConclusionsPatient experiences indicate limited informed consent and decision‐making for cfDNA, discordant with professional guidelines on pre‐screen counseling. Our findings suggest that there should be additional investment in implementing cfDNA in safety net settings to ensure that patients and providers receive the support necessary for effective patient counseling and follow‐on care for the ethical implementation of cfDNA.

Abstract Aims In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. Methods and results An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22–50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3–12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6–31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1–1.3, P < 0.001) were independently associated with non-adherence. Conclusion The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

AbstractObjectiveWe published a list of “must‐know” routine EEG (rEEG) findings for trainees based on expert opinion. Here, we studied the accuracy and inter‐rater agreement (IRA) of these “must‐know” rEEG findings among international experts.MethodsA previously validated online rEEG examination was disseminated to EEG experts. It consisted of a survey and 30 multiple‐choice questions predicated on the previously published “must‐know” rEEG findings divided into four domains: normal, abnormal, normal variants, and artifacts. Questions contained de‐identified 10–20‐s epochs of EEG that were considered unequivocal examples by five EEG experts.ResultsThe examination was completed by 258 international EEG experts. Overall mean accuracy and IRA (AC1) were 81% and substantial (0.632), respectively. The domain‐specific mean accuracies and IRA were: 76%, moderate (0.558) (normal); 78%, moderate (0.575) (abnormal); 85%, substantial (0.678) (normal variants); 85%, substantial (0.740) (artifacts). Academic experts had a higher accuracy than private practice experts (82% vs. 77%; p = .035). Country‐specific overall mean accuracies and IRA were: 92%, almost perfect (0.836) (U.S.); 86%, substantial (0.762) (Brazil); 79%, substantial (0.646) (Italy); and 72%, moderate (0.496) (India). In conclusion, collective expert accuracy and IRA of “must‐know” rEEG findings are suboptimal and heterogeneous.SignificanceWe recommend the development and implementation of pragmatic, accessible, country‐specific ways to measure and improve the expert accuracy and IRA.

Airway inflammation is a key aspect of diseases such as asthma. Several inflammatory cytokines (e.g., TNFα and IL‐13) enhance cytosolic Ca 2+ concentration ([Ca 2+ ] cyto ) triggering airway smooth muscle (ASM) hyperreactivity (enhanced contractile state). Airway inflammation also induces ASM proliferation and remodeling (enhanced ASM synthetic state). In various diseases inflammation induces sarcoplasmic/endoplasmic reticulum (SR/ER) stress, which decreases SR/ER‐mitochondria interactions, with downstream effects on Ca 2+ regulation. In vascular smooth muscle cells, SR/ER stress promotes smooth muscle contraction and proliferation by disrupting SR/ER‐mitochondrial coupling. We hypothesized that inflammation induces SR/ER stress in human ASM, thereby altering expression of mitochondrial fission/fusion proteins (dynamin‐related protein ‐ Drp1 and mitofusin ‐ Mfn2) with downstream impact on ASM Ca 2+ regulation and contractility as well as proliferation. Human ASM cells were isolated from lung specimen incidental to patient surgery and exposed to TNFα or IL‐13 for 24h. Expression of SR/ER stress markers including PERK (protein kinase‐like endoplasmic reticulum kinase), Bip (Binding immunoglobulin protein also known as 78 kDa glucose‐regulated protein), PDI (protein disulfide isomerase), and mitochondrial fission/fusion proteins Drp1 and Mfn2 were evaluated by Western blot. The expression of the spliced isoform of the transcription factor XBP1 was investigated by quantitative real‐time PCR (RT‐PCR). For mitochondrial morphology (fission/fusion), ASM cells were loaded with Mitotracker Green and images analyzed using ImageJ and Matlab to quantify mitochondrial Form Factor and Aspect Ratio. The effect of inflammation induced SR/ER stress on human ASM proliferation was evaluated using CyQUANT assay. We found that after 24 h exposure to TNFα and IL‐13: 1) expression of SR/ER stress protein markers (PERK, BiP and XBP1) increased; 2) Drp1 expression increased and Mfn2 expression decreased; 3) mitochondrial fragmentation increased; 4) [Ca 2+ ] cyt and [Ca 2+ ] mito responses to ACh stimulation were uncoupled; 5) net [Ca 2+ ] cyt increased; 6) contractility increased; and 7) ASM cell proliferation increased. Together these results suggest that inflammation induces SR/ER stress that leads to changes in Mfn2 and Drp1 expression, which alter mitochondrial dynamics and Ca 2+ regulation resulting in ASM hyperreactivity and remodeling. Support or Funding Information NIH grant HL126451 (GCS).

Abstract Background Caesarean sections (CSs) constitute a large proportion of fetal deliveries, yet no consensus exists on optimal surgical method. Objectives To investigate the safety and efficacy of the Pfannenstiel‐Kerr method (PKM) in comparison to Misgav‐Ladach method (MLM) and Modified Misgav‐Ladach method (MMLM) for CS. Search Strategy Cochrane, Embase, PubMed, CiNAHL, Scopus, and Web of Science were searched from database inception to March 2023. Selection Criteria Prospective studies comparing MLM with PKM or MMLM with PKM. Data Collection and Analysis Three authors independently conducted data extraction and assessed quality. Pooled means and proportions were analyzed using inverse variance and Mantel‐Haenszel methods. Main Results Twenty‐seven studies with 15 251 patients, met the selection criteria. Both MLM (mean difference [MD]: −12.09 min, 95% confidence interval [CI]: −14.40, −9.77, Tau 2 = 16.79, I 2 = 97%), (MD: −125.98 mL, 95% CI: −172.13, −79.83, Tau 2 = 3458.59, I 2 = 87%) and MMLM (MD: −11.38 min, 95% CI: −14.72, −8.04, Tau 2 = 30.56, I 2 = 100%), (MD: −62.61 mL, 95% CI: −103.13, −22.09, Tau 2 = 1451.35, I 2 = 92%) demonstrated shorter operative time and decreased blood loss, respectively, compared to PKM. Similarly, both MLM (MD: −1.70 min, 95% CI: −2.26, −1.14, Tau 2 = 0.51, I 2 = 97%), (MD: −0.77 d, 95% CI: −1.35, −0.19, Tau 2 = 0.60, I 2 = 98%) and MMLM (MD: −2.80 min, 95% CI: −3.89, −1.70, Tau 2 = 1.74, I 2 = 100%), (MD: −0.58 d, 95% CI: −1.00, −0.17, Tau 2 = 0.29, I 2 = 100%) demonstrated shorter fetal extraction time and length of hospital stay, respectively, compared to PKM. Conclusions MLM and MMLM should be considered safe and effective alternative approaches to CSs.