Luminal Morphology Research Articles

CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.

Morphology of true lumen and surgical outcomes of acute type A aortic dissection repair with superior mesenteric artery malperfusion

BackgroundAcute type A aortic dissection (ATAD) can cause visceral malperfusion. Central aortic repair may resolve malperfusion, but some require further intervention. This study aimed to review outcomes after ATAD presenting with visceral malperfusion and to evaluate the predictive value of true lumen (TL) morphologies in preoperative computed tomography scan for persistent superior mesenteric artery (SMA) ischemia after central repair. MethodsOpen surgical repair of ATAD performed between 2008 and 2023 at our institution was reviewed retrospectively. Patients with central repair first approach were included for analysis. Patients with inadequate computed tomography scan data to assess luminal morphology were excluded. TL morphology was reviewed at the diaphragm level and categorized as concave or convex. The malperfusion pattern, static vs dynamic, was assessed at SMA orifices. Data were analyzed using a contingency table and parametric and nonparametric methods. ResultsA total of 543 open ATAD repairs were performed. Of these, 263 patients were eligible under the inclusion criteria and, subsequently, analyzed. The mean age was 57±14, and 83 (31%) patients were female. SMA malperfusion developed in 42 (16%) of the 263 patients, including 26 patients with dynamic obstruction, 6 patients with static obstruction, and 10 patients with dynamic and static obstruction. Regarding dissection flap morphology, 78 patients (30%) exhibited concave morphology, while 185 patients (70%) had convex morphology. TL diameter was significantly larger in convex than concave (concave: 6 mm vs convex: 16 mm; P < .0001). The prevalence of clinically significant SMA malperfusion was higher in concave-shaped TL (concave 41% vs convex 5%; P < .0001). Dynamic SMA obstruction was more frequently observed in the concave group (concave 72% vs convex 30%; P < .001). However, significantly more patients with convex-shaped TL required bowel resection than concave (concave 13% vs convex 70%; P < .001). The operative mortality was higher in the convex group, although statistically insignificant (concave 19% vs convex 50%; P = .0059). ConclusionsCentral repair first strategy could resolve more than 80% of SMA malperfusion in ATAD when the TL is concave-shaped at the level of the diaphragm. Convex-shaped TL morphology was associated with less incidence of SMA malperfusion but was more frequently associated with static obstruction and higher incidence of bowel resection. The morphology evaluation of the TL at the diaphragm level may be simple and beneficial for surgical planning for ATAD presenting with SMA malperfusion.

The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.

Abstract 1246: Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features

Abstract Translocations of the ETS family transcription factor ERG are found in nearly 150,000 newly diagnosed prostate cancers (PCas) each year in the United States underscoring the importance of defining the mechanism by which ERG promotes prostate epithelial transformation. A consequence of nearly all ERG translocations is the aberrant expression of ERG in prostate luminal cells under transcriptional control of TMPRSS2. Multiple lines of evidence implicate ERG translocations as an initiating event in prostate cancer. ERG expression is seen in prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy; expression in cancers is typically uniform; and, in the context of PI3K pathway activation, ERG is sufficient to induce cancers in mice. Yet, despite extensive research the mechanism by which ERG initiates prostate cancer is unclear. To gain insight into how ERG translocations cause prostate cancer, we performed both transcriptional profiling (scRNA-seq) and chromatin accessibility via Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) in single cells of an autochthonous mouse model at an early stage of disease initiation. Surprisingly, we observed in prostate epithelial cells broadly expressing ERG enhanced proliferation primarily in a hybrid subpopulation of cells having basal identity but with luminal morphology and cytokeratin expression. Through a series of lineage tracing and primary prostate epithelial transplantation experiments, we confirmed tumor initiating activity resided within a subpopulation of basal cells expressing luminal genes (e.g., Tmprss2 and Nkx3-1). A trajectory analysis from single-cell Chromatin accessibility indicated Erg+ cells began to lose basal (Trp63) accessibility and gained in STAT/NFAT TFs while retaining the ability to rapidly differentiate into luminal cells that reflect the lineage of ERG-positive cancers. These findings help resolve a preexisting debate about the cell of origin of ERG-driven prostate cancer and narrow the focus for future mechanistic studies to a basal-luminal subpopulation of tumor initiating cells. Citation Format: Erik Ladewig, Weiran Feng, Christina Leslie, Charles Sawyers. Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1246.

Rhodomyrtus tomentosa (Aiton) Hassk. (haramonting) protects against allethrin-exposed pulmo damage in rats: mechanistic interleukins.

Inhaling Allethrin (C19H26O3) may induce oxidative stress in lung cells by causing the formation of free radi-cals. Interleukins (IL) are a group of secreted cytokines or proteins and signaling molecules initially produced as an immune response by leukocytes. Rhodomyrtus tomentosa (Aiton) Hassk. (haramonting) contains antioxidants that may prevent lung damage induced by allethrin-containing electric mosquito repellents. In this study, six groups of rats were exposed to allethrin via an electric mosquito repellent, including positive, negative, and comparison control groups and three groups were administered Rhodomyrtus tomentosa (Aiton) Hassk at 100mg/kg BW, 200mg/kg BW, and 300mg/kg BW. After 30days, the pulmonary tissue and the blood were taken for immunohisto-chemical and ELISA analysis. The accumulation of inflammatory cells causes the thickening of the alveolar wall structures. Injuries were more prevalent in the A+ group than in the other groups. The connection between the alveoli and blood capillaries, which can interfere with alveolar gas exchange, is not regulated, and the lu-minal morphology is aberrant, causing damage to the alveolar epithelial cells. Exposure to electric mosquito coils containing allethrin can increase the expression of interleukin-1, interleukin-8, interleukin-9, and interleu-kin-18 in blood serum and tissues while decreasing the expression of interleukin-6 and interleukin-10. Like the Vitamin C group, Rhodomyrtus tomentosa can increase alveolar histological alterations by decreasing the ex-pression of IL-1β, IL-8, IL-9, and IL-18 while increasing IL-6 and IL-10. So that this plant can be developed in the future as a drug to prevent lung harm from exposure.

Impact of plaque and luminal morphology in balloon angioplasty of the femoropopliteal artery: an intravascular ultrasound analysis.

To assess the effect of plaque and luminal morphologies in balloon angioplasty of femoropopliteal lesions using intravascular ultrasound (IVUS). This retrospective, observational study analyzed 836 cross-sectional images using IVUS, from 35 femoropopliteal arteries of patients who underwent endovascular treatment between September 2020 and February 2022. Pre- and post-balloon angioplasty images were matched per 5 mm. Post-balloon angioplasty images were grouped into successful (n = 345) and unsuccessful (n = 491) groups. Plaque and luminal morphologies (such as severity of calcification, vascular remodeling, and plaque eccentricity) were extracted before the balloon angioplasty procedure to identify the predictors of unsuccessful balloon angioplasty. Additionally, 103 images with severe dissection were analyzed using IVUS and angiography. In univariate analyses, the predictive factors for unsuccessful balloon angioplasty were vascular remodeling (p < .001), plaque burden (p < .001), lumen eccentricity (p < .001), and balloon/vessel ratio (p = .01). Predictive factors for severe dissections were the guidewire route (p < .001) and balloon/vessel ratio (p = .04). In multivariate analysis, the predictive factors for unsuccessful balloon angioplasty included lumen eccentricity (odds ratio [OR]: 3.99, 95% confidence interval [CI]: 1.28-12.68, p = .02) and plaque burden (OR: 1.03, 95% CI: 1.02-1.04; p < .001). For severe dissections, the independent risk factor was an eccentric guidewire route (OR: 2.10, 95% CI: 1.22-3.65, p = .01). High plaque burden and luminal eccentricity were risk factors for failed femoropopliteal artery balloon angioplasty. Additionally, eccentric guidewire routes predicted severe dissection.

Abstract A052: Systematic dissection of transcriptional states in pancreatic cancer

Abstract Transcriptional states in pancreatic cancer can stratify patients by response to chemotherapy and clinical outcomes. These include the classical and basal-like states as well as a newly identified neural-like progenitor (NRP) state, which we have previously found to be enriched in primary patient tumors treated with neoadjuvant chemotherapy and radiotherapy. While several transcription factor drivers of classical and basal-like identity have been described, key regulators of the NRP state are unknown. Through in silico approaches, we identified candidate transcription factors of the NRP state, including GLIS3, a Krüppel-like zinc finger protein that mediates neuroendocrine fate during pancreatic development and differentiation of human embryonic stem cells into posterior neural progenitor cells. Our understanding of biologic and clinically-relevant attributes of transcriptional cell states remains limited by state-specific biases in various preclinical models. Existing human cell lines maintained as two-dimensional cultures tend to preferentially represent the basal-like state, whereas human three-dimensional organoid models grown in standard culture conditions best reflect the classical state. These phenotypes are therefore impacted by culture conditions as well as underlying genetic features. Furthermore, most murine pancreatic cancer models do not fully reflect the classical vs. basal-like state heterogeneity observed in humans. To enable systematic study of the classical, basal-like and NRP phenotypes, we developed isogenic KP (KrasG12D/+;Trp53FL/FL) murine organoids with a germline dCas9-VPR system to enable facile overexpression of state-specific transcription factors through CRISPR activation approaches. Quantitative PCR, RNA-sequencing, and proteomics confirmed Gata6, deltaN Trp63, and Glis3 as drivers of classical, basal-like, and NRP identity, respectively. DeltaN Trp63 organoids were further differentiated by loss of luminal morphology. Pairwise comparisons of global transcriptional alterations suggest the greatest similarities between the Gata6- and Glis3-overexpressed models, which is consistent with enhanced associations between classical and NRP states in patient tumors. Finally, although basal-like and NRP states are associated with poorer response to multi-agent chemotherapy, state-specific therapeutic sensitivities to other treatments remain incompletely defined. We therefore performed drug sensitivity assays with a panel of targeted therapies and unveiled state-specific sensitivities. These data were corroborated by drug sensitivity profiling of human patient-derived organoids and cell lines. Taken together, these results suggest a framework for defining cell state-specific vulnerabilities that may aid in stratifying and treating pancreatic cancer patients with new therapies. Citation Format: Jimmy A. Guo, Jennifer Su, Ananya Jambhale, Julien Dilly, Connor J. Hennessey, Carina Shiau, Patrick Yu, Steven Wang, Junning Wang, Laleh Abbassi, James Neiswender, Tate Bertea, Annan Yang, Qijia Yu, Peter Westcott, Jason Schenkel, Daniel Y. Kim, Hannah I. Hoffman, Grissel Cervantes Jaramillo, Giselle A. Uribe, Westley W. Wu, Arnav Mehta, David Ting, Julian A. Pacheco, Amy Deik, Clary Clish, Francisca Vazquez, Brian Wolpin, Aviv Regev, William A. Freed-Pastor, Joseph D. Mancias, Tyler Jacks, William L. Hwang, Andrew J. Aguirre. Systematic dissection of transcriptional states in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A052.

Annular-shaped stenosis in the ureter: Caution should be taken.

To draw the attention of clinicians and avoid the misdiagnosis, we investigate the relationship between annular-shaped stenosis under ureteroscopy and the clinicopathological features and prognosis in patients with primary urothelial carcinoma of the ureter that have been treated by radical nephroureterectomy. We reviewed the records of patients with primary urothelial carcinoma of the ureter who had received radical nephroureterectomy in our hospital between January 2014 and June 2020. Based on the luminal morphology of the ureteral lesion, patients were divided into two groups: Group A for annular stenosis and Group B for non-annular stenosis. The logistic regression and Cox proportional-hazards models were used to explore the relationship between annular stenosis and clinicopathological findings. We investigated a total of 147 patients in this study, including 30 patients (20.4%) in Group A and 117 (79.6%) patients in Group B. The proportion of patients with diabetes mellitus was significantly higher in group A than in group B (66.6% vs. 38.5%, P = 0.006), and the percentage of patients undergoing ureteroscopy with biopsy was also significantly higher in group A than in group B (100% vs. 35.9%, P < 0.001). Besides, the logistic regression model revealed that annular-shaped stenosis was correlated to advanced T-stage (P = 0.002) and worse tumour grade (P < 0.001). During a median follow-up of 35 months (range: 6-73), 45 (30.6%) patients died, including 35 (23.8%) who died of ureteral carcinoma. The 5-year overall survival rate in Group A was significantly lower than in Group B (33.7% vs. 56.1%, P = 0.004). Similarly, the 5-year cancer-specific survival rate in Group A was also considerably lower than Group B (36.7% vs. 64.8%, P = 0.009). According to the multivariate Cox regression analysis that included only preoperative parameters, annular-shaped stenosis was an independent risk factor for both overall survival and cancer-specific survival (P = 0.006, P = 0.012, respectively). Annular-shaped stenosis indicates high carcinoma invasiveness and poor prognosis for patients with primary transitional cell carcinoma of the ureter. This condition can be easily misidentified, so clinicians should pay more attention when making diagnoses. Additionally, we discovered that diabetes mellitus may contribute to the development of annular stenosis.

Comparison of Different Thoracic Aortic Wall Characteristics for Assessment of Disease Activity in Takayasu Arteritis: A Quantitative Study with 3.0 T Magnetic Resonance Imaging

Determination of disease activity in Takayasu arteritis (TAK) is crucial for clinical management but challenging. The value of different magnetic resonance imaging (MRI) characteristics for the assessment of disease activity remains unclear. This study investigated the imaging findings of the thoracic aortic wall and elasticity by using a comprehensive 3.0 T MRI protocol. We prospectively enrolled 52 consecutive TAK patients. TAK activity was recorded according to the ITAS2010. All the patients underwent thoracic aortic MRI. The luminal morphology of the thoracic aorta and its main branches were quantitatively evaluated using a contrast-enhanced magnetic resonance angiography (MRA) sequence. The maximum wall thickness of the thoracic aorta, postcontrast enhancement ratio, and aortic wall edema were analyzed in each patient through pre- and post-enhanced T1-weighted and T2-weighted imaging. Pulse-wave velocity (PWV) of the thoracic aorta was calculated using a four-dimensional flow technique. The majority of the 52 patients had type V disease (34.62%, 18/52). Among all the MRI indicators of the thoracic aorta, the area under the curve was the largest for the maximal wall thickness (0.804, 95% confidence interval [CI] = 0.667-0.941). The maximal wall thickness (93.33%, 95% CI = 68.1%-99.8%) exhibited the highest sensitivity with a cutoff value of 3.12 mm. Wall edema (84.00%, 95% CI = 63.9%-95.5%) presented the highest specificity. A positive correlation was noted between PWV and patients' age (r = 0.54, p < 0.001), disease duration (r = 0.52, p < 0.001), and the maximum wall thickness (r = 0.45, p = 0.001). MRI enabled the comprehensive assessment of aortic wall morphology and functional markers for TAK disease activity. Aortic maximal wall thickness was the most accurate indicator of TAK activity. The early phase was superior to the delay phase for aortic wall enhancement analysis for assessing TAK activity.

Histopathological correlation of near infrared autofluorescence in human cadaver coronary arteries

Background and aimsPrior coronary optical coherence tomography (OCT)-near infrared auto-fluorescence (NIRAF) imaging data has shown a correlation between high-risk morphological features and NIRAF signal intensity. This study aims to understand the histopathological origins of NIRAF in human cadaver coronary arteries. MethodsEx vivo intracoronary OCT-NIRAF imaging was performed on coronary arteries prosected from 23 fresh human cadaver hearts. Arteries with elevated NIRAF were formalin-fixed and paraffin-embedded. Microscopic images of immunostained Glycophorin A (indicating intraplaque hemorrhage) and Sudan Black (indicating ceroid after fixation) stained slides were compared with confocal NIRAF images (ex. 635 nm, em. 655–755 nm) from adjacent unstained slides in each section. Different images from the same section were registered via luminal morphology. Confocal NIRAF-positive 45° sectors were compared to immunohistochemistry and colocalization between NIRAF and intraplaque hemorrhage or ceroid was quantified by Manders’ overlap and Dice similarity coefficients. ResultsThirty-one coronary arteries from 14 hearts demonstrated ≥1.5 times higher NIRAF signal than background, and 429 sections were created from them, including 54 sections (12.6%) with high-risk plaques. Within 112 confocal NIRAF-positive 45° sectors, 65 sectors (58.0%) showed both Glycophorin A-positive and Sudan Black-positive, while 7 sectors (6.3%) and 40 sectors (33.6%) only showed Glycophorin A-positive or Sudan black-positive, respectively. A two-tailed McNemar's test showed that Sudan Black more closely corresponded to confocal NIRAF than Glycophorin A (p < 1.0 × 10−6). NIRAF was also found to spatially associate with both Glycophorin A and Sudan Black, with stronger colocalization between Sudan Black and NIRAF (Manders: 0.19 ± 0.15 vs. 0.13 ± 0.14, p < 0.005; Dice: 0.072 ± 0.096 vs. 0.060 ± 0.090, p < 0.01). ConclusionsAs ceroid associates with oxidative stress and intraplaque hemorrhage is implicated in rapid lesion progression, these results suggest that NIRAF provides additional, complementary information to morphologic imaging that may aid in identifying high-risk coronary plaques via translatable intracoronary OCT-NIRAF imaging.

Target Embolization of Complex Vertebral Artery Dissecting Aneurysm with Endovascular Reconstructive Technique Using Cone-Beam Computed Tomography Angiography: Technical Note

Detailed vasculature of vertebral artery dissecting aneurysms (VADAs) is often complicated owing to the irregular structure with the intimal flap/double lumen. Our aim was to present an endovascular reconstructive technique with assessment of detailed vasculature and the relationship between dissection and surrounding vessels using cone-beam computed tomography angiography (CBCT-A). The study included 6 cases with complex vertebral artery dissecting aneurysm. Selective digital subtraction angiography initially identified the location and shape of dissection. CBCT-A was then performed with selective injection into the affected vertebral artery. Luminal morphology of the dissection and surrounding arterial anatomy were assessed using CBCT-A. CBCT-A clearly demonstrated luminal morphology of the intimal flap/double lumen, the entrance into the pseudolumen, and the entire dissecting segment. Tiny perforator arteries were also identified. In all 6 cases, target coil embolization for the pseudolumen and stent placement using an LVIS stent for the entire dissecting segment were successfully performed with the aid of information obtained from CBCT-A. No complications occurred in the perioperative period, and improvement of dissection was identified in the follow-up period. Target embolization of complex vertebral artery dissecting aneurysm with endovascular reconstructive technique with special reference to the detailed anatomy of dissection using CBCT-A would be useful for safe and effective treatment results.

Influence of thoracic endovascular aortic repair on true lumen helical morphology for Stanford type B dissections

ObjectiveThoracic endovascular aortic repair (TEVAR) can change the morphology of the flow lumen in aortic dissections, which may affect aortic hemodynamics and function. This study characterizes how the helical morphology of the true lumen in type B aortic dissections is altered by TEVAR. MethodsPatients with type B aortic dissection who underwent computed tomography angiography before and after TEVAR were retrospectively reviewed. Images were used to construct three-dimensional stereolithographic surface models of the true lumen and whole aorta using custom software. Stereolithographic models were segmented and co-registered to determine helical morphology of the true lumen with respect to the whole aorta. The true lumen region covered by the endograft was defined based on fiducial markers before and after TEVAR. The helical angle, average helical twist, peak helical twist, and cross-sectional eccentricity, area, and circumference were quantified in this region for pre- and post-TEVAR geometries. ResultsSixteen patients (61.3 ± 8.0 years; 12.5% female) were treated successfully for type B dissection (5 acute and 11 chronic) with TEVAR and scans before and after TEVAR were retrospectively obtained (follow-up interval 52 ± 91 days). From before to after TEVAR, the true lumen helical angle (–70.0 ± 71.1 to –64.9 ± 75.4°; P = .782), average helical twist (–4.1 ± 4.0 to –3.7 ± 3.8°/cm; P = .674), and peak helical twist (–13.2 ± 15.2 to –15.4 ± 14.2°/cm; P = .629) did not change. However, the true lumen helical radius (1.4 ± 0.5 to 1.0 ± 0.6 cm; P < .05) and eccentricity (0.9 ± 0.1 to 0.7 ± 0.1; P < .05) decreased, and the cross-sectional area (3.0 ± 1.1 to 5.0 ± 2.0 cm2; P < .05) and circumference (7.1 ± 1.0 to 8.0 ± 1.4 cm; P < .05) increased significantly from before to after TEVAR. The distinct bimodal distribution of chiral and achiral native dissections disappeared after TEVAR, and subgroup analyses showed that the true lumen circumference of acute dissections increased with TEVAR, although it did not for chronic dissections. ConclusionsThe unchanged helical angle and average and peak helical twists as a result of TEVAR suggest that the angular positions of the true lumen are constrained and that the endografts were helically conformable in the angular direction. The decrease of helical radius indicated a straightening of the corkscrew shape of the true lumen, and in combination with more circular and expanded lumen cross-sections, TEVAR produced luminal morphology that theoretically allows for lower flow resistance through the endografted portion. The impact of TEVAR on dissection flow lumen morphology and the interaction between endografts and aortic tissue can provide insight for improving device design, implantation technique, and long-term clinical outcomes.

Plaque Imaging Using Black-blood MRI

The risk of future ischemic events, such as angiographically determined stenosis and ulceration, in patients with atherosclerosis has long been mainly assessed using luminal morphology. However, recent remarkable advances in vessel wall imaging combined with a deeper understanding of vascular biology have shown that vessel wall characteristics also have a considerable influence on the onset of ischemic events. Among the modalities for vessel wall imaging, such as ultrasound, CT, and MRI, MRI is useful for plaque characterization because of its high accuracy and less invasiveness. Several features of vulnerable plaques, such as intraplaque hemorrhage, large lipid-rich necrotic cores, and ruptured fibrous caps, can be observed using contemporary high-resolution MRI. The assessment of plaque characteristics is essential for the management of atherosclerosis. In this article, the current status of carotid plaque characterization using black-blood MRI will be briefly highlighted, and potential clinical implications of MRI plaque imaging will be demonstrated.

Three-dimensional visualization of aneurysm wall calcification by cerebral angiography: Technical case report

BackgroundWe describe on a 57-year-old man with an incidental middle cerebral artery (MCA) aneurysm in whom a preoperative standard three-dimensional rotational angiogram (3D-RA) was used to depict luminal morphology along with 3D density rendering to precisely locate aneurysm wall calcification. MethodsTo detect aneurysm calcification, a native 3D rotational angiogram was acquired for calcium density visualization, followed by an intraarterial contrast-enhanced 3D rotational angiogram in the same location. Both data sets were postprocessed obtaining a 3D calcium volume rendering on a 3D-RA. ResultsDepiction of both the MCA luminal aneurysm morphology as well as calcium-rich components in the aneurysm wall was valuable to determine treatment strategy towards surgery. ConclusionImaging of luminal morphology and calcification within the same angiographic procedure allows for a plain and simple estimation of the degree and distribution of brain aneurysm wall calcification with limited amount of additional radiation dosage.

Four-dimensional impedance manometry derived from esophageal high-resolution impedance-manometry studies: a novel analysis paradigm.

Background:This study aimed to introduce a novel analysis paradigm, referred to as 4-dimensional (4D) manometry based on biophysical analysis; 4D manometry enables the visualization of luminal geometry of the esophagus and esophagogastric junction (EGJ) using high-resolution-impedance-manometry (HRIM) data.Methods:HRIM studies from two asymptomatic controls and one type-I achalasia patient were analyzed. Concomitant fluoroscopy images from one control subject were used to validate the calculated temporal-spatial luminal radius and time-history of intraluminal bolus volume and movement. EGJ analysis computed diameter threshold for emptying, emptying time, flow rate, and distensibility index (DI), which were compared with bolus flow time (BFT) analysis.Results:For normal control, calculated volumes for 5 ml swallows were 4.1 ml–6.7 ml; for 30 ml swallows 21.3 ml–21.8 ml. With type-I achalasia, >4 ml of intraesophageal bolus residual was present both pre- and post-swallow. The four phases of bolus transit were clearly illustrated on the time-history of bolus movement, correlating well with the fluoroscopic images. In the control subjects, the EGJ diameter threshold for emptying was 8 mm for 5 ml swallows and 10 mm for 30 ml swallows; emptying time was 1.2–2.2 s for 5 ml swallows (BFT was 0.3–3 s) and 3.25–3.75 s for 30 ml swallows; DI was 2.4–3.4 mm2/mmHg for 5 ml swallows and 4.2–4.6 mm2/mmHg for 30 ml swallows.Conclusions:The 4D manometry system facilitates a comprehensive characterization of dynamic esophageal bolus transit with concurrent luminal morphology and pressure from conventional HRIM measurements. Calculations of flow rate and wall distensibility provide novel measures of EGJ functionality.

Quantitative analysis of in vivo high-resolution microendoscopic images for the detection of neoplastic colorectal polyps.

.Colonoscopy is routinely performed for colorectal cancer screening but lacks the capability to accurately characterize precursor lesions and early cancers. High-resolution microendoscopy (HRME) is a low-cost imaging tool to visualize colorectal polyps with subcellular resolution. We present a computer-aided algorithm to evaluate HRME images of colorectal polyps and classify neoplastic from benign lesions. Using histopathology as the gold standard, clinically relevant features based on luminal morphology and texture are quantified to build the classification algorithm. We demonstrate that adenomatous polyps can be identified with a sensitivity and specificity of 100% and 80% using a two-feature linear discriminant model in a pilot test set. The classification algorithm presented here offers an objective framework to detect adenomatous lesions in the colon with high accuracy and can potentially improve real-time assessment of colorectal polyps.

Automated Segmentation of Bioresorbable Vascular Scaffold Struts in Intracoronary Optical Coherence Tomography Images.

Bioresorbable vascular scaffolds (BVS), the next step in the continuum of minimally invasive vascular interventions present new opportunities for patients and clinicians but challenges as well. As they are comprised of polymeric materials standard imaging is challenging. This is especially problematic as modalities like optical coherence tomography (OCT) become more prevalent in cardiology. OCT, a light-based intracoronary imaging technique, provides cross-sectional images of plaque and luminal morphology. Until recently segmentation of OCT images for BVS struts was performed manually by experts. However, this process is time consuming and not tractable for large amounts of patient data. Several automated methods exist to segment metallic stents, which do not apply to the newer BVS. Given this current limitation coupled with the emerging popularity of the BVS technology, it is crucial to develop an automated methodology to segment BVS struts in OCT images. The objective of this paper is to develop a novel BVS strut detection method in intracoronary OCT images. First, we preprocess the image to remove imaging artifacts. Then, we use a K-means clustering algorithm to automatically segment the image. Finally, we isolate the stent struts from the rest of the image. The accuracy of the proposed method was evaluated using expert estimations on 658 annotated images acquired from 7 patients at the time of coronary arterial interventions. Our proposed methodology has a positive predictive value of 0.93, a Pearson Correlation coefficient of 0.94, and a F1 score of 0.92. The proposed methodology allows for rapid, accurate, and fully automated segmentation of BVS struts in OCT images.

Serrated polyps and their alternative pathway to the colorectal cancer: a systematic review.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the world. For a long time, only one pathway of colorectal carcinogenesis was known. In recent years, a new “alternative” pathway through serrated adenoma was described. Recent meta-analysis estimated these cancers as about 10% to 30% of all CRCs. Serrated polyps are the second most popular groups of polyps (after conventional adenomas) found during colonoscopy. Serrated polyps of the colon are clinically and molecularly diverse changes that have common feature as crypt luminal morphology characterized by glandular serration. Evidence suggests that subtypes of serrated polyps, particularly TSA and SSA/P, can lead to adenocarcinoma through the serrated pathway. Moreover, the data indicate that the SSA/P are the precursors of colorectal carcinoma by MSI and may be subject to rapid progression to malignancy. An important step to reduce the incidence of CRC initiated by the serrated pathway is to improve the detection of serrated polyps and to ensure their complete removal during endoscopy. Understanding of the so-called serrated carcinogenesis pathway is an important step forward in expanding possibilities in the prevention of CRC.

Abstract 2014: SHP2 stabilizes EGFR and beta-catenin to promote the transformation and tumorigenic potential of basal-like and triple-negative breast cancer cells

Abstract Basal-like and triple-negative breast cancer (BTBC) causes disproportionately high mortalities in women. One of the major reasons is lack of targeted therapy, and the other is the highly aggressive and metastatic nature of the disease. The primary complication in finding viable drug targets has been the dysregulation of multiple signaling pathways, making one pathway inhibition an unlikely strategy to lead to effective treatment for BTBC. Therefore, targeting multiple pathways or finding proteins that control multiple signaling pathways and targeting them remain to be the only hope. In line with this, we have discovered that the Src homology phosphotyrosyl phosphatase 2 (SHP2) controls EGFR and Wnt/β-catenin signaling, major pathways known to be dysregulated in BTBC. We show that SHP2 overexpression in BTBC tumors is associated with elevated EGFR expression and cytoplasmic and nuclear accumulation of β-catenin. Silencing SHP2 expression in BTBC cells destabilizes EGFR and β-catenin and inhibits respective downstream signaling, confirming that SHP2 overexpression is essential for dysregulation of EGFR and β-catenin in this subtype of breast cancer. Furthermore, we demonstrate that inhibition of SHP2 in BTBC cells induces luminal epithelial morphology, suppresses cell proliferation, reverses transformation, blocks invasiveness in 3D matrigel, and abolishes tumorigenesis and metastasis. These findings suggest that SHP2 controls the EGFR and the Wnt/β-catenin signaling pathways to promote BTBC. Citation Format: Hua Zhao, Yehenew M. Agazie. SHP2 stabilizes EGFR and beta-catenin to promote the transformation and tumorigenic potential of basal-like and triple-negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2014. doi:10.1158/1538-7445.AM2014-2014

Fusion of optical coherence tomographic and angiographic data for more accurate evaluation of the endothelial shear stress patterns and neointimal distribution after bioresorbable scaffold implantation: comparison with intravascular ultrasound-derived reconstructions

Intravascular ultrasound (IVUS)-based reconstructions have been traditionally used to examine the effect of endothelial shear stress (ESS) on neointimal formation. The aim of this analysis is to compare the association between ESS and neointimal thickness (NT) in models obtained by the fusion of optical coherence tomography (OCT) and coronary angiography and in the reconstructions derived by the integration of IVUS and coronary angiography. We analyzed data from six patients implanted with an Absorb bioresorbable vascular scaffold that had biplane angiography, IVUS and OCT investigation at baseline and 6 or 12 months follow-up. The IVUS and OCT follow-up data were fused separately with the angiographic data to reconstruct the luminal morphology at baseline and follow-up. Blood flow simulation was performed on the baseline reconstructions and the ESS was related to NT. In the OCT-based reconstructions the ESS were lower compared to the IVUS-based models (1.29 ± 0.66 vs. 1.87 ± 0.66 Pa, P = 0.030). An inverse correlation was noted between the logarithmic transformed ESS and the measured NT in all the OCT-based models which was higher than the correlation reported in five of the six IVUS-derived models (-0.52 ± 0.19 Pa vs. -0.10 ± 0.04, P = 0.028). Fusion of OCT and coronary angiography appears superior to IVUS-based reconstructions; therefore it should be the method of choice for the study of the effect of the ESS on neointimal proliferation.