Evaluation and Utilization of Flow Artifacts at CT.

Flow artifacts are commonly encountered at contrast-enhanced CT and can be difficult to discern from true pathologic conditions. Therefore, radiologists must be comfortable distinguishing flow artifacts from true pathologic conditions. This is of particular importance when evaluating the pulmonary arteries and aorta, as a flow artifact may be mistaken for a pulmonary embolism or dissection flap. Understanding the mechanics of flow artifacts and how these artifacts are created can help radiologists in several ways. First, this knowledge can help radiologists appreciate how the imaging characteristics of flow artifacts differ from true pathologic conditions. This information can also help radiologists better recognize the clinical conditions that predispose patients to flow artifacts, such as pneumonia, chronic lung damage, and altered cardiac output. By understanding when flow artifacts may be confounding the interpretation of an examination, radiologists can then know when to pursue other troubleshooting methods to assist with the diagnosis. In these circumstances, the radiologist can consider several troubleshooting methods, including adjusting the imaging protocols, recommending when additional imaging may be helpful, and suggesting which imaging study would be the most beneficial. Finally, flow artifacts can also be used as a diagnostic tool when evaluating the vascular anatomy, examples of which include the characterization of shunts, venous collaterals, intimomedial flaps, and alternative patterns of blood flow, as seen in extracorporeal membrane oxygenation circuits. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Don't skip a beat! Critical findings in imaging studies performed in adults with congenital heart disease.

With ongoing advances in both medical and surgical management, the population of adults with congenital heart disease (CHD) continues to grow each year and has surpassed the number of pediatric cases. These adult patients will present to adult emergency departments with increasing frequency. Adults with CHD are at increased risk of developing not only cardiovascular complications, such as aortic dissection and thromboemboli, but also abdominopelvic and neurologic processes at younger ages. These individuals are also more likely to develop less urgent but clinically significant complications including end-organ dysfunction, baffle leaks, or bleeding collateral vessels. Ultimately, imaging can play a critical role in determining the triage, diagnosis, and management of adult CHD patients. To accomplish this goal, radiologists must be able to distinguish acute and chronic complications of treated CHD from benign processes, including expected post-surgical changes or imaging artifacts. Radiologists also need to be familiar with the various long-term risks and complications associated with both treated and untreated forms of CHD, particularly those in adults with complex lesions.

Subclavian Artery: Anatomic Review and Imaging Evaluation of Abnormalities.

The subclavian artery is an important structure that may be overlooked at CT of the chest and neck, in part because of its anatomic location at the periphery of the field of view but also because the clinical indication for CT examinations infrequently directs attention specifically to evaluation of the subclavian artery. As with all arteries, the subclavian artery has the potential to be involved in a variety of abnormalities, including pseudoaneurysms, dissections, stenosis or thrombosis, and vasculopathies. In addition, the subclavian artery can be secondarily involved as a collateral pathway because of an abnormality elsewhere. The subclavian artery may also be involved in surgical procedures to supply blood to other sites in the body or as an arterial access site. In these cases, recognizing the postsurgical appearance of the subclavian artery has become increasingly complex because of the use of the artery in an increasing number of procedures. Recognizing expected postoperative changes remains important to avoid mistaking them for abnormalities. The authors describe the imaging appearance of the normal anatomy of the subclavian artery and its anatomic variants, related abnormalities, and important postsurgical considerations. ©RSNA, 2022.

Impact of Pretransplantation CT on Liver Donation in Potential Deceased Organ Donors.

BACKGROUND: Computed tomography (CT) is routinely used to determine the suitability of potential living donor liver transplants, providing important information about liver size, vascular anatomy, and the presence of other diseases that would preclude it from safe donation. CT is not routinely used, however, when evaluating eligible deceased organ donors after brain death, a group which comprises most orthotopic liver transplants. After the installation of a CT scanner at a local procurement facility, CTs have been performed on potential deceased organ donors and used, in conjunction with other evaluative protocols, to help direct donation decisions and assist in procurement procedures. STUDY DESIGN: A retrospective analysis of data from 373 cases spanning 5 years was systematically collected and analyzed, including information pertaining to patient's medical histories, biopsy results, operative findings, and CT results. RESULTS: CT findings directly impacted the directive decision-making process in 29% of cases in this patient cohort, likely an underestimate, and reliably evaluated important factors including variant vascular anatomy and the presence and severity of hepatic steatosis and cirrhosis. CONCLUSION: Overall, this study suggests that CT has the potential to play a significant role in procurement procedures and the directive decision-making process, thereby improving the efficiency and accuracy by which potential deceased organ donors are evaluated.

CT Appearance of Pulmonary Arteriovenous Malformations and Mimics.

A pulmonary arteriovenous malformation (PAVM) is a fistulous connection between a pulmonary artery and a pulmonary vein that bypasses the normal pulmonary capillary bed resulting in a right-to-left shunt. Because of the potential for paradoxical emboli, PAVMs are treated when their feeding arteries exceed 3 mm or patients are symptomatic. PAVMs are often encountered in patients with suspected hereditary hemorrhagic telangiectasia (HHT). Sporadic cases are uncommon. The radiologist may be called on to diagnose a PAVM after positive transthoracic contrast-enhanced echocardiography in a patient with suspected HHT to direct patient management and avoid potential complications. The radiologist may also be required to evaluate a potential PAVM detected at CT performed for other reasons. Through the authors' experiences at an HHT Center of Excellence in an area endemic with histoplasmosis, the authors have gained a unique perspective on the diagnosis of PAVMs and differentiation of PAVMs from their mimics. Understanding the CT appearance of PAVMs limits misdiagnosis, directs appropriate treatment, and allows subsequent family screening for HHT (and avoidance of unnecessary screening when a PAVM mimic is encountered). Both vascular and nonvascular pulmonary lesions can mimic PAVMs. Vascular mimics include fibrosing mediastinitis, venovenous collaterals, arterial collaterals, pulmonary artery pseudoaneurysms, hepatopulmonary vessels, Sheehan vessels, meandering pulmonary veins, and pulmonary vein varices. Nonvascular mimics include granulomas, nodules, mucoceles, bronchoceles, ground-glass opacities, and atelectasis. The authors review the CT technique for evaluating PAVMs and the appearance of PAVMs and their mimics. ©RSNA, 2022.

Correction: Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.

[This corrects the article DOI: 10.18632/oncotarget.23749.].

Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.

The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.

CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax.

Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,1'-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 protein inhibitors. SIGNIFICANCE STATEMENT: Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.

Tumor Staging of Lung Cancer: Essential Concepts for the Radiologist.

Several important modifications have been proposed for the tumor (T) descriptor for lung cancers. New size cutoffs have been determined and there are new T descriptors for adenocarcinoma in situ, minimally invasive adenocarcinoma, and part-solid adenocarcinomas with a solid component > 0.5 cm to 3 cm (T1a, T1b, T1c). There are also recommendations for multifocal adenocarcinoma, which are classified by the lesion with the highest level T descriptor, and the number of lesions is indicated. Knowledge of these changes is important in the appropriate clinical staging of patients with lung cancer.

Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy.

The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics.

Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ∼3.5-fold and ∼65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC).

Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9.

Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone.

Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.

How the poor can have a voice in government policy

Development thinking has changed significantly in recent years. Policymakers have recognized the ability of the poor to make a valuable contribution to the analysis of poverty and are consulting them directly. This new participatory approach has resulted in a broader definition of poverty and better-informed public policies that are more responsive to the needs of the poor.