Luka Katic

The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an "Achilles heel" for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.

This review commemorates the 10-year anniversary of the discovery of physiological ligands Augα (Augmentor α; ALKAL2; Fam150b) and Augβ (Augmentor β; ALKAL1; Fam150a) for anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK), previously considered orphan receptors. This manuscript provides an in-depth review of the biophysical and cellular properties of ALK family receptors and their roles in cancer, metabolism, pain, ophthalmology, pigmentation, central nervous system (CNS) function, and reproduction. ALK and LTK receptors are implicated in the development of numerous cancers, and targeted inhibition of their signaling pathways can offer therapeutic benefits. Additionally, ALK family receptors are involved in regulating body weight and metabolism, modulating pain signaling, and contributing to eye development and pigmentation. In the CNS, these receptors play a role in synapse modulation, neurogenesis, and various psychiatric pathologies. Lastly, ALK expression is linked to reproductive functions, with potential implications for patients undergoing ALK inhibitor therapy. Further research is needed to better understand the complex interactions of ALK family receptors and Aug ligands and to repurpose targeted therapy for a wide range of human diseases.

Cardiovascular disease (CVD) and lung cancer are among the leading causes of mortality worldwide, with a significant interplay that complicates patient management and treatment outcomes. This review explores the complex relationship between various forms of CVD - such as coronary artery disease, heart failure (HF), arrhythmias, and valvular heart disease - and lung cancer. Shared risk factors, including smoking, aging, and chronic inflammation, contribute to the co-occurrence of these conditions. Additionally, treatments for lung cancer, particularly chemotherapy and radiation therapy, can exacerbate CVD, necessitating a multidisciplinary approach to patient care. We delve into specific CVD-related impacts on lung cancer prognosis and vice versa, examining mechanisms, clinical outcomes, and management strategies. Our findings highlight the need for integrated care involving oncologists, cardiologists, and other healthcare providers to optimize treatment plans and improve patient outcomes. Emphasizing comprehensive cardiovascular risk management in lung cancer patients, we advocate for further research to deepen our understanding and develop novel therapeutic approaches, ultimately enhancing the quality of life and survival rates in patients suffering from both CVD and lung cancer.

BACKGROUND: Artificial intelligence (AI) augmentation of ECG assessment has significant potential to improve patient outcomes in acute coronary syndrome. OBJECTIVE: We sought to evaluate the performance of a novel AI device (PMCardio) in assessing angiographic occlusion myocardial infarction (OMI) and predicting clinical outcomes. METHODS: We used a 1-year retrospective cohort of angiographic data from patients presenting with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). The device analyzed precatheterization ECGs to identify OMI, defined as a culprit vessel with thrombolysis In myocardial infarction (TIMI) 0-2 flow or TIMI 3 flow and peak cardiac troponin I > 10.0 ng/ml. RESULTS: A total of 217 patients were included: 72 STEMI (32%) and 145 NSTEMI (65%). Angiographic OMI was confirmed in 60 (83%) STEMI and 51 (35%) NSTEMI cases. The AI model achieved a sensitivity of 86.5%, specificity of 82.2%, and an area under the curve of 0.84. Traditional STEMI criteria had a sensitivity of 54.1% and a specificity of 88.7%. The AI model was 100% sensitive in detecting STEMI-OMI. The odds ratio for mortality in AI-detected OMI patients was 12.44 (1.56-98.98), unplanned readmissions 1.15 (0.53-2.51), and reduced ejection fraction at 1 year 0.24 (0.26-2.16). CONCLUSIONS: The AI model demonstrated higher sensitivity and similar specificity compared with traditional STEMI criteria, improving OMI detection while reducing false positives. These findings suggest potential benefits in triage accuracy and resource utilization, but further prospective validation is needed to determine its clinical impact.

Background/Objectives: Cardiac sarcoidosis (CS) is a rare entity characterized by granulomatous infiltration of the myocardium, which can lead to myocardial fibrosis, conduction abnormalities, and the development of heart failure, thereby elevating the risk of sudden cardiac death (SCD). While endomyocardial biopsy (EMBx) is regarded as the gold standard for diagnosis, its low sensitivity and inherent procedural risks may limit its practical application. Methods: This study retrospectively explored the role of advanced imaging modalities, specifically cardiovascular magnetic resonance imaging (CMR) and fluorodeoxyglucose positron emission tomography (FDG-PET), in the diagnosis and management of CS within a single center. In this retrospective study, we aimed to assess the utility of advanced imaging modalities in the clinical diagnosis of CS and the monitoring of treatment. Results: A total of 92 patients were identified as having cardiac sarcoidosis, with males constituting 66.3% of the sample and a mean age of 62 years (±11.9). Among these patients, 80 (87%) underwent FDG-PET. Here, the basal inferolateral segment was the most frequently observed segment of the heart with FDG uptake. A total of 77 patients (84%) underwent CMR, with 51 demonstrating late gadolinium enhancement (LGE). The basal inferolateral segment exhibited the highest frequency of LGE (26%). Logistic regression analysis indicated that patients presenting with a combination of LGE, FDG uptake on PET, and a “mismatch pattern” faced a two-fold increase in the risk of experiencing major adverse cardiac events (odds ratio = 2.311, p = 0.077). Conclusions: This study underscores the importance of multimodality imaging as a non-invasive alternative for CS diagnosis and management, reducing reliance on EMBx.