Antiproliferativna aktivnost glutarimidnih derivata iz baze podataka Nacionalnog instituta za rak, SAD - 3D odnos strukture i aktivnosti nezavisan od poravnavanja molekula

Alignment-free, three dimensional structure-activity relationships (3D QSAR) of the antiproliferative potency of twenty-two glutarimide-containing compounds, taken from National Cancer Institute Developmental therapeutics Program database, toward eight representative human tumour cell lines are reported. The descriptors used in the QSAR study were derived from GRID molecular interaction fields. The obtained models readily detect structural motifs positively or negatively correlated with the potency of the studied compounds toward each cell line. In this way, the pharmacophoric pattern required for high potency of compounds is reported. This pattern can serve as guidance for the design and syntheses of novel congeners, planned to be tested toward human tumour cell lines.U tekstu je opisan odnos strukture i antiproliferativne aktivnosti 22 glutarimidna derivata prema osam reprezentativnih linija humanih tumora. Podaci o strukturi jedinjenja i njihovoj aktivnosti su preuzeti iz baze podataka Nacionalnog Instituta za rak, SAD. Deskriptori, nezavisni od poravnavanja molekula (GRIND-2), korišćeni u proučavanju odnosa strukture i aktivnosti su dobijeni upotrebom programa GRID. Modeli jasno prikazuju strukturne elemente jedinjenja koji se pozitivno ili negativno korelišu sa biološkom aktivnošću. Farmakoforna slika dobijena iz modela će biti korišćena za planiranje novih analoga koji sadrže glutarimidni prsten i za koje se očekuje da će pokazati značajnu antiproliferativnu aktivnost

Rare benign lung tumours presenting with high clinical suspicion for malignancy: a case series and review of the literature

Introduction. Incidentally discovered lung nodules can be worrisome for both the patient and their physicians. Although 95% of solitary lung nodules are benign, it is important to distinguish which nodules have high clinical suspicion for malignancy. Existing clinical guidelines do not apply to patients with signs and symptoms related to the lesion and with an increased baseline risk of lung cancer or metastasis. This paper highlights the vital role of pathohistological analysis and immunohistochemistry in the definitive diagnosis of such incidentally discovered lung nodules. Material and methods. The three cases presented were selected based on their similar clinical presentations. A review of the literature was performed using the online database PubMed, for articles published in the period between January of 1973 to February of 2023 using the following medical subject headlines: “primary alveolar adenoma,” “alveolar adenoma,” “primary pulmonary meningioma,” “pulmonary meningioma,” and “pulmonary benign metastasizing leiomyoma.” Results (Case Series). The case series consists of three incidentally discovered lung nodule(s). Although they presented with high clinical suspicion for malignancy, detailed workup confirmed the diagnosis of three rare benign lung tumours: primary alveolar adenoma, primary pulmonary meningioma, and benign metastasizing leiomyoma. Conclusions. Clinical suspicion for malignancy in the presented cases arose from previous and current medical history of malignancy, family history of malignancy, and/or specific radiographic findings. This paper highlights the need for a multidisciplinary approach in the management of incidentally discovered pulmonary nodules. Excisional biopsy and pathohistological analysis remain the gold standard in confirming the presence of a pathologic process and determining the nature of the disease. Common features of the diagnostic algorithm utilized among the three cases include multi-slice computerized tomography, excisional biopsy via atypical wedge resection (if the nodule is peripherally located), and lastly, pathomorphological analysis using haematoxylin and eosin staining and immunohistochemistry

Prediction of Cervical Lymph Node Metastasis in Clinically Node-Negative T1 and T2 Papillary Thyroid Carcinoma Using Supervised Machine Learning Approach

Papillary thyroid carcinoma (PTC) is generally considered an indolent cancer. However, patients with cervical lymph node metastasis (LNM) have a higher risk of local recurrence. This study evaluated and compared four machine learning (ML)-based classifiers to predict the presence of cervical LNM in clinically node-negative (cN0) T1 and T2 PTC patients. The algorithm was developed using clinicopathological data from 288 patients who underwent total thyroidectomy and prophylactic central neck dissection, with sentinel lymph node biopsy performed to identify lateral LNM. The final ML classifier was selected based on the highest specificity and the lowest degree of overfitting while maintaining a sensitivity of 95%. Among the models evaluated, the k-Nearest Neighbor (k-NN) classifier was found to be the best fit, with an area under the receiver operating characteristic curve of 0.72, and sensitivity, specificity, positive and negative predictive values, F1 and F2 scores of 98%, 27%, 56%, 93%, 72%, and 85%, respectively. A web application based on a sensitivity-optimized kNN classifier was also created to predict the potential of cervical LNM, allowing users to explore and potentially build upon the model. These findings suggest that ML can improve the prediction of LNM in cN0 T1 and T2 PTC patients, thereby aiding in individual treatment planning

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life