Search Results (181)

Microtubule-actin cross-linking factor 1 (MACF1), also known as actin cross-linking family protein 7 (ACF7), is a giant cytolinker protein with multiple conserved domains that can orchestrate cytoskeletal networks of actin and microtubules. MACF1 is involved in various biological processes, including cell polarity, cell–cell connection, cell proliferation, migration, vesicle transport, signal transduction, and neuronal development. In this review, we updated the physiological and pathological roles of MACF1, highlighting the components and signaling pathways involved. Novel evidence showed that MACF1 is involved in diverse human diseases, including multiple neuronal diseases, congenital myasthenic syndrome, premature ovarian insufficiency, spectraplakinopathy, osteoporosis, proliferative diabetic retinopathy, and various types of cancer. We also reviewed the physiological roles of MACF1, including its involvement in adhesome formation, bone formation, neuronal aging, and tooth development. In addition, MACF1 plays other roles, functioning as a biomarker for the prediction of infections in patients with burns and as a marker for genome selection breeding. These studies reinforce the idea that MACF1 is a bona fide versatile, multifaceted giant protein. Identifying additional MACF1 functions would finally help with the treatment of diseases caused by MACF1 defects. Full article

Due to the complex anatomy of the pelvis, various tumors may arise in this region. Some of these tumors are well known and have distinctive features that allow them to be identified by magnetic resonance imaging (MRI). These include sacrococcygeal teratoma (SCT), the most prevalent congenital tumor in children, often diagnosed prenatally and most frequently occurring in this anatomical location, and ovarian teratoma, which in its mature form is the most common ovarian neoplasm in children and adolescents. Additionally, rhabdomyosarcoma (RMS), commonly found in the bladder in both genders and in the prostate in males, and Ewing sarcoma (ES), affecting the flat bones of the pelvis, are relatively common tumors. In this study, selected atypical pelvic tumors in children are presented. Most of them are tumors of the reproductive system, such as cervical cancer, small cell neuroendocrine carcinoma of the ovary, ES/primitive neuroectodermal tumor (PNET) of the ovary, diffuse large B-cell lymphoma (DLBCL) of the ovaries and ovarian Sertoli–Leydig cell tumor (SLCT) with RMS due to DICER1 syndrome. Additionally, tumors originating from the nervous system, including neuroblastoma (NBL) and plexiform neurofibroma (pNF), associated and not associated with neurofibromatosis type 1 (NF1), are discussed. Furthermore, Rosai–Dorfman disease involving the pelvic and inguinal lymph nodes is presented. By reviewing the literature and presenting our cases, we tried to find radiological features of individual tumors that would bring the radiologist closer to the correct diagnosis, ensuring the implementation of appropriate treatment. However, the MR images cannot be considered in isolation. Additional patient data, such as the clinical picture, comorbidities/syndromes, and laboratory test results, are necessary. Full article

Mitochondria play a crucial role in multiple cellular processes such as energy metabolism, generation of reactive oxygen species, excitation–contraction coupling, cell survival and death. Dysfunction of mitochondria contributes to the development of cancer; neuromuscular, cardiovascular/congenital heart disease; and metabolic diseases, including diabetes. Mitochondrial dysfunction can result in excessive reactive oxygen species, a decrease in energy production, mitophagy and apoptosis. All these processes are known to be dysregulated in cardiovascular diseases. The focus of this review is to summarize our current knowledge of mitochondrial dysfunction, including mitophagy and apoptosis, in pediatric congenital heart disease due to maternal diabetes or due to structural cardiac defects, with a focus on single-ventricle congenital heart disease. We also discuss recent mitochondria-targeted therapies for cardiovascular diseases. Full article

Background/Objectives: Pregnancy-associated cancer (PAC) presents significant challenges for maternal and neonatal health, and yet its impact on neonatal outcomes remains poorly understood. This systematic review aims to evaluate the neonatal risks associated with PAC. Methods: A systematic search of PubMed, Embase, Scopus, and other databases was conducted up to 1 November 2024, identifying observational studies and randomized controlled trials assessing neonatal outcomes in pregnancies affected by PAC. Outcomes included preterm birth, low birthweight, macrosomia, small and large for gestational age, low Apgar score, congenital anomalies, and neonatal mortality. Results: Eleven high-quality studies encompassing over 46 million births, including 9953 PAC-affected pregnancies, were reviewed. PAC significantly increased the risks of preterm birth (adjusted ORs ranging from 1.48 to 6.34) and low birthweight (adjusted ORs up to 5.5). Other adverse outcomes included low Apgar scores and neonatal mortality, primarily linked to prematurity. Cancer type and treatment timing influenced these outcomes, with gynecological and breast cancers posing higher risks. Conclusions: Neonates of mothers with PAC face increased risks of adverse outcomes, underscoring the importance of tailored, multidisciplinary management. Further prospective studies are needed to clarify the impacts of specific cancer treatments during pregnancy. Full article

The evolution of man on Earth took place under conditions of constant exposure to background ionizing radiation (IR). From this point of view, it would be reasonable to hypothesize the existence of adaptive mechanisms that enable the human organism to safely interact with IR at levels approximating long-term natural background levels. In some situations, the successful operation of molecular mechanisms of protection against IR is observed at values significantly exceeding the natural background level, for example, in cancer cells. In 15–25% of cancer patients, cancer cells develop a phenotype that is resistant to high doses of IR. While further investigations are warranted, the current evidence suggests a strong probability of observing positive health effects, including an increased lifespan, a reduced cancer risk, and a decreased incidence of congenital pathologies, precisely at low doses of ionizing radiation. This review offers arguments primarily based on a phenomenological approach and critically reconsidering existing methodologies for assessing the biological risks of IR to human health. Currently, in the most economically developed countries, there are radiation safety rules that interpret low-dose radiation as a clearly negative environmental factor. Nowadays, this approach may pose significant challenges to the advancement of radiomedicine and introduce complexities in the regulation of IR sources. The review also examines molecular mechanisms that may play a key role in the formation of the positive effects of low-dose IR on human radioadaptive capabilities. Full article

Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer’s disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area. Full article

Background: Accessory breast cancer cases are rarely reported in the literature. Of the reported cases, the predominantly available ones are those localized in the axillary region. Methods: We present here a very rare case of metastatic accessory breast cancer. It was located in the infra-mammary region (IMR). IMR accessory breast cancer is a rare form of breast cancer. Although ectopic nipples are occasionally found in the IMR, because of the lack of ductal tissue malignant changes, they are rare. Results: In our case, the primary tumor was localized in the congenital accessory breast tissue (ABT). It was recognized as invasive lobular accessory breast cancer cT3N1M0 with a second NST carcinoma, cT2N0M0, Stage IIA, in the ipsilateral breast. A multi-modal approach was applied. Adjuvant chemotherapy was carried out with epirubicin, cyclophosphamide, and paclitaxel, with post-chemotherapy ultrasound followed by right radical mastectomy. Adjuvant radiotherapy was given to our patient in the form of 25 fractions of 50 GY for 25 days, followed by hormonal treatment with Letrozole, 2.5 mg/day, to be continued for 5 years. Conclusions: our case demonstrates that since it is rare to find accessory breast cancer in the infra-mammary region, early identification and management with a multi-modal approach can lead to a successful patient outcome. Full article

Dyslipidemia (DL), defined by dysregulated levels of lipids in the bloodstream, is an ever-growing problem in modern society. In addition to those with congenital defects in lipid metabolism, the pervasive nature of high-fat and high-calorie diets in modern industrialized societies has led to a meteoric increase in its incidence. Patients who suffer from this condition subsequently are at a higher risk of developing other co-morbid conditions, most notably diabetes mellitus and coronary artery disease. This review explores another arguably lesser-known consequence of DL, pancreatitis, which is an inflammatory disease of the pancreas. The goal of this article is to review the intersection of these two conditions by briefly highlighting the proposed pathophysiology and exploring the impact of DL (specifically hypertriglyceridemia) on acute, acute recurrent, and chronic pancreatitis. This paper additionally examines the long-term risks of developing pancreatic cancer in patients with pancreatitis secondary to DL and presents unique clinical scenarios that result in DL-associated pancreatitis. Finally, we discuss potential treatment options for hypertriglyceridemia which can potentially mitigate the risk of DL-associated pancreatitis. Full article

Background: Pediatric illnesses not only impose physical challenges on affected children, but also profoundly impact their emotional well-being. Understanding how parents respond to their children’s psychological distress during medical experiences is crucial for enhancing the overall support provided to these families. Aim: This study evaluated the internal structure of the Parental Response Styles Questionnaire (PRSQ), designed to differentiate parental responses to psychological distress in children with pediatric illnesses. Methods: A sample of 701 parents of children with medical issues responded to the PRSQ, reporting their different emotional expressions and responses to their children’s expressions of distress during the medical experience. Results: Factor analysis confirmed, in three of the five subsamples, an internal scale structure consisting of four factors: apathy and dysphoria, irritability and rejection, overprotectiveness, and perceived maladjustment. The invariance analyses revealed that congenital heart disease and neurological disorders are more similar in function to each other than pediatric cancer. Parents of children with neurological disorders exhibited a notably insecure pattern of parental responsiveness. Conclusions: In pediatric contexts, parental responses to their children’s emotional distress are significant factors in the process of adaptation. These responses can be measured, differentiated, and, ideally, managed by nurses and other healthcare professionals. The Parental Response Styles Questionnaire (PRSQ) is a promising tool for assessing parental reactions during their children’s treatment, and its structure appears to be particularly robust across diagnoses such as pediatric cancer, congenital heart disease, and neurological disorders. Full article

Objective: Congenital, non-syndromic orofacial clefts (CL/P) are infrequently monogenic in etiology. However, heterozygous pathogenic CDH1 germline variants were reported in a few non-syndromic CL/P families, as well as in one syndromic form of CL/P: the blepharocheilodontic syndrome. CDH1 encodes epithelial cadherin (E-cadherin), and close to 300 different pathogenic CDH1 variants are listed in the ClinVar mutation database. The majority of CDH1 germline variants are implicated in hereditary diffuse gastric cancer (HDGC) susceptibility. The purpose of this study was to classify the CDH1 c.760G>A (p.Asp254Asn) mutation with respect to its resulting phenotype. Methods: Exome sequencing and targeted Sanger sequencing were performed in a family segregating CL/P. A review of pathogenic CDH1 variants in ClinVar and those identified in a PubMed/MEDLINE search was performed. Results: We identified a family with six individuals, who were 35–77 years old (mean 56 years) at their last examination, uniformly affected with bilateral CL/P. The CDH1 c.760G>A variant segregated with CL/P. This variant had been reported in 21 individuals, most often children and young adults, from six families. We determined a significant sex preponderance for this variant regarding CL/P: all 16 male and 5 of 11 female heterozygotes presented with CL/P. Furthermore, none of the heterozygous individuals in seven families reported any gastrointestinal tumors. Conclusions: The recurrent CDH1 c.760G>A mutation confers a high risk for CL/P, with strong male preponderance. This review of 27 mutation carriers, including 3 who were 68, 70, and 77 years of age, indicates that c.760G>A does not confer an increased risk for HDGC. The relevance of differentiating craniofacial from cancer phenotypes in mutation carriers is substantial for precision medicine and for counseling families. Full article

RASopathies are a group of genetic syndromes caused by germline mutations in genes involved in the RAS/Mitogen-Activated Protein Kinase signaling pathway, which regulates cellular proliferation, differentiation, and angiogenesis. Despite their involvement at different levels of this pathway, RASopathies share overlapping clinical phenotypes. Noonan syndrome is the most prevalent RASopathy, with an estimated incidence of 1 in 2500 live births, and it is typically inherited in an autosomal dominant manner, with 50% of cases involving gain-of-function mutations in the PTPN11 gene. De novo mutations are common, accounting for 60% of cases. The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer. Severe congenital cardiac defects and lymphatic abnormalities significantly impact prognosis, contributing to increased morbidity and mortality. Recent therapeutic advancements have introduced trametinib, an MEK1/2 inhibitor, for treating Noonan syndrome patients with severe cardiac and lymphatic complications. To assess its efficacy, here, we present a case of a newborn with Noonan syndrome who exhibited refractory chylothorax, ventricular hypertrophy, and pulmonary stenosis who was treated with trametinib. The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib’s potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes. Full article

Due to the high prostate cancer incidence worldwide, the development of different methods of treatment continues to be a hot research topic. Since its first clinical application at the beginning of the 2010s, abiraterone in the form of prodrug abiraterone acetate continues to be the most used hormone derivative in the treatment of castration-resistant prostate cancer. This is the reason behind the publication of many scientific results regarding its synthesis, biological activity, metabolism, novel designed steroid derivatives based on its structure, etc. A similar steroid compound with a heterocycle in the C17 position, called galeterone, also designed to treat prostate cancer, continues to be in clinical studies, which provides further proof of the importance of these steroid derivatives. Besides prostate cancer treatment, abiraterone showed indications for possible clinical application in the treatment of breast, ovarian, lung, kidney, salivary gland, and adrenocortical cancer, congenital adrenal hyperplasia, Cushing’s syndrome, and COVID-19, while galeterone is investigated for its use against prostate, pancreatic, and breast cancer. Herein, we report a review comprising methods of synthesis, possible clinical applications, and mechanisms of action, as well as structures and bioactivities of derivatives of these two important steroids. Full article

Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway to maintain genome integrity. FA is characterized by a triad of clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due to the complex genetic background and a broad spectrum of FA clinical symptoms, the diagnostic process is complex and requires the use of classical cytogenetic, molecular cytogenetics and strictly molecular methods. Recent findings indicate the interplay of inflammation, oxidative stress, disrupted mitochondrial metabolism, and impaired intracellular signaling in the FA pathogenesis. Additionally, a shift in the balance towards overproduction of proinflammatory cytokines and prooxidant components in FA is associated with advanced myelosuppression and ultimately BMF. Although the mechanism of BMF is very complex and needs further clarification, it appears that mutual interaction between proinflammatory cytokines and redox imbalance causes pancytopenia. In this review, we summarize the available literature regarding the clinical phenotype, genetic background, and diagnostic procedures of FA. We also highlight the current understanding of disrupted autophagy process, proinflammatory state, impaired signaling pathways and oxidative genotoxic stress in FA pathogenesis. Full article

The past few decades have brought tremendous insight into the molecular and pathophysiological mechanisms responsible for thrombus generation. For a clinician, it is usually sufficient to explain the incident of deep vein thrombosis (DVT) with provoking factors such as trauma with vascular injury, immobilization, hormonal factors, or inherited or acquired coagulation defects. About half of DVTs are, however, lacking such triggers and are called unprovoked. Venous stasis and hypoxia at the valve sinus level may start a chain of reactions. The concept of immunothrombosis has added a new dimension to the old etiological triad of venous stasis, vessel wall injury, and changes in blood components. This is particularly important in COVID-19, where hyperinflammation, cytokines, and neutrophil extracellular traps are associated with the formation of microthrombi in the lungs. To better understand the mechanisms behind DVT and reach beyond the above-mentioned simplifications, animal models and clinical epidemiological studies have brought insight into the complex interplay between leukocytes, platelets, endothelium, cytokines, complements, and coagulation factors and inhibitors. These pathways and the interplay will be reviewed here, as well as the roles of cancer, anticancer drugs, and congenital thrombophilic defects on the molecular level in hypercoagulability and venous thromboembolism. Full article