MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.

Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials.

Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.

Epigenetic Abnormalities in Chondrosarcoma.

In recent years, our understanding of the epigenetic mechanisms involved in tumor pathology has improved greatly. DNA and histone modifications, such as methylation, demethylation, acetylation, and deacetylation, can lead to the up-regulation of oncogenic genes, as well as the suppression of tumor suppressor genes. Gene expression can also be modified on a post-transcriptional level by microRNAs that contribute to carcinogenesis. The role of these modifications has been already described in many tumors, e.g., colorectal, breast, and prostate cancers. These mechanisms have also begun to be investigated in less common tumors, such as sarcomas. Chondrosarcoma (CS) is a rare type of tumor that belongs to sarcomas and is the second most common malignant bone tumor after osteosarcoma. Due to unknown pathogenesis and resistance to chemo- and radiotherapies of these tumors, there is a need to develop new potential therapies against CS. In this review, we summarize current knowledge on the influence of epigenetic alterations in the pathogenesis of CS by discussing potential candidates for future therapies. We also emphasize ongoing clinical trials that use drugs targeting epigenetic modifications in CS treatment.

Back to the future of organolanthanide chemistry.

At the dawn of the development of structural organometallic chemistry, soon after the discovery of ferrocene, the description of the LnCp3 complexes, featuring large and mostly trivalent lanthanide ions, was rather original and sparked curiosity. Yet, the interest in these new architectures rapidly dwindled due to the electrostatic nature of the bonding between π-aromatic ligands and 4f-elements. Almost 70 years later, it is interesting to focus on how the discipline has evolved in various directions with the reports of multiple catalytic reactivities, remarkable potential in small molecule activation, and the development of rich redox chemistry. Aside from chemical reactivity, a better understanding of their singular electronic nature - not precisely as simplistic as anticipated - has been crucial for developing tailored compounds with adapted magnetic anisotropy or high fluorescence properties that have witnessed significant popularity in recent years. Future developments shall greatly benefit from the detailed reactivity, structural and physical chemistry studies, particularly in photochemistry, electro- or photoelectrocatalysis of inert small molecules, and manipulating the spins' coherence in quantum technology.

Impact of COVID-19 on Head and Neck Cancer Advancement Measured by Increasing Numbers of Urgent Dyspnea Cases-What Could Be Improved in the Event of Subsequent Pandemics?

The COVID-19 pandemic has altered all aspects of the healthcare system's organization and impacted patients with head and neck cancer (HNC) who have experienced delayed diagnosis and treatment. The pandemic resulted in the admission of patients with severe dyspnea and a need for tracheotomy due to extremely advanced HNC. This study's objective was to evaluate the clinical characteristics of two multi-center cohorts, "pre-COVID-19" and "COVID-19", of HNC patients admitted as emergencies for dyspnea. The therapeutic activity of HNC patients in four University Departments of Otolaryngology was studied over two time periods: September-February 2019/2020 and 2020/2021. A group of 136 HNC patients who underwent a tracheotomy in two-time cohorts, pre-COVID-19 (N = 59) and COVID-19 (N = 77), was analyzed. The mean tracheotomies incidence proportion was 1.82 (SD: 1.12) for the pre-COVID-19 and 3.79 (SD: 2.76) for COVID-19 period. A rise in the occurrence of emergency dyspnea was observed in the COVID-19 cohort, and the greatest increase was seen in the centers with the highest limitations on planned surgeries. In the pre-COVID-19 period, 66% of patients presented with symptoms for more than a month in comparison to 78% of patients in the COVID-19 period (p = 0.04). There was a higher incidence of laryngeal and laryngopharyngeal cancer in the COVID-19 period (63% vs. 75%, respectively). The number of tracheotomies performed under general anesthesia dropped in favor of local anesthesia during COVID-19 (64% vs. 56%, respectively) due to extremely advanced HNC. In the COVID-19 cohort, most patients received a telemedicine consultation (N = 55, 71%) in comparison to the pre-COVID-19 period (N = 14, 24%). Reorganization of the referral system, adjustment of treatment capacity for an increased number of HNC, and a reserve for more extensive resection and reconstruction surgeries should be made in the profile of otorhinolaryngological departments, ensuring future HNC treatment is not hampered in case of a new pandemic wave.

Synchronous bilateral multifocal basal cell adenomas of the parotid gland-a case report.

BACKGROUND: Bilateral parotid gland tumors account for up to 3% of cases. In this group, the vast majority are Warthin's tumors. However, bilateral presentations of other parotid gland tumor entities is also possible, an example of which is a basal cell adenoma (BCA). Bilateral BCA is extremely rare, which could cause misdiagnosing it as a Warthin tumor. CASE PRESENTATION: The current study reports the unique case of a 48-year-old woman who presented with a 6-month history of slowly growing masses located bilaterally in the parotid region, surgically treated with 5-year follow-up (no recurrence, normal facial nerve function). Magnetic resonance imaging (MRI) revealed three lesions: two in the superficial and deep lobes of the right parotid gland, and one in the superficial lobe of the left parotid gland. A total parotidectomy with facial nerve preservation was performed on the right side, and superficial parotidectomy on the left side 6 months later. Histopathological examination confirmed that all three tumors were BCAs. Molecular analysis didn't show any strong, potential of unknown clinical significance in the studied sample. CONCLUSIONS: Multifocal bilateral lesions of the parotid gland are usually Warthin tumors. Detailed preoperative diagnostics including MRI and histopathological examination is essential to avoid misdiagnosing BCA and Warthin tumors. To our best knowledge, no case of synchronous bilateral multifocal basal cell adenomas of the parotid gland has been reported in English literature so far.

The Pet127 protein is a mitochondrial 5'-to-3' exoribonuclease from the PD-(D/E)XK superfamily involved in RNA maturation and intron degradation in yeasts.

Pet127 is a mitochondrial protein found in multiple eukaryotic lineages, but absent from several taxa, including plants and animals. Distant homology suggests that it belongs to the divergent PD-(D/E)XK superfamily which includes various nucleases and related proteins. Earlier yeast genetics experiments suggest that it plays a nonessential role in RNA degradation and 5' end processing. Our phylogenetic analysis suggests that it is a primordial eukaryotic invention that was retained in diverse groups, and independently lost several times in the evolution of other organisms. We demonstrate for the first time that the fungal Pet127 protein in vitro is a processive 5'-to-3' exoribonuclease capable of digesting various substrates in a sequence nonspecific manner. Mutations in conserved residues essential in the PD-(D/E)XK superfamily active site abolish the activity of Pet127. Deletion of the PET127 gene in the pathogenic yeast Candida albicans results in a moderate increase in the steady-state levels of several transcripts and in accumulation of unspliced precursors and intronic sequences of three introns. Mutations in the active site residues result in a phenotype identical to that of the deletant, confirming that the exoribonuclease activity is related to the physiological role of the Pet127 protein. Pet127 activity is, however, not essential for maintaining the mitochondrial respiratory activity in C. albicans.

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest.

In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

Synthesis and Catalytic Properties of a Very Latent Selenium-Chelated Ruthenium Benzylidene Olefin Metathesis Catalyst.

Herein, we describe a study of the synthesis, characterization, and catalytic properties of a cis-dichlorido seleno-chelated Hoveyda-Grubbs type complex (Ru8). Such a complex has been obtained through a straightforward and high-yielding synthetic protocol in three steps from the commercially available 2-bromobenzaldehyde in good overall yield (54%). The catalytic profile, especially the latency of this complex, has been probed through selected olefin metathesis reactions such as ring-closing metathesis (RCM), self-cross-metathesis (self-CM) and ring-opening metathesis polymerization (ROMP). In addition to its high latency, the selenium Hoveyda-type complex Ru8 exhibits a switchable behavior upon thermal activation. Of interest, while the corresponding sulfur-chelated Hoveyda type catalyst is reported to be only activated by heat, the selenium analogue was found to be active upon both heat and light irradiation.

Value of dynamic contrast enhanced MRI in differential diagnostics of Warthin tumors and parotid malignancies.

To define an algorithm for differential diagnostics of parotid malignancies and Warthin tumors (WTs) based on dynamic contrast enhanced MRI (DCE-MRI). 55 patients with parotid tumors treated surgically were analyzed. Of which, 19 had parotid malignancy and 36 had WTs confirmed with postoperative histopathological examination. Accuracy of DCE-MRI parameters (Tpeak and WR) was compared with the histopathological diagnosis. ROC analysis was performed to determine sensitivity and specificity of DCE-MRI with various Tpeak and WR cut-off values. WT showed significantly lower median Tpeak and higher median WR than malignant lesions. The cut-off values for Tpeak and WR providing maximum sensitivity (84.2%) and specificity (86.1%) for malignant tumors were Tpeak > 60 s and WR ≤ 30%. Different diagnostic algorithm, i.e., lower cut-off value for Tpeak (Tpeak = 60 s), increases sensitivity of DCE-MRI in differentiating parotid malignancies from WTs. However, WR > 30% seems to be a key diagnostic criterion for benign lesions. Precise and reliable preoperative diagnostics of parotid tumors aids in careful surgical planning, thereby assisting in achieving sufficient surgical resection margins and facial nerve preservation.

Pervasive transcription of the mitochondrial genome in Candida albicans is revealed in mutants lacking the mtEXO RNase complex.

The mitochondrial genome of the pathogenic yeast Candida albicans displays a typical organization of several (eight) primary transcription units separated by noncoding regions. Presence of genes encoding Complex I subunits and the stability of its mtDNA sequence make it an attractive model to study organellar genome expression using transcriptomic approaches. The main activity responsible for RNA degradation in mitochondria is a two-component complex (mtEXO) consisting of a 3'-5' exoribonuclease, in yeasts encoded by the DSS1 gene, and a conserved Suv3p helicase. In C. albicans, deletion of either DSS1 or SUV3 gene results in multiple defects in mitochondrial genome expression leading to the loss of respiratory competence. Transcriptomic analysis reveals pervasive transcription in mutants lacking the mtEXO activity, with evidence of the entire genome being transcribed, whereas in wild-type strains no RNAs corresponding to a significant fraction of the noncoding genome can be detected. Antisense ('mirror') transcripts, absent from normal mitochondria are also prominent in the mutants. The expression of multiple mature transcripts, particularly those translated from bicistronic mRNAs, as well as those that contain introns is affected in the mutants, resulting in a decreased level of proteins and reduced respiratory complex activity. The phenotype is most severe in the case of Complex IV, where a decrease of mature COX1 mRNA level to ~5% results in a complete loss of activity. These results show that RNA degradation by mtEXO is essential for shaping the mitochondrial transcriptome and is required to maintain the functional demarcation between transcription units and non-coding genome segments.

Yeast pentatricopeptide protein Dmr1 (Ccm1) binds a repetitive AU-rich motif in the small subunit mitochondrial ribosomal RNA.

PPR proteins are a diverse family of RNA binding factors found in all Eukaryotic lineages. They perform multiple functions in the expression of organellar genes, mostly on the post-transcriptional level. PPR proteins are also significant determinants of evolutionary nucleo-organellar compatibility. Plant PPR proteins recognize their RNA substrates using a simple modular code. No target sequences recognized by animal or yeast PPR proteins were identified prior to the present study, making it impossible to assess whether this plant PPR code is conserved in other organisms. Dmr1p (Ccm1p, Ygr150cp) is a S. cerevisiae PPR protein essential for mitochondrial gene expression and involved in the stability of 15S ribosomal RNA. We demonstrate that in vitro Dmr1p specifically binds a motif composed of multiple AUA repeats occurring twice in the 15S rRNA sequence as the minimal 14 nt (AUA)4AU or longer (AUA)7 variant. Short RNA fragments containing this motif are protected by Dmr1p from exoribonucleolytic activity in vitro. Presence of the identified motif in mtDNA of different yeast species correlates with the compatibility between their Dmr1p orthologs and S. cerevisiae mtDNA. RNA recognition by Dmr1p is likely based on a rudimentary form of a PPR code specifying U at every third position, and depends on other factors, like RNA structure.

Structural analysis of mtEXO mitochondrial RNA degradosome reveals tight coupling of nuclease and helicase components.

Nuclease and helicase activities play pivotal roles in various aspects of RNA processing and degradation. These two activities are often present in multi-subunit complexes from nucleic acid metabolism. In the mitochondrial exoribonuclease complex (mtEXO) both enzymatic activities are tightly coupled making it an excellent minimal system to study helicase-exoribonuclease coordination. mtEXO is composed of Dss1 3'-to-5' exoribonuclease and Suv3 helicase. It is the master regulator of mitochondrial gene expression in yeast. Here, we present the structure of mtEXO and a description of its mechanism of action. The crystal structure of Dss1 reveals domains that are responsible for interactions with Suv3. Importantly, these interactions are compatible with the conformational changes of Suv3 domains during the helicase cycle. We demonstrate that mtEXO is an intimate complex which forms an RNA-binding channel spanning its entire structure, with Suv3 helicase feeding the 3' end of the RNA toward the active site of Dss1.

A novel in-frame deletion in MEN1 (p.Ala416del) causes familial multiple endocrine neoplasia type 1 with an aggressive phenotype and unexpected inheritance pattern.

The present study describes a family with multiple endocrine neoplasia type 1 (MEN1) caused by a previously undescribed in-frame deletion c.1246_1248delGCC (Ala416del) in the MEN1 gene. Evidence for the pathogenic character of this mutation, which triggers an aggressive clinical outcome, is demonstrated. Aggregation analysis in the tested family was strongly suggestive of causality of the detected mutation. This was supported by the analysis of LOH (loss of heterozygosity) in tumor-derived DNA and by computational analysis of the functional and structural implications of the mutation. Different phenotypic characteristics were identified among family members, which is typical for MEN1. Additionally, an unexpected disease inheritance pattern was observed in this kindred, in which either all or none of the siblings of one branch inherited the disease.

Noninsulinoma pancreatogenous hypoglycaemia in adults--a spotlight on its genetics.

Hyperinsulinaemic hypoglycaemia (HH) is also classically referred to as "nesidioblastosis". Heterogeneous clinical manifestation of the disease causes risk of late diagnosis or even misdiagnosis. In infants and children, it can lead to serious and permanent damage to the central nervous system, which leads to the manifesting mental retardation. HH is characterised by unregulated insulin secretion from pancreatic ß-cells. This effect has been correlated with nine genes: ABCC8, KCNJ11, GCK, GLUD-1, HADH1, SLC16A1, HNF4A, HNF1A, and UCP2. Mutations in these genes were found in approximately 48% of cases. The genetic background of the remaining cases is unknown. Understanding the genetic basis of familial hyperinsulinism has changed the early look at the disease. It has allowed for the differentiation of specific types of the disease. Depending on which of the nine disease-associated loci bears a pathogenic mutation, they differ in phenotype and pattern of inheritance. This review provides a brief overview of the genetic mechanisms of HH and its possible clinical presentations.

Effect of histatin-5 and lysozyme on the ability of Streptococcus mutans to form biofilms in in vitro conditions.

INTRODUCTION: The mechanisms of adhesion to solid surfaces enable S. mutans to colonize oral cavities and form biofilms, which play an important role in caries development. Additional properties enabling the survival of S. mutans in the oral cavity include its ability to survive in acidic environments and specific interactions with other microorganisms inhabiting this ecosystem. AIM OF THE STUDY: The aim of this study was to determine the antibacterial activity of saliva histatin-5 (peptide) and lysozyme (protein) against S. mutans and L. rhamnosus, as representatives of physiological flora. MATERIALS AND METHODS: The study involved strains of physiological (L. rhamnosus) and cariogenic (S. mutans) flora isolated from one patient with diagnosed early caries of the deciduous teeth. RESULTS: It was proved that the presence of probiotic L. rhamnosus bacteria in the environment had a negative impact on the ability of S. mutans to produce biofilm. Moreover, the antibacterial activity of histatin-5 was confirmed, and it inhibited S. mutans growth at concentrations of 27.2 µg/ml and 54.4 µg/ml, both individually and in a mixture with lysozyme (in a total concentration of 54.4 µg/ml). CONCLUSIONS: The data obtained constitute a promising result due to their potential future application in the prevention and early diagnosis of caries.

[PPR proteins--modular factors regulating expression of organellar genomes]. / Bialka PPR--molekularne czynniki regulujace ekspresje genomów organelli.

PPR proteins make up the most numerous family of RNA-binding proteins identified to date. They localize almost exclusively to plastids and mitochondria of eukaryotic organisms. The most striking feature of this family is the expansion of PPR protein-encoding genes in vascular plants, which likely coincided with plants colonizing land. PPR proteins participate in stabilizing, editing, splicing, degradation and processing of policistronic transcripts, as well as translation activation in mitochondria and plastids. Although the number of PPR proteins in non-plant organisms is significantly smaller than in plants, they still play a crucial role in regulating the expression of mtDNA. Disruptions of PPR protein-encoding genes usually result in severe phenotypic consequences. Plant PPR proteins bind RNA in a sequence-specific manner, where a single PPR motif recognizes an individual nucleotide in a given sequence. This opens up possibilities for engineering de novo synthetic protein sequences that would interact with precisely determined organellar sequences, thus enabling modulation of mtDNA and ctDNA expression.

The usefulness of biotyping in the determination of selected pathogenicity determinants in Streptococcus mutans.

BACKGROUND: Streptococcus mutans is known to be a primary etiological factor of dental caries, a widespread and growing disease in Polish children. Recognition of novel features determining the pathogenicity of this pathogen may contribute to understanding the mechanisms of bacterial infections.The goal of the study was to determine the activity of prephenate dehydrogenase (PHD) and to illuminate the role of the enzyme in S. mutans pathogenicity. The strains were biotyped based on STREPTOtest 24 biochemical identification tests and the usefulness of biotyping in the determination of S. mutans pathogenicity determinants was examined. RESULTS: Out of ninety strains isolated from children with deciduous teeth fifty three were classified as S. mutans species. PDH activity was higher (21.69 U/mg on average) in the experimental group compared to the control group (5.74 U/mg on average) (P <0.001). Moreover, it was demonstrated that biotype I, established basing on the biochemical characterization of the strain, was predominant (58.5%) in oral cavity streptococcosis. Its dominance was determined by higher PDH activity compared to biotypes II and III (P = 0.0019). CONCLUSIONS: The usefulness of biotyping in the determination of Streptococcus mutans pathogenicity determinants was demonstrated. The obtained results allow for better differentiation of S. mutans species and thus may contribute to recognition of pathogenic bacteria transmission mechanisms and facilitate treatment.

[Introduction to human genome sequencing in diagnostics]. / Wprowadzenie do sekwencjonowania ludzkiego genomu w diagnostyce.

The increasing efficiency of genetic analyzers together with the decreasing price of DNA sequencing per single nucleotide read, makes the method of individual genomes sequencing more available for diagnostic laboratories. Nowadays genome sequencing applications are predominantly used for research purposes but in nearest future we will be using them in routine patient evaluation as we are using analytic approaches based on Sanger method now. New generation sequencing is a tool which gives the researchers excellent possibilities for the realization of personalized medicine assumptions. However, before we will be able to make full use of it, there are still some questions to be answered, as for example who should perform the analysis, interpret results and finally who should be responsible for data management.

How far are we from understanding the genetic basis of Hashimoto's thyroiditis?

Hashimoto's thyroiditis (HT), an autoimmune thyroid disease (AITD), is becoming more and more prevalent in the recent years. Data on family and twin studies carry evidence for strong genetic influence on AITD susceptibility and development. The most common approaches to unravel the background of those diseases are whole genome screening and candidate gene analysis. Common Hashimoto's thyroiditis and Graves' disease (GD) genes have been identified, as well as genes that are characteristic for only one of those diseases. Because of the complex nature of AITD, caused by their polygenic nature and a complex mode of inheritance, there are still more questions to be answered than answers that can be given, especially about the nature of Hashimoto's thyroiditis. There are plenty of papers concerning the pathogenesis of AITD. However, not seldom do they end up in conclusions about GD, because the results for this disease are far clearer and more unambiguous than those obtained for HT. Similarly, meta-analyses and especially reviews most often concentrate on AITD in general or on GD alone. In this review, Hashimoto's thyroiditis is the main player. It aims to review the state of the art about the background of the development of this disease.