Hasil untuk "Cytology"

Aiyarin Kittilukkana, Puwapong Nimkingratana, Dumnoensun Pruksakorn et al.

Stem cell therapy represents an intrinsic part of regenerative medicine, with expanding applications in orthopedic and musculoskeletal research. Although studies span from small-animal models to early-phase clinical trials, the field remains fragmented, with wide variation in stem cell types, delivery methods, and target tissues. A consolidated overview is needed to inform future directions and bridge the gap between preclinical promise and clinical application. This scoping review synthesized evidence from 500 preclinical and clinical studies, identified through systematic searches and screened in accordance with PRISMA-ScR guidelines. Data were extracted on stem cell type and source, delivery approach, targeted tissue and organ, and disease indication. We found that autologous bone marrow-derived mesenchymal stem cells were the most used, with adipose- and perinatal-derived cells gaining prominence in recent years. Small-animal models such as rats and rabbits predominated, while large-animal and human studies focused mainly on knee osteoarthritis. Intra-articular injection was the principal delivery method across both preclinical and clinical settings. By mapping prevailing practices and emerging trends, this review provides a comprehensive reference for researchers, clinicians, and regulatory stakeholders. It highlights translational pathways, identifies critical gaps, and offers evidence to guide the design of safe, effective, and scalable regenerative therapies in orthopedics.

Jiaxin Bai, Ning Li, Hua Ye et al.

Abstract Insufficient coverage of cervical cytology screening in resource-limited areas remains a major bottleneck for women’s health, as traditional centralized methods require significant investment and many qualified pathologists. Using consumer-grade electronic hardware and aspherical lenses, we design an ultra-low-cost and compact microscope. Given the microscope’s low resolution, which hinders accurate identification of lesion cells in cervical samples, we train a coarse instance classifier to screen and extract feature sequences of the top 200 instances containing potential lesions from a slide. We further develop Att-Transformer to focus on and integrate the sparse lesion information from these sequences, enabling slide grading. Our model is trained and validated using 3510 low-resolution slides from female patients at four hospitals, and subsequently evaluated on four independent datasets. The system achieves area under the receiver operating characteristic curve values of 0.87 and 0.89 for detecting squamous intraepithelial lesions on 364 slides from female patients at two external primary hospitals, 0.89 on 391 newly collected slides from female patients at the original four hospitals, and 0.85 on 570 human papillomavirus positive slides from female patients. These findings demonstrate the feasibility of our AI-assisted approach for effective detection of high-risk cervical precancer among women in resource-limited regions.

Chao Fang, Pan Ren, Yejun He et al.

Abstract Background Mitochondria play a crucial role in shaping the macrophage inflammatory response during bacterial infections. Spinster homolog 2 (Spns2), responsible for sphingosine-1-phosphate (S1P) secretion, acts as a key regulator of mitochondrial dynamics in macrophages. However, the link between Spns2/S1P signaling and mitochondrial functions remains unclear. Methods Peritoneal macrophages were isolated from both wild-type and Spns2 knockout rats, followed by non-targeted metabolomics and RNA sequencing analysis to identify the potential mediators through which Spns2/S1P signaling influences the mitochondrial functions in macrophages. Various agonists and antagonists were used to modulate the activation of Spns2/S1P signaling and its downstream pathways, with the underlying mechanisms elucidated through western blotting. Mitochondrial functions were assessed using flow cytometry and oxygen consumption assays, as well as morphological analysis. The impact on inflammatory response was validated through both in vitro and in vivo sepsis models, with the specific role of macrophage-expressed Spns2 in sepsis evaluated using Spns2 flox/flox Lyz2-Cre mice. Additionally, the regulation of mitochondrial functions by Spns2/S1P signaling was confirmed using THP-1 cells, a human monocyte-derived macrophage model. Results In this study, we unveil prostaglandin E2 (PGE2) as a pivotal mediator involved in Spns2/S1P-mitochondrial communication. Spns2/S1P signaling suppresses PGE2 production to support malate-aspartate shuttle activity. Conversely, excessive PGE2 resulting from Spns2 deficiency impairs mitochondrial respiration, leading to intracellular lactate accumulation and increased reactive oxygen species (ROS) generation through E-type prostanoid receptor 4 activation. The overactive lactate-ROS axis contributes to the early-phase hyperinflammation during infections. Prolonged exposure to elevated PGE2 due to Spns2 deficiency culminates in subsequent immunosuppression, underscoring the dual roles of PGE2 in inflammation throughout infections. The regulation of PGE2 production by Spns2/S1P signaling appears to depend on the coordinated activation of multiple S1P receptors rather than any single one. Conclusions These findings emphasize PGE2 as a key effector of Spns2/S1P signaling on mitochondrial dynamics in macrophages, elucidating the mechanisms through which Spns2/S1P signaling balances both early hyperinflammation and subsequent immunosuppression during bacterial infections.

Ilaria Petraroia, Patrizia Ghidotti, Giulia Bertolini et al.

Abstract Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.

Hui Sun, Xu Wang, Xin Wang et al.

Abstract Despite advances in anticancer therapy, the prognosis of gastric cancer (GC) remains unsatisfactory. Research in recent years has shown that the malignant behavior of cancer is not only attributable to tumor cells but is partly mediated by the activity of the cancer stroma and controlled by various molecular networks in the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are one of the most abundant mesenchymal cell components of the stroma and extensively participate in the malignant development of GC malignancy. CAFs modulate the biological properties of tumor cells in multiple ways, including the secretion of various bioactive molecules that have effects through paracrine and autocrine signaling, the release of exosomes, and direct interactions, thereby affecting GC initiation and development. However, there is marked heterogeneity in the cellular origins, phenotypes, and functions of CAFs in the TME of GC. Furthermore, variations in factors, such as proteins, microRNAs, and lncRNAs, affect interactions between CAFs and GC cells, although, the potential molecular mechanisms are still poorly understood. In this review, we aim to describe the current knowledge of the cellular features and heterogeneity of CAFs and discuss how these factors are regulated in CAFs, with a focus on how they affect GC biology. This review provides mechanistic insight that could inform therapeutic strategies and improve the prognosis of GC patients.

Ilias P. Nikas, Cheol Lee, Min Ji Song et al.

Abstract Background High‐grade serous ovarian carcinoma (HGSOC), the most common histologic subtype of ovarian epithelial cancer, is associated with treatment resistance, enhanced recurrence rates, and poor prognosis. HGSOCs often metastasize to the peritoneal cavity, while fluid cytology examination could identify such metastases. This retrospective study aimed to identify potential biomarker discrepancies between paired HGSOC primary tissues and metastatic peritoneal fluid cytology samples, processed as cell blocks (CBs). Methods Twenty‐four pairs of formalin‐fixed, paraffin‐embedded primary tissues and metastatic CBs from an equal number of treatment‐naïve patients were used, and immunohistochemistry (IHC) for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor, programmed cell death‐1 ligand 1 (PD‐L1), and CD147 was applied. Results 13/24 pairs showed discordant EGFR IHC results; in all these 13 patients, EGFR was positive (≥1+ membranous staining intensity found in at least 10% of the cancer cells) in the peritoneal, yet negative in the primary tissue samples. Notably, EGFR IHC was positive in 15/24 of the metastatic, whereas in just 2/24 of the primary HGSOC samples (p < 0.001). Although most PD‐L1 results were concordant, 5/24 and 6/24 pairs exhibited discordant results when stained with the E1L3N and 22C3 clones, respectively. Lastly, CD147 overexpression was found more often in the metastatic rather than the matched primary HGSOCs stained with CD147, though the difference was not significant. Conclusions Cytology from effusions could be considered for biomarker testing when present, even when tissue from the primary cancer is also available and adequately cellular, as it could provide additional information of potential clinical significance.

Pranab Dey

Sara Petillo, Cristina Capuano, Rosa Molfetta et al.

Abstract Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

Yat-Ping Tsui, Guy Lam, Kenneth Lap-Kei Wu et al.

Transplantation of oligodendrocyte precursors (OPs) is potentially therapeutic for myelin disorders but a safe and accessible cell source remains to be identified. Here we report a two-step protocol for derivation of highly enriched populations of OPs from bone marrow stromal cells of young adult rats (aMSCs). Neural progenitors among the aMSCs were expanded in non-adherent sphere-forming cultures and subsequently directed along the OP lineage with the use of glial-inducing growth factors. Immunocytochemical and flow cytometric analyses of these cells confirmed OP-like expression of Olig2, PDGFRα, NG2, and Sox10. OPs so derived formed compact myelin both in vitro, as in co-culture with purified neurons, and in vivo, following transplantation into the corpus callosum of neonatal shiverer mice. Not only did the density of myelinated axons in the corpus callosum of recipient shiverer mice reach levels comparable to those in age-matched wild-type mice, but the mean lifespan of recipient shiverer mice also far exceeded those of non-recipient shiverer mice. Our results thus promise progress in harnessing the OP-generating potential of aMSCs towards cell therapy for myelin disorders.

Yunxiang Zhou, Anwen Shao, Yihan Yao et al.

Abstract Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocyte-derived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporal-environment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies. Video Abstract

Zhi Lv, Liping Sun, Qian Xu et al.

Abstract Background N 6-methyladenosine (m6A) modification might be closely associated with the genesis and development of gastric cancer (GC). Currently, the evidence established by high-throughput assay for GC-related m6A patterns based on long non-coding RNAs (lncRNAs) remains limited. Here, a joint analysis of lncRNA m6A methylome and lncRNA/mRNA expression profiles in GC was performed to explore the regulatory roles of m6A modification in lncRNAs. Methods Three subjects with primary GC were enrolled in our study and paired sample was randomly selected from GC tissue and adjacent normal tissue for each case. Methylated RNA Immunoprecipitation NextGeneration Sequencing (MeRIP-Seq) and Microarray Gene Expression Profiling was subsequently performed. Then co-expression analysis and gene enrichment analysis were successively conducted. Results After data analysis, we identified 191 differentially m6A-methylated lncRNAs, 240 differentially expressed lncRNAs and 229 differentially expressed mRNAs in GC. Furthermore, four differentially m6A-methylated and expressed lncRNAs (dme-lncRNAs) were discovered including RASAL2-AS1, LINC00910, SNHG7 and LINC01105. Their potential target genes were explored by co-expression analysis. And gene enrichment analysis suggested that they might influence the cellular processes and biological behaviors involved in mitosis and cell cycle. The potential impacts of these targets on GC cells were further validated by CCLE database and literature review. Conclusions Four novel dme-lncRNAs were identified in GC, which might exert regulatory roles on GC cell proliferation. The present study would provide clues for the lncRNA m6A methylation-based research on GC epigenetic etiology and pathogenesis.

Jennifer B. Kwon, Adarsh R. Ettyreddy, Ashish Vankara et al.

Delivery of therapeutic transgenes with adeno-associated viral (AAV) vectors for treatment of myopathies has yielded encouraging results in animal models and early clinical studies. Although certain AAV serotypes efficiently target muscle fibers, transduction of the muscle stem cells, also known as satellite cells, is less studied. Here, we used a Pax7nGFP;Ai9 dual reporter mouse to quantify AAV transduction events in satellite cells. We assessed a panel of AAV serotypes for satellite cell tropism in the mdx mouse model of Duchenne muscular dystrophy and observed the highest satellite cell labeling with AAV9 following local or systemic administration. Subsequently, we used AAV9 to interrogate CRISPR/Cas9-mediated gene editing of satellite cells in the Pax7nGFP;mdx mouse. We quantified the level of gene editing using a Tn5 transposon-based method for unbiased sequencing of editing outcomes at the Dmd locus. We also found that muscle-specific promoters can drive transgene expression and gene editing in satellite cells. Lastly, to demonstrate the functionality of satellite cells edited at the Dmd locus by CRISPR in vivo, we performed a transplantation experiment and observed increased dystrophin-positive fibers in the recipient mouse. Collectively, our results confirm that satellite cells are transduced by AAV and can undergo gene editing to restore the dystrophin reading frame in the mdx mouse.

Gulnur Zhunussova, Gulnur Zhunussova, Gulnur Zhunussova et al.

Background: Colorectal cancer (CRC) incidence is rising worldwide, as well as in the Republic of Kazakhstan, while its occurrence is also increasing in the younger population. Hereditary forms associated with the development of colon and rectal cancer and early-onset CRC have never been studied in the population of Kazakhstan. The aim of this research was to investigate the spectrum of CRC-related gene mutations to determine which mutations cause early onset of CRC in the Kazakhstan population.Methods: The study included 125 unrelated patients from Kazakhstan (range 17–50 years in age) with early onset CRC. Genomic DNA was obtained from peripheral blood of the patients. Next-generation sequencing was performed using the TruSightCancer Kit on the MiSeq platform. The Studio Variant was used to annotate and interpret genetic variants.Results: Bioinformatics analysis of Next-generation sequencing data revealed 11,152 variants from 85 genes, of them, 3,790 missense, 6,254 synonymous variants, 44 3′UTR variants, 10 frameshift variants, five stop-gain variants, four in-frame deletions, two splice donors, one splice acceptor variant, and 1,042 intron or non-coding variants. APC, BRCA2/1, ALK, BRIP1, EGFR, FANCA, FANCD2, FANCI, HNF1A, MEN1, NSD1, PMS2, RECQL4, RET, SLX4, WRN, and XPC genes mutated most often. According to the ACMG guidelines and LOVD/ClinVar databases, 24 variants were pathogenic (10 frameshifts, five missenses, five stop-gain, one in-frame deletion, and three splice-site mutations), and 289 were VUS with population frequency &lt;1%, 131 of them were attributed as deleterious. In the study, 50% of all pathogenic mutations found in Kazakhstani patients with early CRC onset were identified in the subgroups with a family history of CRC and primary multiple tumors. In APC, pathogenic mutations were most often (21%).Conclusion: Pathogenic and likely pathogenic mutations were found in 20 (16%) out of 125 patients. Eight novel pathogenic mutations detected in FANCI, APC, BMPR1, ATM, and DICER1 genes have not been reported in previous literature. Given the high frequency and wide spectrum of mutations, NGS analysis must be carried out in families with a history of CRC/CRC-related cancers with the purpose to identify cause-effective mutations, clarify the clinical diagnosis, and prevent the development of the disease in other family members.

Lingyun Zhang, Yufeng He, Ximing Wu et al.

We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (&#8722;)-epigallocatechin-3-gallate (EGCG) in mice. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of p21. In human tongue cancer TCA8113 cells, melatonin-induced p21 and EGCG-mediated formation of quinoproteins were positively associated with the oncostatic effects of melatonin and EGCG. Melatonin-stimulated an increase in p21 which was correlated with a pronounced nuclear translocation of thioredoxin 1 and thioredoxin reductase 1, both of which are known to induce p21 via promoting p53 trans-activation. Melatonin did not influence the EGCG-mediated increase of quinoprotein formation nor did EGCG impair melatonin-induced p21 up-regulation. Co-treatment with both agents enhanced the cell-killing effect as well as the inhibitory activities against cell migration and colony formation. It is known that p21 also plays a powerful anti-apoptotic role in some cancer cells and confers these cells with a survival advantage, making it a target for therapeutic suppression. In human hepatocellular carcinoma HepG2 cells, melatonin suppressed p21 along with the induction of pro-survival proteins, PI3K and COX-2. However, EGCG prevented against melatonin-induced PI3K and COX-2, and melatonin probably sensitized HepG2 cells to EGCG cytotoxicity via down-regulating p21, Moreover, COX-2 and HO-1 were significantly reduced only by the co-treatment, and melatonin aided EGCG to achieve an increased inhibition on Bcl2 and NF&#954;B. These events occurring in the co-treatment collectively resulted in an enhanced cytotoxicity. In addition, the co-treatment also enhanced the inhibitory activities against cell migration and colony formation. Overall, the results gathered from these two cancer cell lines with a divergent p21 response to melatonin show that the various oncostatic activities of melatonin and EGCG together are more robust than each agent alone, suggesting that they may be useful partners in fighting cancer.

Aleksandra Salvador Ribeiro, Carla Tereza Ruiz Cerqueira

Introdução: a criptococose é uma micose sistêmica que possui como agente etiológico o fungo Criptococcus neoformans, nas variedades neoformans (o agente etiológico principal) e gatti. A infecção primária ocorre nos pulmões a partir da inalação do patógeno (via de transmissão inalatória), acometendo principalmente indivíduos imunodeprimidos, podendo se apresentar de maneira assintomática ou sob a forma meningoencefálica (apresentação mais comum) e com acometimento pulmonar (segunda forma mais comum). Relato de caso: o paciente apresentou, inicialmente, queixas neurológicas associadas a um achado incidental de formação cística pulmonar, culminando com posterior achado de calcificação nodular cerebral e suspeita diagnóstica de neoplasia cerebral metastatizada em sítios pulmonares. A suspeita foi descartada após a realização da citologia de líquido biológico e exame anátomo patológico de um nódulo pulmonar que confirmaram o diagnóstico de criptococose. O tratamento foi realizado com Fluconazol por seis meses havendo melhora do quadro radiológico e sintomatológico da doença. Discussão: há relação comprovada entre a criptococose e os excrementos de aves ricos em nitrogênio, principalmente de pombos, que atuam como vetor principal do fungo, e o paciente descrito relata que um mês antes do início das manifestações da doença, esteve em contatos íntimos com as aves. Conclusão: o relato de caso ilustra a incidência da criptococose na população de menor prevalência da doença e revela a importância do diagnóstico clínico correto nesses pacientes, pois ela pode se revelar como um desafio diagnóstico, o que incentiva posteriores estudos para sua melhor compreensão. Palavras chave: criptococose, neoplasia, diagnóstico, desafio. ABSTRACT Introduction: cryptococcosis is a systemic mycosis that has the etiological agent Cryptococcus neoformans, in the varieties neoformans (the main etiological agent) and gatti. Primary infection occurs in the lungs from the inhalation of the pathogen (inhalation transmission route), affecting mainly immunocompromised individuals and may present asymptomatic or meningoencephalic (most common presentation) and pulmonary involvement (second most common form). Case report: the patient initially presented neurological complaints associated with an incidental finding of pulmonary cystic formation, culminating with later finding of cerebral nodular calcification and suspected diagnosis of metastatic cerebral neoplasm in lung sites. The suspicion was discarded after performing the cytology of biological fluid and anatomical pathological examination of a pulmonary nodule that confirmed the diagnosis of cryptococcosis. The treatment was performed with Fluconazole for six months, with an improvement in the radiological and symptomatic picture of the disease. Discussion: there is a proven relationship between cryptococcosis and excrements of birds rich in nitrogen, mainly pigeons, which act as the main vector of the fungus, and the described patient reports that one month before the onset of the disease, he was in intimate contact with the birds. Conclusion: the case report illustrates the incidence of cryptococcosis in the population with the lowest prevalence of the disease and reveals the importance of the correct clinical diagnosis in these patients, because it can be a diagnostic challenge, which encourages further studies for better understanding.

Robin Lüling, Harald John, Thomas Gudermann et al.

The chemosensory transient receptor potential ankyrin 1 (TRPA1) ion channel perceives different sensory stimuli. It also interacts with reactive exogenous compounds including the chemical warfare agent sulfur mustard (SM). Activation of TRPA1 by SM results in elevation of intracellular calcium levels but the cellular consequences are not understood so far. In the present study we analyzed SM-induced and TRPA1-mediated effects in human TRPA1-overexpressing HEK cells (HEKA1) and human lung epithelial cells (A549) that endogenously exhibit TRPA1. The specific TRPA1 inhibitor AP18 was used to distinguish between SM-induced and TRPA1-mediated or TRPA1-independent effects. Cells were exposed to 600 &micro;M SM and proteome changes were investigated 24 h afterwards by 2D gel electrophoresis. Protein spots with differential staining levels were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and nano liquid chromatography electrospray ionization tandem mass spectrometry. Results were verified by RT-qPCR experiments in both HEKA1 or A549 cells. Heat shock 70 kDa protein 6 (HSPA6) was identified as an SM-induced and TRPA1-mediated protein. AP18 pre-treatment diminished the up-regulation. RT-qPCR measurements verified these results and further revealed a time-dependent regulation. Our results demonstrate that SM-mediated activation of TRPA1 influences the protein expression and confirm the important role of TRPA1 ion channels in the molecular toxicology of SM.

Alice Barateau, Nathalie Vadrot, Onnik Agbulut et al.

Specific mutations in LMNA, which encodes nuclear intermediate filament proteins lamins A/C, affect skeletal muscle tissues. Early-onset LMNA myopathies reveal different alterations of muscle fibers, including fiber type disproportion or prominent dystrophic and/or inflammatory changes. Recently, we identified the p.R388P LMNA mutation as responsible for congenital muscular dystrophy (L-CMD) and lipodystrophy. Here, we asked whether viral-mediated expression of mutant lamin A in murine skeletal muscles would be a pertinent model to reveal specific muscle alterations. We found that the total amount and size of muscle fibers as well as the extent of either inflammation or muscle regeneration were similar to wildtype or mutant lamin A. In contrast, the amount of fast oxidative muscle fibers containing myosin heavy chain IIA was lower upon expression of mutant lamin A, in correlation with lower expression of genes encoding transcription factors MEF2C and MyoD. These data validate this in vivo model for highlighting distinct muscle phenotypes associated with different lamin contexts. Additionally, the data suggest that alteration of muscle fiber type identity may contribute to the mechanisms underlying physiopathology of L-CMD related to R388P mutant lamin A.

Haiyang Zhang, Jingjing Duan, Yanjun Qu et al.

ABSTRACT Gastric cancer is one of the most common malignancies worldwide; however, the molecular mechanism in tumorigenesis still needs exploration. BCL2L11 belongs to the BCL-2 family, and acts as a central regulator of the intrinsic apoptotic cascade and mediates cell apoptosis. Although miRNAs have been reported to be involved in each stage of cancer development, the role of miR-24 in GC has not been reported yet. In the present study, miR-24 was found to be up-regulated while the expression of BCL2L11 was inhibited in tumor tissues of GC. Studies from both in vitro and in vivo shown that miR-24 regulates BCL2L11 expression by directly binding with 3′UTR of mRNA, thus promoting cell growth, migration while inhibiting cell apoptosis. Therefore, miR-24 is a novel onco-miRNA that can be potential drug targets for future clinical use.

Kebkalo А., Reyti A.

Introduction. Doctors of various specialties – endocrinologists, endocrine surgeons, oncologists – pay much attention to the choice of tactics of treatment of small focal forms of thyroid gland. However, despite the tangible progress, the transition to a molecular or genetic level of the diagnosis is a reality of the next decades, but today we should not underestimate the need to improve the existing diagnostic methods. Aim. To find out the informativeness of preoperative examinations and causes of diagnostic errors in patients with thyroid nodes ≤ 1.0 cm. Materials and methods. A retrospective analysis of information from out-patient cards, history of diseases and protocols of operations of randomly selected 1 266 patients operated on thyroid lesions (thyroid nodules up to 1.0 cm) in the surgical department of the Kyiv Regional Clinical Hospital N 1 in 2009-2014 was conducted. The results of the pathomorphological, cytological and ultrasound findings were compared, the sensitivity and specificity of the ultrasound examination and the fine needle aspiration biopsy using the ultasound in a diagnosis of the subsantimetric thyroid nodes, including microcarcinoma were evaluated. The frequency of the erroneous results of the histological and ultrasound diagnostics of the thyroid microcarcinoma were determined. Results. Sensitivity and specificity of commonly used diagnostic methods of thyroid ultrasonography and thyroid gland with the following cytological examination are 73.9, 79.5 and 71.9 and 83.9% respectively, and therefore can not be applied separately for the verification of small thyroid glands. The reason for the diagnostic errors, in our opinion, in each case is a separate, rather than a comprehensive analysis of the results of the survey. Obtaining the informative material from the patients with the nodes less than 1 cm in diameter in the thyroid gland, depends on the concerted actions of the doctor of ultrasound and the surgeon, as well as the correct choice of nodes, which need to point out first. Conclusions. Today, for the early diagnosis of thyroid cancer in sub-arterial nodes, a comprehensive evaluation of the results of ultrasound scans and an aiming thin-blooded aspiration biopsy with the subsequent cytological study of the material are most optimal.

V. S. Yusov, M. G. Evdokimov, B. M. Tatina

The variability of combining ability depending on growing conditions was studied in spring durum wheat varieties in a topcross system. It was found that the manifestation of the traits under study was determined by additive effects of genes and general combination ability variances were most susceptible to environmental conditions.