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Aim: The therapeutic targeting of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors in cancer, including non-small cell lung cancer (NSCLC), is a widely studied approach for tumor selective apoptotic cell death therapy. However, apoptosis resistance is often encountered. The main aim of this study was to investigate the apoptotic mechanism underlying TRAIL sensitivity in three bortezomib (BTZ)-resistant NSCLC variants, combining induction of both the intrinsic and extrinsic pathways. Methods: Sensitivity to TRAIL in BTZ-resistant variants was determined using a tetrazolium (MTT) and a clonogenic assay. A RT-qPCR profiling mRNA array was used to determine apoptosis pathway-specific gene expression. The expression of these proteins was determined through ELISA assays and western Blotting, while apoptosis (sub-G1) and cytokine expression were determined using flow cytometry. Apoptotic genes were silenced by specific siRNAs. Lipid rafts were isolated with fractional ultracentrifugation. Results: A549BTZR (BTZ-resistant) cells were sensitive to TRAIL in contrast to parental A549 cells, which are resistant to TRAIL. TRAIL-sensitive H460 cells remained equally sensitive for TRAIL as H460BTZR. In A549BTZR cells, we identified an increased mRNA expression of TNFRSF11B [osteoprotegerin (OPG)] and caspase-1, -4 and -5 mRNAs involved in cytokine activation and immunogenic cell death. Although the OPG, interleukin-6 (IL-6), and interleukin-8 (IL-8) protein levels were markedly enhanced (122-, 103-, and 11-fold, respectively) in the A549BTZR cells, this was not sufficient to trigger TRAIL-induced apoptosis in the parental A549 cells. Regarding the extrinsic apoptotic pathway, the A549BTZR cells showed TRAIL-R1-dependent TRAIL sensitivity. The shift of TRAIL-R1 from non-lipid into lipid rafts enhanced TRAIL-induced apoptosis. In the intrinsic apoptotic pathway, a strong increase in the mRNA and protein levels of the anti-apoptotic myeloid leukemia cell differentiation protein (Mcl-1) and B-cell leukemia/lymphoma 2 (Bcl-2) was found, whereas the B-cell lymphoma-extra large (Bcl-xL) expression was reduced. However, the stable overexpression of Bcl-xL in the A549BTZR cells did not reverse the TRAIL sensitivity in the A549BTZR cells, but silencing of the BH3 Interacting Domain Death Agonist (BID) protein demonstrated the importance of the intrinsic apoptotic pathway, regardless of Bcl-xL. Conclusion: In summary, increased sensitivity to TRAIL-R1 seems predominantly related to the relocalization into lipid rafts and increased extrinsic and intrinsic apoptotic pathways.
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Background and Purpose: Radiation-induced lymphopenia (RIL) is a common side effect of radiotherapy (RT) that may negatively impact survival. We aimed to identify RIL predictors in patients with non-small-cell lung cancer (NSCLC) treated intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Materials and Methods: We retrospectively analysed data of 306 patients who underwent radical RT for NSCLC. Absolute lymphocyte count (ALC) loss was evaluated for each patient by fitting an exponential decay curve to data from first 45 days since treatment start, and percentage ALC loss relative to baseline was calculated based on area under the decay curve and baseline ALC. We compared IMRT and VMAT treatment plans and used linear regression to predict ALC loss. Results: ALC decreased during RT in the whole patient group, while neutrophil counts remained stable and decreased only in those treated with concurrent chemoradiotherapy (CRT). Percentage ALC loss ranged between 11 and 78 % and was more strongly than lymphocyte nadir correlated with dose-volume metrics for relevant normal structures. We found evidence for the association of high radiation dose to the lungs, heart and body with percentage ALC loss, with lung volume exposed to 20-30 Gy being most important predictors in patients treated with IMRT. A multivariable model based on CRT use, baseline ALC and first principal component (PC1) of the dose-volume predictors showed good predictive performance (bias-corrected R2 of 0.40). Conclusion: Percentage lymphocyte loss is a robust measure of RIL that is predicted by baseline ALC, CRT use and dose-volume parameters to the lungs, heart and body.
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Introduction: Recent years, microbiota-associated aspects have been analysed in multiple disorders regarding cancers. Existing evidence pints that gut microorganisms might take part in tumour origin and therapy efficacy. Nevertheless, to date, data on faecal metabolomics in cancer patients is still strongly limited. Therefore, we aimed to analyse gut untargeted metabolome in gastrointestinal cancer patients (i.e., gastric and colorectal cancer). Patients and methods: There were 12 patients with either gastric (n=4) or colorectal cancer (n=8) enrolled and 8 analysed (n=4 each). Stool samples were collected prior to anti-cancer treatments. Untargeted metabolomics analyses were conducted by means of mass spectrometry. Results: A plethora of metabolites in cancer patients we analysed were noted, with higher homogenity in case of gastric cancer patients. We found that the level of Deoxyguanosine,m/z 266.091,[M-H]-, Uridine,m/z 245.075,[M+H]+, Deoxyguanosine,m/z 268.104,[M]+, 3-Indoleacetic acid,m/z 176.07,[M+H]+, Indoxyl,m/z 132.031,[M-H]-, L-Phenylalanine,m/z 164.073,[M-H]-, L-Methionine,m/z 150.058,[M+NH4]+, was significantly higher in colorectal cancer patients and Ethyl hydrogen malonate,m/z 133.031,[M+H]+ in gastric cancer. Conclusion: The overall insights into untargeted metabolomics showed that most often higher levels of analysed metabolites were detected in colorectal cancer patients compared to gastric cancer patients. The link between gut metabolome and both local and distal metastasis might exist, however it requires confirmation in further multi-centre studies regarding larger sample size.
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Neoplasias Colorretais , Fezes , Microbioma Gastrointestinal , Metaboloma , Metabolômica , Neoplasias Gástricas , Humanos , Neoplasias Colorretais/metabolismo , Metabolômica/métodos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Masculino , Fezes/química , Fezes/microbiologia , Feminino , Pessoa de Meia-Idade , Idoso , Espectrometria de MassasRESUMO
Head and neck squamous cell carcinoma (HNSCC) exhibits significant genetic heterogeneity and primarily concerns the oral cavity and oropharynx. These cancers occur more frequently in men with a 5-year survival rate below 50%. Major risk factors include human papilloma virus (HPV) (notably type 16), Epstein-Barr virus, tobacco, alcohol, and poor oral hygiene with approximately 4.5% of global cancers linked to HPV. Notably, differences in the microbiome between healthy individuals and patients with head and neck cancers (HNCs) have been identified. Recent studies highlight the significance of certain oral microbes in risk assessment and the potential of the microbiome as a biomarker for HNCs. Additionally, role of the microbiome in metastasis has been acknowledged. Treatment for HNCs includes local methods, such as surgery and radiotherapy, and systemic approaches, such as immunotherapy. Numerous side effects accompany these treatments. Emerging research suggests the beneficial role of preoperative immunonutrition and probiotics in patient outcomes, emphasizing the influence of the microbiome on treatment efficacy. This review explores the reciprocal effects of HNC treatment and the gut microbiome using radiotherapy, brachytherapy, surgery, immunotherapy, and chemotherapy.
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Infecções por Vírus Epstein-Barr , Neoplasias de Cabeça e Pescoço , Microbiota , Infecções por Papillomavirus , Masculino , Humanos , Herpesvirus Humano 4 , Neoplasias de Cabeça e Pescoço/terapiaRESUMO
Intestinal bacteria are equipped with an enzyme apparatus that is involved in the active biotransformation of xenobiotics, including drugs. Pharmacomicrobiomics, a new area of pharmacology, analyses interactions between bacteria and xenobiotics. However, there is another side to the coin. Pharmacotherapeutic agents can significantly modify the microbiota, which consequently affects their efficacy. In this review, we comprehensively gathered scientific evidence on the interplay between anticancer therapies and gut microbes. We also underlined how such interactions might impact the host response to a given therapy. We discuss the possibility of modulating the gut microbiota to increase the effectiveness/decrease the incidence of adverse events during tumor therapy. The anticipation of the future brings new evidence that gut microbiota is a target of interest to increase the efficacy of therapy.
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Antineoplásicos , Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Microbioma Gastrointestinal/fisiologia , Medicina de Precisão , Neoplasias/microbiologia , Antineoplásicos/efeitos adversos , Microbiota/fisiologiaRESUMO
Despite tremendous progress in cancer treatment in recent years, treatment resistance is still a major challenge for a great number of patients. One of the main causes is regulatory T lymphocytes (Tregs), which suppress excessive inflammatory responses via the secretion of immunosuppressive cytokines and upregulate the immune checkpoints. Their abundance causes an immunosuppressive reprogramming of the tumor environment, which is ideal for tumor growth and drug inefficiency. Hence, regiments that can regain tumor immunogenicity are a promising strategy to overcome Tregs-mediated drug resistance. However, to develop effective therapeutic regimens, it is essential to understand the molecular mechanisms of Treg-mediated resistance. In this article, we gathered a comprehensive summary of the current knowledge on molecular mechanisms and the role of Tregs in cancer treatment resistance, including cancer immunotherapy, targeted therapy, chemotherapy, and radiotherapy.
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Neoplasias , Radioterapia (Especialidade) , Humanos , Linfócitos T Reguladores , Imunoterapia , Citocinas , Imunossupressores , Neoplasias/terapiaRESUMO
The gut microbiome has been increasingly understood to play a critical role in carcinogenesis and cancer disease progression. The most recent research advancements have shown that different tools of microbiota manipulation contribute to gut microbiome-immune-oncology axis modulation, offering exciting opportunities for targeted interventions aimed at improving the efficacy of established anti-cancer therapy. Postbiotics are a new entry among the biotics showing beneficial effects on human health while not requiring living cells to obtain the health effect and therefore not subjected to food safety rules for live microorganisms. Postbiotics are recently defined as the "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host" and have gradually become the focus of the scientific community. Since the beginning of research on this topic, numerous studies about postbiotics have been proven to strengthen the gut barrier, reduce inflammation, and promote antimicrobial activity. However, research on the potential application of cancer therapy is still at the early stages of its efforts to uncover all the secrets surrounding postbiotics. This review aims to increase our understanding of the anti-cancer effect of postbiotics throughout a "bibliographic journey" on the biological activity of their components, including exopolysaccharides, cell wall fragments, tryptophan metabolites, enzymes, bacterial lysates, extracellular vesicles, and short-chain fatty acids, highlighting their perspective as a new supportive therapeutic method of treatment and identifying the literature gaps where further research is needed.
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Despite a great success of immunotherapy in cancer treatment, a great number of patients will become resistant. This review summarizes recent reports on immune checkpoint inhibitor retreatment or rechallenge in order to overcome primary resistance. The systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was performed using PubMed, Web of Science and Scopus. In total, 31 articles were included with a total of 812 patients. There were 16 retreatment studies and 13 rechallenge studies. We identified 15 studies in which at least one parameter (overall response rate or disease control rate) improved or was stable at secondary treatment. Interval treatment, primary response to and the cause of cessation for the first immune checkpoint inhibitors seem to be promising predictors of secondary response. However, high heterogeneity of investigated cohorts and lack of reporting guidelines are limiting factors for current in-depth analysis.
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Microbiome is a keystone polymicrobial community that coexist with human body in a beneficial relationship. These microorganisms enable the human body to maintain homeostasis and take part in mechanisms of defense against infection and in the absorption of nutrients. Even though microbiome is involved in physiologic processes that are beneficial to host health, it may also cause serious detrimental issues. Additionally, it has been proven that bacteria can migrate to other human body compartments and colonize them even although significant structural differences with the area of origin exist. Such migrations have been clearly observed when the causes of genesis and progression of colorectal cancer (CRC) have been investigated. It has been demonstrated that the oral microbiome is capable of penetrating into the large intestine and cause impairments leading to dysbiosis and stimulation of cancerogenic processes. The main actors of such events seem to be oral pathogenic bacteria belonging to the red and orange complex (regarding classification of bacteria in the context of periodontal diseases), such as Porphyromonas gingivalis and Fusobacterium nucleatum respectively, which are characterized by significant amount of cancerogenic virulence factors. Further examination of oral microbiome and its impact on CRC may be crucial on early detection of this disease and would allow its use as a precise non-invasive biomarker.
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Neoplasias Colorretais , Microbiota , Doenças Periodontais , Humanos , Doenças Periodontais/microbiologia , Porphyromonas gingivalis , Fatores de Virulência , Fusobacterium nucleatumRESUMO
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer in the world. Despite its prevalence, it is often recognized in advanced stages (III or IV) when it has already spread to local lymph nodes. In this study, we investigate the V-domain Ig suppressor of T cell activation (VISTA) as a potential prognostic factor in OSCC. Tissue samples were collected from 71 oral squamous cell carcinoma patients to determine protein expression levels (using immunochemistry and the semi-quantitative H-score method). Moreover, RT-qPCR was additionally performed in 35 patients. Clinical factors in our cohort study had no impact on VISTA expression. However, VISTA expression is largely correlated with Il-33 levels in tumor cells and lymphocytes and with PD-L1 in tumor cells. The impact of VISTA expression on overall survival (OS) is rather limited, but in the case of a 5-year survival rate, a significant association has been proven. VISTA seems to be a rather weak clinicopathological marker but needs further evaluation in the context of survival. In addition, the potential of VISTA combination with Il-33 or PD-L1 should be further investigated in OSCC.
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There is an urgent need to search for new screening methods that allow early detection of esophageal cancer and thus achieve better clinical outcomes. Nowadays, it is known that the esophagus is not a sterile part of the gastrointestinal tract. It is colonized with various microorganisms therefore a "healthy" esophageal microbiome exists. The dysbiotic changes of esophageal microbiome can lead to the development of esophageal diseases including esophageal cancer. There is a strong consensus in the literature that the intestinal microbiome may be involved in esophageal carcinogenesis. Recently, emphasis has also been placed on the relationship between the oral microbiome and the occurrence of esophageal cancer. According to recent studies, some of the bacteria present in the oral cavity, such as Tannerella forsythia, Streptococcus anginosus, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Fusobacterium nucleatum may contribute to the development of this cancer. Moreover, the oral microbiome of patients with esophageal cancer differs significantly from that of healthy individuals. This opens new insights into the search for a microbiome-associated marker for early identification of patients at high risk for developing this cancer.
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Neoplasias Esofágicas , Microbioma Gastrointestinal , Microbiota , Humanos , Neoplasias Esofágicas/diagnóstico , Fusobacterium nucleatum , BocaRESUMO
Paraganglioma and pheochromocytoma are rare medical conditions. Thus, there are still a small number of studies, clinical trials, and evidence-based data in this field. This makes clinical decisions more difficult. In this study, we present a case report enriched with a short review of available essential clinical data, indicating the need for constant metoxycatecholamine level observation and a proper diagnostic imaging approach, especially in terms of ongoing pandemics. Our research also provides a summary of the molecular background of these diseases, indicating their future role in clinical management. We analyzed the ClinicalTrials.gov dataset in order to show future perspectives. In this paper, the use of the PET-CT before MRI or CT is proposed in specific cases during diagnosis processes contrary to the guidelines. PET-CT may be as effective as standard procedures and may provide a faster diagnosis, which is important in periods with more difficult access to health care, such as during the COVID-19 pandemic.
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Periodontal disease (PD) is one of the most common oral conditions affecting both youths and adults. There are some research works suggesting a high incidence of PD in pregnant women. As an inflammatory disease of bacterial origin, PD may result in the activation of the pathways affecting the course and the pregnancy outcome. The authors, based on the literature review, try to answer the PICO question: Does maternal periodontitis (exposure) influence the incidence of complications rates in pregnancy and the development of systemic diseases in childhood and adult offspring (outcome) in the humans of any race (population) compared to the offspring of mothers with healthy periodontium (comparison)? The authors try to describe the molecular pathways and mechanisms of these interdependencies. There is some evidence that maternal periodontitis may affect the pregnancy course and outcome, resulting in preeclampsia, preterm delivery, vulvovaginitis and low birth weight. It can be suggested that maternal periodontitis may affect offspring epigenome and result in some health consequences in their adult life.
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Doenças Periodontais , Periodontite , Nascimento Prematuro , Adolescente , Adulto , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Doenças Periodontais/complicações , Periodontite/complicações , Periodontite/epidemiologia , Gravidez , Resultado da Gravidez , Nascimento Prematuro/etiologiaRESUMO
Kienböck's disease is a rare disease described as progressive avascular osteonecrosis of the lunate. The typical manifestations include a unilateral reduction in wrist motion with accompanying pain and swelling. Besides recent advances in treatment options, the etiology and pathophysiology of the disease remain poorly understood. Common risk factors include anatomical features including ulnar variance, differences in blood supply, increased intraosseous pressure along with direct trauma, and environmental influence. The staging of Kienböck's disease depends mainly on radiographic characteristics assessed according to the modified Lichtman scale. The selection of treatment options is often challenging, as radiographic features may not correspond directly to initial clinical symptoms and differ among age groups. At the earliest stages of Kienböck disease, the nonoperative, unloading management is generally preferred. Patients with negative ulnar variance are usually treated with radial shortening osteotomy. For patients with positive or neutral ulnar variance, a capitate shortening osteotomy is a recommended option. One of the most recent surgical techniques used in Stage III Kienböck cases is vascularized bone grafting. One of the most promising procedures is a vascularized, pedicled, scaphoid graft combined with partial radioscaphoid arthrodesis. This technique provides excellent pain management and prevents carpal collapse. In stage IV, salvage procedures including total wrist fusion or total wrist arthroplasty are often required.
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More than 500,000 new cases of head and neck cancer (HNC) occur each year worldwide [...].
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Periodontitis is prevalent in half of the adult population and raises critical health concerns as it has been recently associated with an increased risk of cancer. While information about the topic remains somewhat scarce, a deeper understanding of the underlying mechanistic pathways promoting neoplasia in periodontitis patients is of fundamental importance. This manuscript presents the literature as well as a panel of tables and figures on the molecular mechanisms of Porphyromonas gingivalis and Fusobacterium nucleatum, two main oral pathogens in periodontitis pathology, involved in instigating tumorigenesis. We also present evidence for potential links between the RANKL-RANK signaling axis as well as circulating cytokines/leukocytes and carcinogenesis. Due to the nonconclusive data associating periodontitis and cancer reported in the case and cohort studies, we examine clinical trials relevant to the topic and summarize their outcome.
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Neoplasias Bucais/microbiologia , Doenças Periodontais/microbiologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Citocinas/metabolismo , Progressão da Doença , Fusobacterium nucleatum/patogenicidade , Regulação da Expressão Gênica , Humanos , Neoplasias Bucais/metabolismo , Doenças Periodontais/metabolismo , Porphyromonas gingivalis/patogenicidade , Transdução de SinaisRESUMO
Gut microbiota plays a significant role in the human body providing many beneficial effects on the host. However, its dysbiotic alterations may affect the tumorigenic pathway and then trigger the development of pancreatic cancer. This dysbiosis can also modulate the aggressiveness of the tumor, influencing the microenvironment. Because pancreatic cancer is still one of the most lethal cancers worldwide with surgery as the only method that influences prognosis and has curative potential, there is a need to search for other strategies which will enhance the efficiency of standard therapy and improve patients' quality of life. The administration of prebiotics, probiotics, next-generation probiotics (Faecalibacterium prausnitzii, Akkermansia muciniphila), synbiotics, postbiotics, and fecal microbiota transplantation through multiple mechanisms affects the composition of the gut microbiota and may restore its balance. Despite limited data, some studies indicate that the aforementioned methods may allow to achieve better effect of pancreatic cancer treatment and improve therapeutic strategies for pancreatic cancer patients.
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Disbiose/terapia , Microbioma Gastrointestinal , Neoplasias Pancreáticas/microbiologia , Disbiose/microbiologia , Transplante de Microbiota Fecal , Humanos , Prebióticos/administração & dosagem , Probióticos/uso terapêutico , Simbióticos/administração & dosagem , Microambiente TumoralRESUMO
Nowadays, allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy that is mainly recommended for hematologic malignancies. However, complications (such as graft-versus-host disease, mucositis, disease relapse, and infections) associated with the HSCT procedure contribute to the development of gut microbiota imbalance, gut-barrier disruption, and increased intestinal permeability. In the present narrative review, the crosstalk between gut microbiota products and intestinal homeostasis is discussed. Notably, gut-microbiota-related aspects have an impact on patients' clinical outcomes and overall survival. In accordance with the most recent published data, gut microbiota is crucial for the treatment effectiveness of many diseases, not only gastrointestinal cancers but also hematologic malignancies. Therefore, it is necessary to indicate a therapeutic method allowing to modulate gut microbiota in HSCT recipients. Currently, fecal microbiota transplantation (FMT) is the most innovative method used to alter/restore gut microbiota composition, as well as modulate its activity. Despite the fact that some previous data have shown promising results, the knowledge regarding FMT in HSCT is still strongly limited, except for the treatment of Clostridium difficile infection. Additionally, administration of prebiotics, probiotics, synbiotics, and postbiotics can also modify gut microbiota; however, this strategy should be considered carefully due to the high risk of fungemia/septicemia (especially in case of fungal probiotics).
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Dental implants are, nowadays, established surgical devices for the restoration of lost teeth. Considered as an alternative for traditional prosthetic appliances, dental implants surpass them in reliability and patient feedback. Local drug delivery around the implants promotes osseointegration and reduces peri-implantitis. However, there are currently no methods of a multiple, precise topical administration of drugs to the implant area. Engineering coatings on the implants, drug application on carriers during implantation, or gingival pockets do not meet all requirements of dental surgeons. Therefore, there is a need to create porous implants and other medical devices that will allow a multiple drug delivery at a controlled dose and release profile without traumatic treatment. Due to the growing demand for the use of biologically active agents to support dental implant treatment at its various stages (implant placement, long-term use of dental superstructures, treatment of the peri-implant conditions) and due to the proven effectiveness of the topical application of pharmacological biologically active agents to the implant area, the authors would like to present a review and show the methods and devices that can be used by clinicians for local drug administration to facilitate dental implant treatment. Our review concludes that there is a need for research in the field of inventions such as new medical devices or implants with gradient solid-porous structures. These devices, in the future, will enable to perform repeatable, controllable, atraumatic, and repeatable injections of active factors that may affect the improvement of osteointegration and the longer survival of implants, as well as the treatment of peri-implantitis.
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ZNF-281 is a zinc finger factor which can lead to cancer progression and metastasis. Its up-regulation reported in many cancers was correlated with metastasis and worsened patients' prognosis. This is the first study describing ZNF-281 in the context of OSCC. Oral tissue samples drawn from 66 OSCC patients and 36 control patients were collected to determine protein (using immunochemistry and the semi-quantitative H-score method) and mRNA expression levels (using the RT-qPCR reaction). Our aim was to assess the ZNF-281 expression level in OSCC and the control group. Moreover, we determined the impact of ZNF-281 on survival parameters and the association of diversified clinical parameters with ZNF-281 expression. Clinical factors such as grade, AJCC stage and radiotherapy have an impact on the ZNF-281 H-score level, whereas AJCC stage and grade have an influence on ZNF-281 mRNA expression. Our survival analysis indicated that the impact on overall survival is not statistically significant, and the prognostic potential of ZNF-281 is rather limited. Our findings show that both levels of the ZNF-281 H-score and mRNA are decreased in OSCC in comparison to normal tissue. Moreover, we estimated that the H-score can differentiate normal tissue from OSCC with a sensitivity of 97% and specificity of 93.7%.