BRIEF REPORT | doi:10.20944/preprints202111.0392.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: oral leukoplakia; Bayesian Networks; malignant transformation
Online: 22 November 2021 (13:05:31 CET)
Oral squamous cell carcinoma often arises from an oral potentially malignant disorder called oral leukoplakia (OL). With this work we aimed to develop a novel data-driven predictive model based on gene expression profiles to distinguish OL patients who underwent malignant transformation from those who did not. We used the Tree Augmented Naïve (TAN) Bayes classifier to predict the posterior probability of having oral cancer given the data. 86 patients were included with a median follow-up of 7.11 years. Fifty-one patients (51/86; 59%) underwent malignant transformation. We found that 16 genes were predictors of oral cancer in patients with OL and these included SLC7A11, SPINK6, SERPINA12, VIT, ATP1B3, CST6, FLRT2, ELMOD1, AZGP1, RNASE13, DIO2, ECM1, CYP4F11, SYTL4, AKR1C1, and AKR1C3. In conclusion, we showed that Bayesian gene networks are a data-driven approach which could be used also in other predictor models in oncology.
ARTICLE | doi:10.20944/preprints202104.0573.v1
Subject: Engineering, Automotive Engineering Keywords: fluorescence microscopy; fluorescence emission, malignant tumor, diagnosis, animal experiment
Online: 21 April 2021 (11:47:14 CEST)
A surgical microscope is large in size, which makes it impossible to be portable. The distance between the surgical microscope and the observation tissue is 15–30 cm, and the adjustment range of the right and left of the camera is a maximum of 30°. Therefore, the surgical microscope is generated attenuation (above 58%) of irradiation optical source owing to the long working distance. Moreover, the observation of tissue is affected because of dazzling by ambient light as the optical source power is strong (55 to 160 mW/cm2). Further, observation blind spot phenomena will occur due to the limitations in adjusting the right and left of the camera. Therefore, it is difficult to clearly observe the tumor. In this study, a compact pen-type probe with a portable surgical microscope is presented. The proposed surgical microscope comprises a small and portable pen-type probe that can adjust the working distance between the probe and the observed tissue. In addition, it allows the adjustment of the viewing angle and fluorescence brightness. The proposed probe has no blind spots or optical density loss.
ARTICLE | doi:10.20944/preprints202104.0557.v1
Subject: Engineering, Automotive Engineering Keywords: fluorescence microscopy; fluorescence emission; malignant tumor; diagnosis; animal experiment
Online: 21 April 2021 (08:30:11 CEST)
A surgical microscope is large in size, making portability impossible. The distance between the surgical microscope and the observation tissue is 15 to 30 cm, while the maximum adjustment range of the camera to the right and left is 30°. Therefore, surgical microscopes cause attenuation (above 58%) of the irradiation optical source owing to the long working distance. Moreover, the observation of tissue was dazzled with ambient light because the optical power source was strong (50 to 160 mW/cm2). Owing to the limited ability to adjust the camera to the right and left, a blind spot occurs with a surgical microscope. Therefore, it is difficult to clearly observe a tumor. In this study, a compact pen-type probe with a portable surgical microscope is proposed. The pen-type probe is small with a portable shape, and is capable of adjusting the working distance between itself and the observed tissue. It is also possible to adjust the viewing angle and fluorescence brightness. The proposed pen-type probe has no blind spots or optical density loss.
ARTICLE | doi:10.20944/preprints202010.0624.v1
Subject: Medicine & Pharmacology, Allergology Keywords: medical record systems; cutaneous malignant melanoma; survival analysis; immunotherapy
Online: 29 October 2020 (16:02:44 CET)
Background: Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained. Methods: CNMR collects data of patients with a histologically confirmed diagnosis of primary CMM treated in one of the 38 Italian institutions (hospitals, research institutes, etc.) participating in the network. Melanoma-specific survival and Overall survival were calculated. Kaplan-Meier curves and medians of OS and 95% CI are presented overall and by immunotherapy and target treatments. The Log-rank test compared curves by treatments. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CMM were included in the analysis with completed information about therapies.Global immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by nivolumab/pembrolizumab immunotherapy (anti-PD1 HR=0.25 95% CI 0.14-0.42), globally immunotherapy was significantly associated with improved survival, either for anti-CTL A4 monotherapy or combined with anti-PD1 (HR=0.47;95% CI 0.33-0.66 and HR=0.26; 95% CI 0.15-0.46, respectively). Conclusions: The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.
ARTICLE | doi:10.20944/preprints202009.0380.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: malignant pleural mesothelioma; CXCL12/CXCR4; EAAT1; glutamine synthetase; invasion; migraiton
Online: 17 September 2020 (07:29:16 CEST)
Purpose: To elucidate the mechanism of CXCR4/EAAT1/GS pathway in CXCL12 regulating invasion and migration in malignant pleural mesothelioma (MPM). Methods: Immunohistochemistry for CXCL12, CXCR4, EAAT1 and GS stainings and correlation analysis between them were conducted in MPM and normal tissues. Western blot and real-time PCR were performed to examine the CXCR4, EAAT1 and GS expression in H2052 cells. Wound healing and transwell assay were applied to determine the cell migration and invasion. MTT was utilized to assess cell viability. Results: CXCL12, CXCR4, EAAT1 and GS were highly expressed in MPM tissues and correlated with each other. CXCL12 upregulated both in protein and mRNA levels of CXCR4, EAAT1 and GS in H2052 cells. The EAAT1 and GS expression upregulated or not by CXCL12 were decreased by CXCR4 and EAAT1 knockdown. CXCR4 antagonist AMD3100 and EAAT1 antagonist TFB-TBOA also resulted in the same effects as CXCR4 and EAAT1 knockdown, respectively. CXCL12 promoted cell invasion and migration and increased the Matrix metalloproteinase 9 (MMP9) mRNA level. CXCR4 and EAAT1 knockdown suppressed all these functions. Furthermore, CXCL12 promoted H2052 cells growth in nude mice, both AMD3100 and TFB-TBOA inhibited this promotion. Conclusions: CXCL12 regulated the invasion and migration through CXCR4/EAAT1/GS pathway in H2052 cells.
ARTICLE | doi:10.20944/preprints201911.0117.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: malignant mesothelioma; epidemiology; association rule mining; Apriori method; imbalanced dataset
Online: 10 November 2019 (16:15:14 CET)
Malignant mesothelioma is a rare proliferative cancer that develops in the thin layer of tissues surrounding the lungs. Malignant mesothelioma is associated with an extremely poor prognosis and the majority of patients do not show symptoms. The epidemiology of mesothelioma is important for the identification of disease. The primary aim of this study is to explore the risk factors associated with mesothelioma. The dataset consists of healthy and mesothelioma patients but only mesothelioma patients were selected for the identification of symptoms. The raw data set has been pre-processed and then the Apriori method was utilized for association rules with various configurations. The pre-processing task involved the removal of duplicated and irrelevant attributes, balanced the dataset, numerical to the nominal conversion of attributes in the dataset and creating the association rules in the dataset. Strong associations of disease’s factors; asbestos exposure, duration of asbestos exposure, duration of symptoms, erythrocyte sedimentation rate and Pleural to serum LDH ratio determined via Apriori algorithm. The identification of risk factors associated with mesothelioma may prevent patients from going into the high danger of the disease. This will also help to control the comorbidities associated with mesothelioma which are cardiovascular diseases, cancer-related emotional distress, diabetes, anemia, and hypothyroidism.
ARTICLE | doi:10.20944/preprints202301.0325.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Immune checkpoint inhibitors; Anti-tumor immunity; Predictive biomarker; Malignant melanoma; NSCLC
Online: 18 January 2023 (08:39:18 CET)
Immune checkpoint inhibitors (ICI) are currently use in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. Aim of our study was to find predictive biomarkers of ICI treatment. We analyzed by immunohistochemistry various cell subsets, including CD3+ cells, CD8+ cells, CD68+ cells, CD20+ cells, FoxP3+ cells, and molecules as LAG-3, IDO1, TGfβ. Comprehensive genomic profiles were analyzed. Correlation of various biomarkers with efficacy of ICI treatment in patients with advanced solid tumors was evaluated. We evaluated 56 patients treated with ICI monotherapy. Longer median progression-free survival (PFS) was found in tumors negative for nuclear FoxP3 (P = 0.002, HR 0.14) and in TMB-high tumors (P = 0.024, HR 0.38). Longer overall survival (OS) was found in patient with intraepithelial CD8 negativity (P = 0.045, HR 0.47). In malignant melanoma CD68 negativity, FoxP3 negativity and PDL TPS ≥ 1 was associated with longer PFS. In NSCLC FoxP3 was associated with longer PFS and OS. We found that absence of expression of several biomarkers such as CD68 and FoxP3 is associated with better survival. TMB-high and PD-L1 expression not universally but in certain disease could predict response.
REVIEW | doi:10.20944/preprints202208.0452.v1
Subject: Biology, Other Keywords: lactate; lactic acid; glycolysis; carcinogenesis; malignant tumor; evolutionary oncology; Warburg effect
Online: 26 August 2022 (07:13:46 CEST)
The role of lactic acid (lactate) in cell metabolism has been significantly revised in recent dec-ades. Initially, lactic acid was attributed to the role of a toxic end product of metabolism, which accumulation in the cell and extracellular space leads to acidosis, muscle pain and other adverse effects. However, it has now become obvious that lactate is not only a universal fuel molecule and the main substrate for gluconeogenesis, but also one of the most ancient metabolites with signaling function, which has a wide range of regulatory activity. The Warburg effect described 100 years ago (that means intensification of glycolysis associated with high lactate production), which is characteristic of many malignant tumors, confirms the key role of lactate not only in physiological conditions, but also in pathologies. The study of lactate’s role in the malignant transformation becomes more relevant in the light of the “atavistic theory of carcinogenesis,” which suggests that tumor cells return to a more primitive hereditary phenotype during micro-evolution. In this review, we attempted to summarize the accumulated knowledges about the functions of lactate in cell metabolism and its role in the process of carcinogenesis, and to con-sider the possible evolutionary significance of the Warburg effect.
ARTICLE | doi:10.20944/preprints202109.0229.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: intraoperative photodiagnosis; malignant glioma; fluorescence-guided surgery; intraoperative cytology; fluorescence microscope
Online: 14 September 2021 (10:02:54 CEST)
Objective: Surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain-tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence-guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we developed an intraoperative rapid fluorescence cytology system, and evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: Twenty-five selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence.Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was a useful to evaluate the presence of tumor cells in the resection cavity walls, and provides surgical implications for the more complete resection of malignant gliomas.
ARTICLE | doi:10.20944/preprints202012.0686.v1
Subject: Medicine & Pharmacology, Allergology Keywords: malignant neoplasia; transoral reconstruction; polydimethyl siloxane; Ag nanoparticles; fatigue strenght; prosthesis
Online: 28 December 2020 (11:24:53 CET)
This study aims to establish whether the use of biomaterials, particularly polydimethylsiloxane (PDMS), for surgical reconstruction of the esophagus with templates, Montgomery salivary tube, after radical oncology surgery for malignant neoplasia is an optimal choice for patients’ safety and for optimal function preservation and organ rehabilitation. Methods: Structural analysis by Raman spectrometry and biomechanical properties with dynamic mechanical analysis are performed for fatigue strength and toughness, essential factors in durability of a prosthesis in the reconstruction practice of the esophagus. Nanocomposites with silicone elastomers and nanoparticles used in implantable devices and in the reconstruction surgery are facing risks of infection and fatigue strength when required to perform a mechanical effort for long periods of time. Results: This report takes into account the effect of silver (Ag) nanoparticles on the fatigue strength using polydimethylsiloxane (PDMS) matrix, representative for silicon elastomers used in implantable devices. PDMS with 5% (wt) Ag nanoparticles of 100-150 nm during mechanical fatigue testing at shear strength loses elasticity properties after 400 loading-unloading cycles and up to 15% shear strain. The fatigue strength, toughness, maximum shear strength are the key issues in designing Montgomery salivary tube with appropriate biomechanical behavior for each patient. Conclusions: Prosthesis design needs to indulge both clinical outcome as well as design methods and research in the field of biomaterials.
REVIEW | doi:10.20944/preprints202002.0209.v1
Subject: Life Sciences, Molecular Biology Keywords: bone morphogenetic protein 4; molecular mechanism; delivery; clinical application; malignant glioma
Online: 16 February 2020 (04:19:22 CET)
Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We have previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its’ potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicate its’ potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, especially in pediatric malignant gliomas. We also summarize BMP4 delivery strategies, with a focus on biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.
ARTICLE | doi:10.20944/preprints201910.0373.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: malignant melanoma; BRAF V600E mutation; proteomics; mass spectrometry genetics; heterogeneity; prognosis
Online: 31 October 2019 (10:36:32 CET)
In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.
REVIEW | doi:10.20944/preprints202201.0208.v1
Subject: Life Sciences, Other Keywords: End of Life; Advance Directives; Advance Care Planning; Intensive Care, Medical Oncology; malignant hemopathy
Online: 14 January 2022 (11:34:51 CET)
Patients living with cancer often experience serious adverse events due to their condition or its treatments. Those events may lead to a critical care unit admission or even result in death. One of the most important but challenging part of care is to build a caring plan according to the patient’s wishes, meeting his goals and values. Advance directives (ADs) allow everyone to give their preferences in advance regarding life sustaining treatments, continuation, and withdrawal or withholding of treatments in case one is not able to speak his mind anymore. While the absence of ADs is associated with a greater probability of receiving unwanted intensive care around the end of his life, their existence correlates with the respect of the patient’s desires and his greater satisfaction. Although progress has been made to promote ADs’ completion, they are still scarcely used among cancer patients in many countries. Several limitations to their acceptation and use can be detected. Efforts should be made to provide tailored solutions for the identified hindrances. This narrative review aims to depict the situation of ADs in the oncology context, and to highlight the future areas of improvement.
ARTICLE | doi:10.20944/preprints201910.0229.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: malignant melanoma; head and neck cancer; cancer stem cell; melanoma metastasis; induced pluripotent stem cell
Online: 19 October 2019 (17:15:36 CEST)
Cancer stem cells (CSCs) have been identified in many cancer types. This study identified and characterized CSCs in head and neck metastatic malignant melanoma (HNmMM) to regional lymph nodes using induced pluripotent stem cell (iPSC) markers. Immunohistochemical (IHC) staining performed on 20 HNmMM tissue samples demonstrated expression of iPSC markers OCT4, SOX2, KLF4 and c-MYC in all samples while NANOG was expressed at low levels in two samples. Immunofluorescence (IF) staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ CSC subpopulation within the tumor nests (TNs) and another within the peritumoral stroma (PTS) of HNmMM tissues. IF also showed expression of NANOG by some OCT4+/SOX2+/KLF4+/c-MYC+ cells within the TNs in an HNmMM tissue sample that expressed NANOG on IHC staining. In situ hybridization (n=6) and reverse-transcription quantitative polymerase chain reaction (n=5) on the HNmMM samples confirmed expression of all five iPSC markers. Western blotting of four primary cell lines derived from four of the 20 HNmMM tissue samples showed expression of SOX2, KLF4, and c-MYC but not OCT4 and NANOG, and three of these cell lines formed tumorspheres in vitro. We demonstrate the presence of two putative CSC subpopulations within HNmMM, which may be a novel therapeutic target in the treatment of this aggressive cancer.
ARTICLE | doi:10.20944/preprints202212.0557.v1
Subject: Biology, Other Keywords: biologic system; feedback; malignant transformations; Lie algebra; coquaternion; indefinite metric; quadratic form; hierarchy; entropy; anabolism; catabolism
Online: 29 December 2022 (09:10:32 CET)
Different hypotheses of carcinogenesis have been proposed based on local genetic factors and physiologic mechanisms. It is assumed that changes of the metric invariants of a biologic system (BS) determine general mechanisms of cancer development. Numerous data demonstrate an existence of three invariant feedback patterns of BS: negative feedback (NFB), positive feedback (PFB) and reciprocal links (RL). These base patterns represent basis elements of a Lie algebra sl(2,R) and imaginary part of coquaternion. Considering coquaternion as a model of a functional core of a BS, conditions of the system can be identified with the points of three families of hypersurfaces in R42: hyperboloids of one sheet, hyperboloids of two sheets and double-cones. Corresponding quadratic form relates negative and positive entropy contributions of base elements to the energy level of the system, so that anabolic states of the system will correspond to the points of a hyperboloid of one sheet, while catabolic conditions to the points of a hyperboloid of two sheets. Equilibrium states will lie in a double cone. Hypothetically anabolic and catabolic states dominate intermittently oscillating around the equilibrium. Deterioration of base elements increases positive entropy and causes domination of catabolic states which is the main metabolic determinant of cancer. Corresponding trajectory of a malfunctioning system will have a tendency to remain inside the double cone.
ARTICLE | doi:10.20944/preprints202205.0148.v2
Subject: Biology, Other Keywords: biologic system; feedback; malignant transformations; Lie algebra; coquaternion; indefinite metric; quadratic form; hierarchy; entropy; anabolism, catabolism
Online: 21 October 2022 (03:58:52 CEST)
Different hypotheses of carcinogenesis have been proposed based on local genetic factors and physiologic mechanisms. It is assumed that changes of the metric invariants of a biologic system (BS) determine general mechanisms of cancer development. Numerous data demonstrate an existence of three invariant feedback patterns of BS: negative feedback (NFB), positive feedback (PFB) and reciprocal links (RL). These base patterns represent basis elements of a Lie algebra and imaginary part of coquaternion. Considering coquaternion as a model of a functional core of a BS, conditions of the system can be identified with the points of three families of hypersurfaces in R42: hyperboloids of one sheet, hyperboloids of two sheets and double-cones. Corresponding quadratic form relates negative and positive entropy contributions of base elements to the energy level of the system, so that anabolic states of the system will correspond to the points of a hyperboloid of one sheet, while catabolic conditions to the points of a hyperboloid of two sheets. Equilibrium states will lie in a double cone. Hypothetically anabolic and catabolic states dominate intermittently oscillating around the equilibrium. Deterioration of base elements increases positive entropy and causes domination of catabolic states which is the main metabolic determinant of cancer. Corresponding trajectory of a malfunctioning system will have a tendency to remain inside the double cone.
REVIEW | doi:10.20944/preprints201712.0052.v1
Subject: Biology, Other Keywords: cell programming; stress resistance; gene overexpression; radiation; oxidative stress; chemical genotoxins; malignant transformation; diversity of mechanisms
Online: 9 December 2017 (13:26:14 CET)
Different organisms, cell types, and even similar cell lines can dramatically differ in resistance to genotoxic stress. This testifies to the wide opportunities for genetic and epigenetic regulation of stress resistance. These opportunities could be used to increas the effectiveness of cancer therapy, develop new varieties of plants and animals, and search for new pharmacological targets to enhance human radioresistance, for example, for -manned deep space expeditions. Based on the comparison of transcriptomic studies in cancer cells, in this review we propose that there is a high diversity of genetic mechanisms of development of genotoxic stress resistance. This review focused onpossibilities and limitations of the proposed regulation of the resistance of normal cells whole organisms to genotoxic and oxidative stress by overexpressing of stress-response genes. Moreover, the existing experimental data on the effect of such overexpression on the resistance of cells and organisms to various genotoxic agents has been analyzed and systematized. We suggest that the recent advances in the development of multiplex and highly customizable gene overexpression technology that utilizes the mutant Cas9 protein and the wealth of available data on gene functions and their signal networks open new opportunities for research in this field.
ARTICLE | doi:10.20944/preprints202301.0280.v1
Subject: Life Sciences, Genetics Keywords: Fanconi anemia; oral cancer; oral potentially malignant lesion; liquid biopsy; saliva; oral rinse; plasma; next generation sequencing; cancer gene panel; early diagnosis; diagnostic test; deep sequencing
Online: 16 January 2023 (09:10:06 CET)
Fanconi anemia (FA) patients display an exacerbated risk of oral squamous cell carcinoma (OSCC) and precursor lesions at young ages, mainly at the oral cavity. As patients have defects in DNA repair mechanisms, standard-of-care treatments to OSCC such as radiotherapy and chemotherapy give rise to severe toxicities. New methods for early diagnosis are urgently necessary to allow treatments in early disease stages and achieve better clinical outcomes. We have conducted a prospective, longitudinal study whereby liquid biopsies from sixteen lesion/tumor-free patients were analyzed for the presence of mutations in cancer genes. DNA from saliva and plasma were sequentially collected and deep-sequenced, and the clinical evolution followed during a median time of around 2 years. In 9/16 FA patients we detected mutations in cancer genes (mainly TP53) with molecular allele frequencies (MAF) down to 0.07 %. Importantly, all patients having mutations and clinical follow-up data after mutation detection (n=6) developed oral precursor lesions or OSCC. Lead-time between mutation detection and tumor diagnosis ranged from 23 to 630 days. Strikingly, FA patients without mutations display significantly lower risk of developing precursor lesions or OSCC. Therefore, our diagnostic approach could help to stratify FA patients into risk groups, which would allow closer surveillance for OSCC or precursor lesions.
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Neuroendocrine Neoplasms; NOTCH; cancer driven genes; mutational mechanism; germline mutations.; small cell lung carcinoma; pancreatic NET; small bowel NET; medullary thyroid carcinoma; malignant castration-resistant prostatic cells
Online: 23 July 2019 (10:34:50 CEST)
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies mainly originated from hormones secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout MEN-1 gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signaling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally, act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the roles and the potential therapeutic implications of gene mutations and NOTCH signaling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential roles across all NEN subtypes is required.
REVIEW | doi:10.3390/sci2030068
Subject: Keywords: COVID-19; pooling clinical trials; hyperinfection; steroids; treatment; targeted healthcare; population health management; cancer treatment; clinical research; clinical trials; developing vaccines; ranking and rating hospital quality; school closures; interventions for delirium; assessments of COVID-19 death inequities; regulatory safeguards; preventing child abuse and maltreatment; prevalence of health care worker burnout; nursing home ratings; challenging oncology practice; addressing racial; ethnic; social and economic divides; violence against sexual minority adolescents; primary tumors; metastasis; stages of cancer; reforming cancer clinical trials; supporting carers; protection and prevention; benign and malignant tumors; reforming cancer clinical trials; protection of healthcare personnel; comparing excess deaths in NYC; 1918 influenza pandemic; the possibility of full recovery from COVID-19; mental health impact of COVID-19 on young adults; ranking and rating nursing home quali
Online: 21 August 2020 (00:00:00 CEST)
The SARS-CoV-2 virus that causes the COVID-19 disease has wreaked havoc on the world community in terms of every imaginable parameter. The research output on COVID-19 has been nothing short of phenomenal, especially in the medical and biomedical sciences, where the search for a potential vaccine is being conducted in earnest. Much of the advanced research has been distributed in the leading medical journals, including the Journal of the American Medical Association (JAMA), where the latest research is distributed on a daily basis. The purpose of this paper is to provide some perspectives on 44 interesting and highly topical research papers that have been published in JAMA, at the time of writing, within the past two weeks. The diverse topics include public health, general medicine, internal medicine, oncology, paediatrics, geriatrics, and biostatistics.