Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer

xlomafota13 shared this article with you from Inoreader Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5374-5387. eCollection 2021. ABSTRACT Endometrial cancer (EC) is a highly obesity-driven cancer, with limited treatment options. ONC201 is an imipridone that selectively antagonizes the G protein-coupled receptors dopamine receptor D2 and D3 (DRD2/3) and activates human mitochondrial caseinolytic protease P (ClpP). It is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through induction of the integrated stress response (ISR) as well as through stimulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and subsequent induction of apoptosis. ONC201 is being evaluated in Phase II clinical trials for solid tumors and hematological malignancies, including EC. ONC206 is an analog of ONC201 with nanomolar potency in Phase I clinical trials. This study evaluated the anti-tumor efficacy of ONC206 in EC cell lines and the Lkb1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. ONC206 revealed greater potency than ONC201 in the inhibition of proliferation in EC cell lines, with IC50 concentration ranges of 0.21-0.32 µM for ONC026 versus 2.14-3.53 µM for ONC201. ONC206 induced cellular stress, apoptosis and cell cycle G1 arrest, accompanied by inhibition of the AKT/mTOR/S6 pathways in EC cells. Diet-induced obesity accelerated tumor growth in Lkb1fl/flp53fl/fl mice. ONC206 inhibited EC tumor size and weight in both obese and lean mice after 4 weeks of treatment. Treatment with ONC206 led to a decrease in expression of Ki67, BCL-XL and phosphorylation of S6, as well as an increase in ClpP in endometrial tumors under both obese and lean conditions. Overall, the pre-clinical efficacy of ONC206 is promising and worthy of further exploration in clinical trials for endometrioid EC. PMID:34873466 | PMC:PMC8640798 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genome-wide identification of m6A-associated functional SNPs as potential functional variants for thyroid cancer

xlomafota13 shared this article with you from Inoreader Genome-wide identification of m6A-associated functional SNPs as potential functional variants for thyroid cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5402-5414. eCollection 2021. ABSTRACT m6A methylation has been demonstrated to be one of the most important epigenetic regulation mechanisms in cell differentiation and cancer development especially m6A derived diagnostic and prognostic biomarkers have been identified in the past several years. However, systemic investigation to the interaction between germline single-nucleotide polymorphisms (SNPs) and m6A has not been conducted yet. In this study, we collected previous identified significant thyroid cancer associated SNPs from UKB cohort (358 cases and 407,399 controls) and ICR cohort (3,001 patients and 287,550 controls) and thyroid eQTL (sample size = 574 from GTEx project) and m6A-SNP (N = 1,678,126) were applied to prioritize the candidate SNPs. Finally, five candidate genes (PLEKHA8, SMUG1, CDC123, RMI2, ACSM5) were identified to be thyroid cancer associated m6A-related genetic suscepti bility. Loss and gain function studies of m6A writer proteins confirm that ACSM5 is regulated by m6A methylation of mRNA. Moreover, ACSM5 is downregulated in thyroid cancer and inversely correlated with PTC malignancy and patient survival. Together, our study highlight mRNA-seq and m6A-seq double analysis provided a novel approach to identify cancer biomarkers and understanding the heterogeneity of human cancers. PMID:34873468 | PMC:PMC8640822 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context

xlomafota13 shared this article with you from Inoreader Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5625-5643. eCollection 2021. ABSTRACT Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin's role in cancer immunity. Insight in these complex molecular networks, will simplify application o f metformin in clinical trials and contribute to improvement of anti-cancer therapy. PMID:34873484 | PMC:PMC8640802 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling

xlomafota13 shared this article with you from Inoreader New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5214-5232. eCollection 2021. ABSTRACT Progesterone, the ovarian steroid hormone, regulates a plentitude of biological processes in tissues ranging from the brain to bones. Recognizing the role of progesterone and its receptors in physiological processes and maladies can prevent and treat various diseases. Apart from its physiological functions, its role in developing diseases, especially breast cancer, is a recent topic of deliberation. There exists conflicting experimental and epidemiological evidence linking progesterone to breast cancer. This review tries to describe the physiological functions of progesterone and its receptors, genomic and non-genomic signaling, splice variants, and a different aspect of progesterone signaling. Furthermore, we seek to address or attempt to discuss the following pertinent questions on steroid hormone signaling; How does progesterone influence breast cancer progres sion? How does it change the molecular pathways in breast cancer with different receptor statuses, the specific role of each isoform, and how does the ER/and PR ratio affect progesterone signaling? PMID:34873457 | PMC:PMC8640821 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

DNA methylation markers in esophageal cancer: an emerging tool for cancer surveillance and treatment

xlomafota13 shared this article with you from Inoreader DNA methylation markers in esophageal cancer: an emerging tool for cancer surveillance and treatment Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5644-5658. eCollection 2021. ABSTRACT Esophageal carcinoma (EC) is one of the most pervasive cancers in the world, with upwards of 500,000 new diagnoses, annually. Despite its prominence, advancements in the detection and treatment of EC have been marginal over the past 30 years and the survival rate continues to stay below 20%. This is due to the uncommonly heterogeneous presentation of EC which presents unprecedented challenges in improving patient survival and quality of care. However, distinct epigenetic alterations to the DNA methylome may provide an avenue to drastically improve the detection and treatment of EC. Specifically, the creation of novel biomarker panels that consist of EC-specific methylation markers have shown promise as a potential alternative to the more invasive, contemporary diagnostic methods. Additionally, growing insight into the biological and clinical properties of EC-spec ific methylation patterns have opened a window of opportunity for enhanced treatment; of growing interest is the application of "DNMT inhibitors" - a class of drugs which inhibit excessive methylation and have been shown to re-sensitize chemoresistant tumors. Here we provide a comprehensive review of the current advancements in EC DNA methylation to underscore a potential approach to its detection and treatment. PMID:34873485 | PMC:PMC8640794 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting the oncogenic TBX3:nucleolin complex to treat multiple sarcoma subtypes

xlomafota13 shared this article with you from Inoreader Targeting the oncogenic TBX3:nucleolin complex to treat multiple sarcoma subtypes Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5680-5700. eCollection 2021. ABSTRACT Sarcomas are diverse cancers of mesenchymal origin, with compromised clinical management caused by insufficient diagnostic biomarkers and limited treatment options. The transcription factor TBX3 is upregulated in a diverse range of sarcoma subtypes, where it plays a direct oncogenic role, and it may thus represent a novel therapeutic target. To identify versatile ways to target TBX3, we performed affinity purification coupled by mass spectrometry to identify putative TBX3 protein cofactors that regulate its oncogenic activity in sarcomas. Here we identify and validate the multifunctional phosphoprotein nucleolin as a TBX3 cofactor. We show that nucleolin is co-expressed with TBX3 in several sarcoma subtypes and their expression levels positively correlate in sarcoma patients which are associated with poor prognosis. Furthermore, we demonstrate that nucleolin and TBX3 interact in chondrosarcoma, liposarcoma and rhabdomyosarcoma cells where they act together to enhance proliferation and migration and regulate a common set of tumor suppressor genes. Importantly, the nucleolin targeting aptamer, AS1411, exhibits selective anti-cancer activity in these cells and mislocalizes TBX3 and nucleolin to the cytoplasm which correlates with the re-expression of the TBX3/nucleolin target tumor suppressors CDKN1A (p21CIP1) and CDKN2A (p14ARF). Our findings provide the first evidence that TBX3 requires nucleolin to promote features of sarcomagenesis and that disruption of the oncogenic TBX3-nucleolin interaction by AS1411 may be a novel approach for treating sarcomas. PMID:34873487 | PMC:PMC8640805 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Development of KAM score to predict metastasis and worse survival in breast cancer

xlomafota13 shared this article with you from Inoreader Development of KAM score to predict metastasis and worse survival in breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Nov 15;11(11):5388-5401. eCollection 2021. ABSTRACT Some may think that prediction of metastasis is meaningless since metastatic breast cancer is currently incurable. We argue that effective identification of developing metastasis will enable us to design and conduct clinical trials specifically targeting those patients at high risk. The current study sought to generate the KAM score by 4 genes (BRSK2, EYA1, SIGLEC15, and AGTR1) overexpressed in primary breast cancer that developed metastasis to bone compared with matched controls without metastasis longer than 10 years. A high KAM score was prognostic of poor overall (OS), disease free survival (DFS), and disease specific survival (DSS) in the METABRIC, and OS in the GSE96058 cohorts. A high KAM score was significantly associated with clinical aggressiveness, such as high American Joint Committee Cancer (AJCC) stage, lymph node metastasis, Nottingha m pathological grade, and triple negative breast cancer (TNBC). Subgroup analysis revealed that a high KAM score was associated with worse OS in ER-positive/HER2-negative breast cancer in both cohorts. A high KAM breast cancer enriched all 5 cell proliferation-related gene sets of the Hallmark collection and interferon (IFN)-γ response gene sets. Furthermore, a high KAM breast cancer was significantly infiltrated with a high fraction of not only anti-cancer but also pro-cancer immune cells and associated with high level of cytolytic activity. Finally, a high KAM breast cancer was significantly associated with lung metastasis. In conclusion, we developed KAM score using 4 gene expressions that predict lung metastasis and patient survival in breast cancer. PMID:34873467 | PMC:PMC8640803 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Morphometric analysis of the lumbar vertebrae and intervertebral discs in relation to abdominal aorta: CT-based study

xlomafota13 shared this article with you from Inoreader Morphometric analysis of the lumbar vertebrae and intervertebral discs in relation to abdominal aorta: CT-based study Via radiol anat Surg Radiol Anat. 2021 Dec 7. doi: 10.1007/s00276-021-02865-9. Online ahead of print. ABSTRACT PURPOSE: Although lumbar discectomy is the most common procedure in spine surgery, reports about anatomical relations between discs and prevertebral vessels are limited. Aim of this research was to investigate morphometric of the lumbar region and the relations between intervertebral discs (IVDs) and abdominal aorta. METHODS: 557 abdominal computed tomography scans were assess ed. For each spinal column level from Th12/L1 down to L4/L5, we investigated: intervertebral disc's and vertebra's height, width, length, and distance from aorta or common iliac artery (CIA). Those arteries were also measured in two dimensions and classified based on location. RESULTS: 54.58% of patients were male. There was a significant difference in arterial-disc distances (ADDs) between genders at the levels: L1/L2 (1.32 ± 1.97 vs. 0.96 ± 1.78 mm; p = 0.0194), L2/L3 (1.97 ± 2.16 vs. 1.15 ± 2.01 mm; p < 0.0001), L3/L4 (2.54 ± 2.78 vs. 1.71 ± 2.61 mm; p = 0.0012), also for both CIAs (left CIA 3.64 ± 3.63 vs. 2.6 ± 3.06 mm; p = 0.0004 and right CIA: 7.96 ± 5.06 vs. 5.8 ± 4.57 mm; p < 0.001)-those ADDs were higher in men at all levels. The length and width of IVD increased alongside with disc level with the maximum at L4/L5. CONCLUSION: Bifurcations of the aorta in most cases occurred at the L4 level. Collected data suggest that at the highest lumbar leve ls, there is a greater possibility to cause injury of the aorta due to its close anatomical relationship with discs. Females have limited, in comparison to males, ADD at L1/L2, L2/L3, and L3/L4 levels what should be taken into consideration during preoperative planning of surgical intervention. PMID:34874459 | DOI:10.1007/s00276-021-02865-9 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Exoscopic visualisation with VITOM® 3D in paediatric cochlear implantation: preliminary results

xlomafota13 shared this article with you from Inoreader Exoscopic visualisation with VITOM® 3D in paediatric cochlear implantation: preliminary results Via Clinical Otolaryngology Abstract 3D exoscopy is an emerging visualisation technique designed to improve ergonomics and image quality during surgeries. We present a novel application of the VITOM® 3D exoscope in cochlear implantation (IDEAL Stage 2a prospective case series). The system enabled high-quality visualisation during both posterior tympanotomy and electrode insertion. Both the chief surgeon and the staff members rated the ergonomics of the system highly. 3D exoscopy is a useful alternative to conventional microscopy, but the two techniques remain to be directly compared in larger studies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Prediction of Oxygen Desaturation by Using Sound Data From a Noncontact Device: A Proof‐of‐Concept Study

xlomafota13 shared this article with you from Inoreader Prediction of Oxygen Desaturation by Using Sound Data From a Noncontact Device: A Proof‐of‐Concept Study Via The Laryngoscope Objectives/Hypothesis Prediction of the apnea-hypopnea index (AHI) from breathing sounds during sleep could be used to prescreen for obstructive sleep apnea (OSA). In addition, the oxygen desaturation index (ODI) is a known risk factor for developing cardiovascular disease in OSA patients. This study focused on estimation of ODI from a noncontact manner from sleep breathing sounds. Study Design Retrospective study. Methods Patients who visited the sleep center due to snoring or sleep apnea underwent polysomnography in lab overnight. Sound recordings were made during polysomnography using a microphone. After noise reduction, the sound data were segmented into 5 seconds windows and features were extracted. Binary classification and regression analyses were performed to estimate the ODI during sleep (model 1). This was re-tested after inclusion of body mass index (BMI) and age as additional features (model 2: BMI only, model 3: BMI and age). Results We included 116 patients. The mean age and AHI of all patients were 50.4 ± 16.7 years and 23.0 ± 24.0 events/hr. In binary classification, for ODI cutoff values of 5, 15, and 30 events/hr, the areas under the curve were 0.88, 0.93, 0.91, respectively, and accuracies were 85.34, 86.21, and 87.07, respectively. In regression analysis, the correlation coefficient and mean absolute error were 0.80 and 9.60 events/hr, respectively. In models 2 and 3, the correlation coefficient and mean absolute error were 0.82, 9.44 events/hr and 0.81, 9.6 events/hr, respectively. Conclusion Prediction of ODI from sleep sound seems to be feasible. Additional clinical feature such as BMI may increase overall predictability. Level of Evidence IV Laryngoscope, 2021 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Third molar surgical difficulty scales: systematic review and preoperative assessment form

xlomafota13 shared this article with you from Inoreader Third molar surgical difficulty scales: systematic review and preoperative assessment form Via pubmed: "med oral patol oral... Med Oral Patol Oral Cir Bucal. 2021 Dec 7:24951. doi: 10.4317/medoral.24951. Online ahead of print. ABSTRACT BACKGROUND: The main objective of this systematic review was to collect the pre-existing scales for assessing the difficulty of third molar extraction. The secondary objective was to design a proposal for a preoperative evaluation protocol for the difficulty of third molar extraction. MATERIAL AND METHODS: Two independent researchers conducted an electronic search in Pubmed (MEDLINE), Cochrane, and Scopus databases during March 2021. Included studies evaluated the prediction of the difficulty of surgical removal of impacted upper or lower third molars using new indices/scales or pre-existing scales with or without modifications. Articles referring to coronectomies or assessing pre-surgical difficulty using other tools were excluded. Neither language nor publication date restrictions were applied. RESULTS: Out of 242 articles, 13 prospective cohort studies were finally selected. Seven developed new indices/scales, and 6 assessed the predictive ability of some pre-existing scales. Most of the indices/scales contained radiological variables and few added any patient-related variables. We proposed a preoperative assessment protocol of the difficulty of third molar extraction to facilitate treatment planning and/or considerate referral in cases of high difficulty. This proposal used patient-related, radiological and surgical variables. CONCLUSIONS: Using a preoperative protocol to evaluate the surgical difficulty, including different patient-specific, radiological and surgical variables, could facilitate treatment planning, help clinicians prevent complications and assess the possibility of referral. PMID:34874928 | DOI:10.4317/medoral.24951 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.