Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells.

p.aythelady61 shared this article with you from Inoreader Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells. Via Head and Neck Related Articles Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells. Cancer Immunol Res. 2020 Dec 04;: Authors: Drijvers JM, Gillis JE, Muijlwijk T, Nguyen TH, Gaudiano EF, Harris IS, LaFleur MW, Ringel AE, Yao CH, Kurmi K, Juneja VR, Trombley JD, Haigis M, Sharpe AH Abstract Metabolic constraints in the tumor microenvironment constitute a barrier to effective anti-tumor immunity and similarities in the metabolic properties of T cells and cancer cells impede the specific therapeutic targeting of metabolism in either population. To identify distinct metabolic vulnerabilities of CD8+ T cells and cancer cells, we developed a high-throughput in vitro pharmacologic screening platform and used it to measure the cell type-specific sensitivities of activated CD8+ T cells and B16 melanoma cells to a wide array of metabolic perturbations during antigen-specific killing of cancer cells by CD8+ T cells. We illustrated the applicability of this screening platform by showing that CD8+ T cells were more sensitive to ferroptosis than B16 and MC38 cancer cells. Overexpression of ferroptosis suppressor protein 1 (FSP1) or cytosolic GPX4 yielded ferroptosis-resistant CD8+ T cells without compromising their function, while genetic deletion of the ferroptosis sensitiv ity-promoting enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) protected CD8+ T cells from ferroptosis, but impaired anti-tumor CD8+ T cell responses. Our screen also revealed high T cell-specific vulnerabilities for compounds targeting NAD+ metabolism or autophagy and ER stress pathways. We focused the current screening effort on metabolic agents. However, this in vitro screening platform may also be valuable for rapid testing of other types of compounds to identify regulators of anti-tumor CD8+ T-cell function and potential therapeutic targets. PMID: 33277233 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting of CD40 and PD-L1 pathways inhibit progression of oral premalignant lesions in a carcinogen-induced model of oral squamous cell carcinoma.

p.aythelady61 shared this article with you from Inoreader Targeting of CD40 and PD-L1 pathways inhibit progression of oral premalignant lesions in a carcinogen-induced model of oral squamous cell carcinoma. Via Head and Neck Related Articles Targeting of CD40 and PD-L1 pathways inhibit progression of oral premalignant lesions in a carcinogen-induced model of oral squamous cell carcinoma. Cancer Prev Res (Phila). 2020 Dec 04;: Authors: Monteiro de Oliveira Novaes JA, Hirz T, Guijarro I, Nilsson M, Pisegna MA, Poteete A, Barsoumian HB, Fradette JJ, Chen LN, Gibbons DL, Tian X, Wang J, Myers JN, McArthur MJ, Bell D, William WN, Heymach JV Abstract We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen induced murine model of OSCC. It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed the current study to further characterize the immune landscape of OPLs and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4NQO model. The immune pathways were targeted using monoclonal antibodies or, in the case of the PD-1/PD-L1 pathway, using PD-L1 knockout mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist monoclonal antibody was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combinatio n with CTLA-4 inhibition, or PD-L1 knockout, also reduced progression of OPL to OSCC albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T-lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T-cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as a potential immunoprevention agents in this setting. PMID: 33277316 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Risk of stroke in cancer survivors.

p.aythelady61 shared this article with you from Inoreader Risk of stroke in cancer survivors. Via Head and Neck Related Articles Risk of stroke in cancer survivors. Neurology. 2020 Dec 04;: Authors: Zhang F, Wang K, Du P, Yang W, He Y, Li T, Mei Z Abstract OBJECTIVE: Accumulating evidence suggests that cancer survivors may have a relatively higher risk of stroke. The hypothesis of this meta-analysis was to determine whether cancer survivors have a relatively higher risk of stroke than non-cancer populations based on the published data from population-based cohort studies. METHODS: Pubmed, Embase and Cochrane Library were searched from inception to February 8, 2020 for population-based cohort studies. Effect estimates with 95% CIs were pooled using the random-effects model. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results. RESULTS: Twenty population-based cohort studies involving 10,479,530 participants were identified. Overall, the RR for stroke in cancer survivors was 1.66 (95% CI, 1.35-2.04; p < 0.001) compared with that in non-cancer controls, among which survivors of head and neck, hematologic, lung, pancreas and stomach cancer (all p < 0.05) showed consistent significant results, whereas no significant increased risk was observed for other cancer types. The effects were more prominent in cancer survivors with female gender (RR 1.38, 1.18-1.61; p < 0.001), younger age at cancer diagnosis (<45 years) (RR 2.57, 95% CI, 1.27-5.19; p = 0.009) and shorter cancer survival duration (≥1-2 years) (RR 1.69, 95% CI, 1.18-2.42; p = 0.004). Moreover, cancer survivors had a significantly increased risk of ischemic stroke (RR 1.53, 95% CI, 1.28-1.84; p < 0.001) compared with hemorrhagic stroke. CONCLUSIONS: Cancer plays a critical role in the etiologic of stroke. Due to the existence of substantial heterogeneity among the included studies, the results should be interpreted with caution. However, early prevention and effective intervention of stroke in cancer survivors requires attention from the health policy makers. PMID: 33277416 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis and Metastasis in Aneuploid Cancers.

p.aythelady61 shared this article with you from Inoreader A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis and Metastasis in Aneuploid Cancers. Via Head and Neck Related Articles A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis and Metastasis in Aneuploid Cancers. Mol Cancer Ther. 2020 Dec 04;: Authors: Kawakami M, Mustachio LM, Chen Y, Chen Z, Liu X, Wei CH, Roszik J, Kittai AS, Danilov AV, Zhang X, Fang B, Wang J, Heymach JV, Tyutyunyk-Massey L, Freemantle SJ, Kurie JM, Liu X, Dmitrovsky E Abstract Cyclin dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically-tractable anti-neoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Anti-neoplastic activity was studied in pre-clinical models. CYC065-treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active anti-neoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase (FAK) and Src phosphorylation that regulate metastasis were each repressed by CYC065-treatment. Intriguingly, CYC065-treatment decreased lung cancer metastases in in vivo mur ine models. CYC065-treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemical analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 anti-tumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065-treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic. PMID: 33277443 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Radiomic features based on Hessian index for prediction of prognosis in head-and-neck cancer patients.

p.aythelady61 shared this article with you from Inoreader Radiomic features based on Hessian index for prediction of prognosis in head-and-neck cancer patients. Via Head and Neck Related Articles Radiomic features based on Hessian index for prediction of prognosis in head-and-neck cancer patients. Sci Rep. 2020 Dec 04;10(1):21301 Authors: Le QC, Arimura H, Ninomiya K, Kabata Y Abstract This study demonstrated the usefulness of radiomic features based on the Hessian index of differential topology for the prediction of prognosis prior to treatment in head-and-neck (HN) cancer patients. The Hessian index, which can indicate tumor heterogeneity with convex, concave, and other points (saddle points), was calculated as the number of negative eigenvalues of the Hessian matrix at each voxel on computed tomography (CT) images. Three types of signatures were constructed in a training cohort (n = 126), one type each from CT conventional features, Hessian index features, and combined features from the conventional and index feature sets. The prognostic value of the signatures were evaluated using statistically significant difference (p value, log-rank test) to compare the survival curves of low- and high-risk groups. In a test cohort (n = 68), the p values of the models built with conventional, index, combined features, and clinical variables were 2.95 [Formula : see text] 10-2, 1.85 [Formula: see text] 10-2, 3.17 [Formula: see text] 10-2, and 1.87 [Formula: see text] 10-3, respectively. When the features were integrated with clinical variables, the p values of conventional, index, and combined features were 3.53 [Formula: see text] 10-3, 1.28 [Formula: see text] 10-3, and 1.45 [Formula: see text] 10-3, respectively. This result indicates that index features could provide more prognostic information than conventional features and further increase the prognostic value of clinical variables in HN cancer patients. PMID: 33277570 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Radiomics of high-resolution computed tomography for the differentiation between cholesteatoma and middle ear inflammation: effects of post-reconstruction methods in a dual-center study.

p.aythelady61 shared this article with you from Inoreader Radiomics of high-resolution computed tomography for the differentiation between cholesteatoma and middle ear inflammation: effects of post-reconstruction methods in a dual-center study. Via Head and Neck Related Articles Radiomics of high-resolution computed tomography for the differentiation between cholesteatoma and middle ear inflammation: effects of post-reconstruction methods in a dual-center study. Eur Radiol. 2020 Dec 04;: Authors: Arendt CT, Leithner D, Mayerhoefer ME, Gibbs P, Czerny C, Arnoldner C, Burck I, Leinung M, Tanyildizi Y, Lenga L, Martin SS, Vogl TJ, Schernthaner RE Abstract OBJECTIVES: To evaluate the performance of radiomic features extracted from high-resolution computed tomography (HRCT) for the differentiation between cholesteatoma and middle ear inflammation (MEI), and to investigate the impact of post-reconstruction harmonization and data resampling. METHODS: One hundred patients were included in this retrospective dual-center study: 48 with histology-proven cholesteatoma (center A: 23; center B: 25) and 52 with MEI (A: 27; B: 25). Radiomic features (co-occurrence and run-length matrix, absolute gradient, autoregressive model, Haar wavelet transform) were extracted from manually defined 2D-ROIs. The ten best features for lesion differentiation were selected using probability of error and average correlation coefficients. A multi-layer perceptron feed-forward artificial neural network (MLP-ANN) was used for radiomics-based classification, with histopathology serving as the reference standard (70% of cases for training, 30% for validation). The analysis was performed five times each on (a) unmodified data and on data that were (b) resampled to the same matrix size, and (c) corrected for acquisition protocol differences using ComBat harmonization. RESULTS: Using unmodified data, the MLP-ANN classification yielded an overall median area under the receiver operating characteristic curve (AUC) of 0.78 (0.72-0.84). Using original data from center A and resampled data from center B, an overall median AUC of 0.88 (0.82-0.99) was yielded, while using ComBat harmonized data, an overall median AUC of 0.89 (0.79-0.92) was revealed. CONCLUSION: Radiomic features extracted from HRCT differentiate between cholesteatoma and MEI. When using multi-centric data obtained with differences in CT acquisition parameters, data resampling and ComBat post-reconstruction harmonization clearly improve radiomics-based lesion classification. KEY POINTS: • Unenhanced high-resolution CT coupled with radiomics analysis may be useful for the differentiation between cholesteatoma and middle ear inflammation. • Pooling of data extracted from inhomogeneous CT datasets does not appear meaningful without further post-processing. • When using multi-centric CT data obtained with differences in acquisition parameters, post-reconstruction harmonization and data resampling clearly improve radiomics-based soft-tissue differentiation. PMID: 33277670 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cross-sectional study of pigmented lesions of the head and neck in adults aged 40 years and above.

p.aythelady61 shared this article with you from Inoreader Cross-sectional study of pigmented lesions of the head and neck in adults aged 40 years and above. Via Head and Neck Related Articles Cross-sectional study of pigmented lesions of the head and neck in adults aged 40 years and above. Australas J Dermatol. 2020 Dec 05;: Authors: Chiu FP, McLaren D, Pool L, Shao E, De'Ambrosis B, Muir J Abstract The diagnosis of junctional and lentiginous naevi on sun-damaged skin of the head and neck in adults has been questioned in the literature, with the implication that these lesions should be classified as melanoma in situ. This could result in the overdiagnosis and overtreatment of non-malignant lesions. We conducted a cross-sectional study of the histopathological diagnosis of pigmented lesions biopsied from the head and neck of adults ≥40 years of age that were submitted to a large, Queensland-based pathology centre over seven months. Out of 543 lesions assessed, 293 (54.0%) were flat and 250 (46.0%) were raised. Flat naevi consisted of junctional/lentiginous and compound naevi, either with or without dysplasia. Collectively, flat naevi had a prevalence slightly less than that of melanoma (15.0% versus 19.0% among flat lesions, respectively, and 8.1% versus 11.2% among all lesions, respectively). The mean age of biopsy for all junctional/lentiginous naevi was signific antly greater than that of all compound naevi (65.0 years versus 52.2 years; P = 0.001). Junctional/lentiginous naevi were significantly more associated with the neck than intradermal naevi (P < 0.001). In conclusion, benign, flat naevi account for a significant proportion of head and neck lesions in adults ≥40 years of age, and their location alone should not outweigh their histopathology when reaching a diagnosis. PMID: 33277699 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Long-term quality of life & functional outcomes after treatment of oropharyngeal cancer.

p.aythelady61 shared this article with you from Inoreader Long-term quality of life & functional outcomes after treatment of oropharyngeal cancer. Via Head and Neck Related Articles Long-term quality of life & functional outcomes after treatment of oropharyngeal cancer. Cancer Med. 2020 Dec 04;: Authors: Scott SI, Kathrine Ø Madsen A, Rubek N, Charabi BW, Wessel I, Fredslund Hadjú S, Jensen CV, Stephen S, Patterson JM, Friborg J, Hutcheson KA, Kehlet H, von Buchwald C Abstract Functional and QoL outcomes were compared longitudinally in a cohort of patients treated for oropharyngeal squamous cell carcinoma (OPSCC) with primary transoral robotic surgery (TORS) or radiotherapy (RT). Forty-four patients undergoing primary TORS (n = 31) or RT (n = 13) for any stage OPSCC were included. Only low-stage disease was treated with TORS. Functional outcomes were: salivary flow rate, image-based swallowing function, and a self-reported 10-point scale comparing current swallowing function to baseline (CvB scale). QoL was assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30), Head & Neck Module (EORTC QLQ-HN35), and MD Anderson Dysphagia Inventory (MDADI). Shoulder impairment was assessed with Neck Dissection Impairment Index (NDII) and Oxford Shoulder Score (OSS). In the RT group, salivary flow rates had significantly declined at 12-month follow-up, with the biggest dec lines in QoL subscale scores recorded in the RT group for dry mouth and sticky saliva. Swallowing function on imaging studies was overall good, with no severe dysphagia within 1 year although, both treatment groups showed significant deterioration relative to baseline at the 12-month follow-up with increased DIGEST scores and pharyngeal retention. Shoulder impairment was rare at 1 year in both groups. A comprehensive examination of this cohort treated for OPSCC showed overall good functional and QoL outcomes 1 year after treatment. However, persistent impairment was seen in both groups with regards to swallowing function. In the TORS group, at 12-months follow-up, the QoL questionnaires showed worse scores in only one subscale (sticky saliva). PMID: 33277795 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Micro-RNAs signatures in papillary thyroid carcinoma.

p.aythelady61 shared this article with you from Inoreader Micro-RNAs signatures in papillary thyroid carcinoma. Via Head and Neck Related Articles Micro-RNAs signatures in papillary thyroid carcinoma. J BUON. 2020 Sep-Oct;25(5):2144-2146 Authors: Mastronikolis N, Tsiambas E, Roukas D, Fotiades P, Chrysovergis A, Papanikolaou V, Kyrodimos E, Mastronikoli S, Niotis A, Ragos V Abstract Among biomarkers that should be useful for a molecular discrimination of patients regarding treatment strategies and prognosis in solid malignancies, novel micro-RNAs (miRs) are under investigation. Quite recently, miRs are considered very promising and significant genetic markers for categorizing patients by their molecular characteristics, as well as extending their complicated genetic signatures. miRs are short, non-coding RNAs consisting of 20-25 nucleotides located at intra- or inter-gene regions. Functional miRs mediate a positive regulation of posttranscriptional gene silencing. Their deregulation in cancer cells due to genetic (e.g., mutations, translocations), epigenetic (e.g., DNA hyper-methylation of tumor suppressor genes, extensive genomic DNA hypo-methylation, aberrant histone modification patterns) and transcriptional alterations lead to a loss of miRs-mediated repression of target mRNA. Interestingly, a biphasic role of miRs in cancers of different histogeneti c origin has been confirmed. In some of them, their upregulation is correlated with an increased oncogenic activity, whereas in others, the same miR type acts as a suppressor agent. Thyroid carcinoma comprises different histological subtypes, such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), anaplastic thyroid cancer (ATC), and medullary thyroid carcinoma. In the current molecular review, we explored the role of a specific fraction of miRs in PTC subtype by categorizing them according to their up- or down-regulation status. PMID: 33277828 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Research on the efficacy of laryngendoscopic low-temperature plasma ablation on early glottic cancer.

p.aythelady61 shared this article with you from Inoreader Research on the efficacy of laryngendoscopic low-temperature plasma ablation on early glottic cancer. Via Head and Neck Related Articles Research on the efficacy of laryngendoscopic low-temperature plasma ablation on early glottic cancer. J BUON. 2020 Sep-Oct;25(5):2382-2388 Authors: Jing J, Li L, Zheng L, Wu Y, Jiang S, Zhang L, Wang H, Liu G Abstract PURPOSE: To evaluate the efficacy and safety of self-retaining laryngendoscope-assisted low-temperature plasma ablation (LTPA) in the treatment of patients with early glottic cancer. METHODS: The clinical data of 84 patients with early glottic cancer treated in our department from May 2013 to May 2016 were collected. All patients were divided into the Plasma group (n=42, treated with the laryngendoscopic LTPA) and the Laryngofissure group (n=42, treated with traditional laryngofissure). The operation conditions, pain and cough visual analogue scale (VAS) scores, postoperative complications, mucosal recovery and voice recovery indexes were compared between the two groups, the postoperative recurrence rate was recorded, and the patients were followed up for tumor recurrence and survival. RESULTS: In the Plasma group, the operation time was significantly shorter than that in the Laryngofissure group, the amount of intraoperative bleeding was significantly less than that in the Laryngofissure group (p<0.001), and the postoperative hospitalization time was also significantly shorter than that in the Laryngofissure group. The postoperative pain and cough VAS scores in the Plasma group were obviously lower than those in the Laryngofissure group. The proportion of smooth vocal mucosa after operation in the Plasma group was evidently higher than that in the Laryngofissure group. In Plasma group, the voice parameters Jitter, Shimmer and harmonic to noise ratio (HNR) were all remarkably superior to those in the Laryngofissure group. The overall survival (OS) and progression-free survival (PFS) had no statistically significant differences between the two groups according to the log-rank test. CONCLUSIONS: Self-retaining laryngendoscope-assisted LTPA has definite efficacy in the treatment of early glottic cancer, after which the recurrence rate and survival rate are similar to those after open laryngofissure, but LTPA is characterized by short operation time, less postoperative bleeding, quick recovery of patients and better voice recovery. PMID: 33277859 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.