نتائج البحث

91

Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis

المؤلفون: Changzhong Li, Chong Wang, Hui Zhang, Xiaoyan Qin, Wenjing Sun, Xingbo Zhao, Mingjiang Li

المصدر: Reproductive Biology and Endocrinology : RB&E
Reproductive Biology and Endocrinology, Vol 19, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: 0301 basic medicine, Adult, B7 Antigens, QH471-489, PD-L2, Gene Expression, Andrology, 03 medical and health sciences, Endometrium, Inducible T-Cell Co-Stimulator Ligand, 0302 clinical medicine, Endocrinology, Immune system, Hormone Antagonists, Downregulation and upregulation, Follicular phase, medicine, Humans, Adenomyosis, Immune Checkpoint Inhibitors, Chemistry, Reproduction, Research, Obstetrics and Gynecology, Gynecology and obstetrics, Mifepristone, Middle Aged, V-Set Domain-Containing T-Cell Activation Inhibitor 1, medicine.disease, Programmed Cell Death 1 Ligand 2 Protein, Pathophysiology, Immune checkpoint, B7-H2, 030104 developmental biology, B7-H4, Reproductive Medicine, B7-H3, 030220 oncology & carcinogenesis, RG1-991, Immunohistochemistry, Female, Developmental Biology, medicine.drug

الوصف: Background The immune mechanism was shown to be involved in the development of adenomyosis. The aim of the current study was to evaluate the expression of the immune checkpoints B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis and to explore the effect of mifepristone on the expression of these immune checkpoints. Methods The expression of B7-H2, B7-H3, B7-H4 and PD-L2 in normal endometria and adenomyosis patient samples treated with or without mifepristone was determined by immunohistochemistry analysis. Results In adenomyosis patient samples, the expression of B7-H2, B7-H3 and B7-H4 was increased in the eutopic and ectopic endometria compared with normal endometria, both in the proliferative and secretory phases. Moreover, the expression of B7-H2 and B7-H3 was higher in adenomyotic lesions than in the corresponding eutopic endometria, both in the proliferative and secretory phases. The expression of PD-L2 was higher in adenomyotic lesions than in normal endometria in both the proliferative and secretory phases. In the secretory phase but not the proliferative phase, the expression of B7-H4 and PD-L2 in adenomyotic lesions was significantly higher than that in the corresponding eutopic endometria. In normal endometria and eutopic endometria, the expression of B7-H4 was elevated in the proliferative phase compared with that in the secretory phase, while in the ectopic endometria, B7-H4 expression was decreased in the proliferative phase compared with the secretory phase. In addition, the expression of B7-H2, B7-H3, B7-H4 and PD-L2 was significantly decreased in adenomyosis tissues after treatment with mifepristone. Conclusions The expression of the immune checkpoint proteins B7-H2, B7-H3, B7-H4 and PD-L2 is upregulated in adenomyosis tissues and is downregulated with mifepristone treatment. The data suggest that B7 immunomodulatory molecules are involved in the pathophysiology of adenomyosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f812779031b0faa979f2ce47a4cafd8cTest
http://europepmc.org/articles/PMC8293536Test

92

Prognostic significance of hypoxia-inducible factor-1α expression in advanced pharyngeal cancer without human papillomavirus infection

المؤلفون: Hiroyuki Maeda, Shunsuke Kondo, Narumi Hasegawa, Asanori Kiyuna, Hitoshi Hirakawa, Shinya Agena, Mikio Suzuki, Yukashi Yamashita, Noritomo Kise, Jin Uezato, Akira Ganaha, Taro Ikegami, Hidetoshi Kinjyo

المصدر: The Journal of laryngology and otology. 135(7)

مصطلحات موضوعية: Oncology, Adult, Male, medicine.medical_specialty, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Risk factor, Stage (cooking), 030223 otorhinolaryngology, Aged, Neoplasm Staging, Aged, 80 and over, Univariate analysis, Hypopharyngeal Neoplasms, business.industry, Squamous Cell Carcinoma of Head and Neck, Glucose transporter, Hypopharyngeal cancer, Pharyngeal Neoplasms, General Medicine, Middle Aged, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Prognosis, Immunohistochemistry, Survival Rate, Oropharyngeal Neoplasms, Pharyngeal Neoplasm, Otorhinolaryngology, Excitatory Amino Acid Transporter 2, 030220 oncology & carcinogenesis, Multivariate Analysis, Female, business, Glucose Transporter Type 1

الوصف: ObjectiveThis study aimed to clarify the association between both hypoxia-inducible factor-1α and glucose transporter type-1 expression and survival outcome in advanced pharyngeal cancer without human papillomavirus infection.MethodTwenty-five oropharyngeal and 55 hypopharyngeal cancer patients without human papillomavirus infection were enrolled. All patients had stage III–IV lesions and underwent concurrent chemoradiotherapy or surgery. Hypoxia-inducible factor-1α and glucose transporter type-1 expression were investigated in primary lesions by immunohistochemistry.ResultsThere were 41 and 39 cases with low and high hypoxia-inducible factor-1α expression, and 28 and 52 cases with low and high glucose transporter type-1 expression, respectively. There was no significant correlation between hypoxia-inducible factor-1α and glucose transporter type-1 expression. In univariate analysis, nodal metastasis, clinical stage and high hypoxia-inducible factor-1α expression, but not glucose transporter type-1 expression, predicted significantly worse prognosis. In multivariate analysis, hypoxia-inducible factor-1α overexpression was significantly correlated with poor overall survival, disease-specific survival and recurrence-free survival.ConclusionHigh hypoxia-inducible factor-1α expression was an independent risk factor for poor prognosis for advanced human papillomavirus-unrelated pharyngeal cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5cb55a7cfe4fecd6fc280b6d6b47011cTest
https://pubmed.ncbi.nlm.nih.gov/34108057Test

93

ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

المؤلفون: Laris Achlaug, Lina Somri-Gannam, Zvi Laron, Ilan Bruchim, Shoshana Yakar, Haim Werner, Manisha Dixit, Mordechai Hallak, Shilhav Meisel-Sharon, Rive Sarfstein

المصدر: Frontiers in Endocrinology
Frontiers in Endocrinology, Vol 12 (2021)

مصطلحات موضوعية: 0301 basic medicine, p53, Adult, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Cell Cycle Proteins, Growth hormone receptor, Disease, Carcinoma, Ovarian Epithelial, Diseases of the endocrine glands. Clinical endocrinology, Receptor, IGF Type 1, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Medicine, Animals, Humans, Receptor, Pathological, IGF1 receptor, Insulin-like growth factor 1 receptor, Original Research, Aged, Aged, 80 and over, Ovarian Neoplasms, business.industry, Ovary, Middle Aged, medicine.disease, RC648-665, ZYG11A, Gene Expression Regulation, Neoplastic, 030104 developmental biology, ovarian cancer, insulin-like growth factor-1 (IGF1), 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, Biomarker (medicine), Female, Neoplasm Grading, Tumor Suppressor Protein p53, business, Ovarian cancer

الوصف: The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::673a50450e7c43d5d5e986cb44f6752eTest
http://europepmc.org/articles/PMC8249937Test

94

Gonadotroph tumours with a low SF‐1 labelling index are more likely to recur and are associated with enrichment of the PI3K‐AKT pathway

المؤلفون: Pamela U. Freda, Beatriz Lopes, Markus D. Siegelin, Phyllis L. Faust, Alexander G. Khandji, Marc L. Otten, Xena E. Flowers, Richard A. Hickman, Jeffrey N. Bruce

المصدر: Neuropathol Appl Neurobiol

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Histology, Steroidogenic Factor 1, Article, Pathology and Forensic Medicine, Cohort Studies, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, SOX2, Physiology (medical), Labelling, Biomarkers, Tumor, medicine, Humans, Pituitary Neoplasms, Prospective cohort study, Gene, PI3K/AKT/mTOR pathway, Aged, business.industry, Middle Aged, Staining, Neuroendocrine Tumors, 030104 developmental biology, Neurology, Immunohistochemistry, Female, Neurology (clinical), Neoplasm Recurrence, Local, Stem cell, business, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Signal Transduction

الوصف: AIMS: The gonadotroph tumour (GT) is the most frequently resected pituitary neuroendocrine tumour. Whilst many symptomatic GT are successfully resected, some recur. We sought to identify histological biomarkers that may predict recurrence and explore biological mechanisms that explain this difference in behaviour. METHODS: SF-1 immunohistochemistry of 51 GT, a subset belonging to a longitudinal prospective cohort study (n=25), were reviewed. Four groups were defined: Group 1- recently diagnosed GT (n=20), Group 2- non-recurrent GT with long-term follow up (n=11), Group 3- initial resections of GT that recur (n=7), and Group 4- recurrent GT (n=13). The percentage of SF-1 immunolabeling in the lowest staining fields (SF-1 labelling index (SLI)) was assessed and RNA sequencing was performed on 5 GT with SLI80%. RESULTS: Diffuse, strong SF-1 immunolabelling was the most frequent pattern in Groups 1/2, whereas patchy SF-1 staining predominated in Groups 3/4. There was a lower median SLI in Groups 3/4 than 1/2. Overall, GT with SLI80%. Differential expression analysis identified 89 statistically significant differentially expressed genes (FDR

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d55771abd4680c011caeeca6a1d9975Test
https://doi.org/10.1111/nan.12675Test

95

Clinical Evaluation of P21 Activated Kinase 1 (PAK1) Activation in Gliomas and Its Effect on Cell Proliferation

المؤلفون: Venu Akkanapally, Ganesh Krishnamurthy, Archana B, Sowmiya Murugan, Veena Kumari Vuttaradhi, D Prathiba, Dymova Mayya Alexandrovna, Rahul Kanumuri, Lawrence D'Cruze, Ganesh Venkatraman, Rayala Suresh Kumar

المصدر: Cancer Investigation. 39:98-113

الوصف: Glioblastomas are the primary malignant tumors of brain tissues with poor prognosis and highly invasive phenotypes. Till now Ki-67 LI has emerged as a well-studied proliferation marker that aids in tumor grading, but labeling index alone cannot predict overall survival in gliomas. P21 activated kinase 1 (PAK1) - a serine/threonine kinase has been shown to function as downstream nodule for various oncogenic signaling pathways that promote neoplastic changes. This study is designed to evaluate the expression of PAK1 across various grades and its correlation with Ki-67 LI and overall survival rates among a total number of 140 clinical brain tumors of glioma patients. We also studied the activation status of phospho PAK1 in glioma tissues and established the role of PAK1 in proliferation of glioblatoma cell lines under γ-irradiation.This study provides molecular evidence signifying the role of PAK1 and its activation status in the progression of Gliomas to more aggressive phenotypes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5fff7db336576c387235aab93943de97Test
https://doi.org/10.1080/07357907.2020.1858097Test

96

Immune phenotype of patients with stage IV metastatic inflammatory breast cancer

المؤلفون: Lakshmanan Annamalai, Yulan Gong, Sandra V. Fernandez, R. Katherine Alpaugh, Mowafaq Jillab, Kathy Q. Cai, Maria F. Arisi, Kerry S. Campbell, Alexander W. MacFarlane, Jennifer H. Yearley, Massimo Cristofanilli

المصدر: Breast Cancer Research, Vol 22, Iss 1, Pp 1-16 (2020)
Breast Cancer Research : BCR

مصطلحات موضوعية: CD3 Complex, Lymphocyte, medicine.medical_treatment, Biopsy, T-Lymphocytes, Programmed Cell Death 1 Receptor, NK cells, Lymphocyte Activation, Tumor-infiltrating lymphocytes, B7-H1 Antigen, 0302 clinical medicine, PD-1, Breast, skin and connective tissue diseases, 0303 health sciences, Immunity, Cellular, Inflammatory breast cancer (IBC), Middle Aged, Flow Cytometry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, medicine.anatomical_structure, Tumor microenvironment, 030220 oncology & carcinogenesis, Female, Inflammatory Breast Neoplasms, Immunotherapy, Checkpoint inhibitors, Research Article, Adult, PD-L1, T cell, Stage IV IBC, T cells, lcsh:RC254-282, Immunophenotyping, 03 medical and health sciences, Immune system, Lymphocytes, Tumor-Infiltrating, Lymphopenia, medicine, Biomarkers, Tumor, Humans, 030304 developmental biology, Aged, Neoplasm Staging, Retrospective Studies, Cytolytic granule, business.industry, Carcinoma, Antigens, CD20, Metastatic IBC, Case-Control Studies, Cancer research, business, CD8

الوصف: Background Inflammatory breast cancer (IBC) is a rare but aggressive carcinoma characterized by severe erythema and edema of the breast, with many patients presenting in advanced metastatic disease. The “inflammatory” nature is not due to classic immune-mediated inflammation, but instead results from tumor-mediated blockage of dermal lymphatic ducts. Previous work has shown that expression of PD-L1 on tumor cells can suppress T cell activation in triple-negative (TN) non-IBC breast cancer. In the present work, we investigated immune parameters in peripheral blood of metastatic IBC patients to determine whether cellular components of the immune system are altered, thereby contributing to pathogenesis of the disease. These immune parameters were also compared to PD-1 and PD-L1 expression in IBC tumor biopsies. Methods Flow cytometry-based immune phenotyping was performed using fresh peripheral blood from 14 stage IV IBC patients and compared to 11 healthy age-similar control women. Immunohistochemistry for CD20, CD3, PD-1, and PD-L1 was performed on tumor biopsies of these metastatic IBC patients. Results IBC patients with Stage IV disease had lymphopenia with significant reductions in circulating T, B, and NK cells. Reductions were observed in all subsets of CD4+ T cells, whereas reductions in CD8+ T cells were more concentrated in memory subsets. Immature cytokine-producing CD56bright NK cells expressed higher levels of FcγRIIIa and cytolytic granule components, suggesting accelerated maturation to cytolytic CD56dim cells. Immunohistochemical analysis of tumor biopsies demonstrated moderate to high expression of PD-1 in 18.2% of patients and of PD-L1 in 36.4% of patients. Interestingly, a positive correlation was observed between co-expression levels of PD-L1 and PD-1 in tumor biopsies, and higher expression of PD-L1 in tumor biopsies correlated with higher expression of cytolytic granule components in blood CD4+ T cells and CD56dim NK cells, and higher numbers of CD8+ effector memory T cells in peripheral blood. PD-1 expression in tumor also correlated with increased infiltration of CD20+ B cells in the tumor. Conclusions Our results suggest that while lymphocyte populations are severely compromised in stage IV IBC patients, an immune response toward the tumor had occurred in some patients, providing biological rationale to evaluate PD-1/PD-L1 immunotherapies for IBC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::854eee64edb0e7cbc484af024b57a732Test
https://doaj.org/article/6bbb7ddf9f254fc4a9ff80dea3bff104Test

97

Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome

المؤلفون: Luis J Leandro-García, Guillermo Velasco, Bruna Calsina, Georgia Anguera, Pablo Maroto, Rocío Letón, Maria José Santos, María Monteagudo, Ángel M Martínez-Montes, Eduardo Caleiras, Jesús García-Donas, Cristina Rodríguez-Antona, Cristina Montero-Conde, Alberto Cascón, Javier Lanillos, Mercedes Robledo, Juan María Roldan-Romero

المصدر: MODERN PATHOLOGY
r-IIB SANT PAU: Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
Institut dInvestigació Biomèdica Sant Pau (IIB Sant Pau)
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, DNA Mutational Analysis, Chromophobe Renal Cell Carcinoma, medicine.disease_cause, Tuberous Sclerosis Complex 1 Protein, Pathology and Forensic Medicine, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Tuberous Sclerosis Complex 2 Protein, Biomarkers, Tumor, Carcinoma, Humans, Medicine, PTEN, Genetic Predisposition to Disease, Phosphorylation, Carcinoma, Renal Cell, PI3K/AKT/mTOR pathway, Survival analysis, Aged, Aged, 80 and over, Mutation, biology, business.industry, Ribosomal Protein S6 Kinases, TOR Serine-Threonine Kinases, PTEN Phosphohydrolase, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, Immunohistochemistry, Kidney Neoplasms, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Tumor Suppressor Protein p53, business

الوصف: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a50154d9d97b395a18bd54a21f25602Test
https://doi.org/10.1038/s41379-020-0607-zTest

98

INSM1 immunostaining in solid papillary carcinoma of the breast

المؤلفون: Noritaka Kudo, Nobuyuki Arima, Jun Takano, Shinji Kudoh, Takaaki Ito

المصدر: Pathology International. 71:51-59

الوصف: Solid papillary carcinoma (SPC) is a histological subtype of breast carcinomas. At least 50% of SPC show neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a transcription factor now employed as a useful neuroendocrine marker. It is suppressed by the Notch signaling pathway in other neuroendocrine tumors. However, the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC of the breast currently remain unclear. To clarify the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC, we performed immunohistochemistry using 19 tissue specimens of SPC of the breast. We complementarily analyzed public RNA sequencing data on breast carcinomas. Immunohistochemical examinations revealed that the staining intensity of INSM1 was significantly higher in the neuroendocrine group than in the non-neuroendocrine group. Positive correlations were observed between INSM1 and synaptophysin (SYP), or chromogranin-A (CHGA). In all cases, NOTCH 2 and 3 were positive, while NOTCH 1 and 4 were negative. According to public RNA data analyses, there were positive correlations between INSM1 and SYP, or CHGA, and negative correlations between INSM1 and NOTCH1-3. INSM1 is useful as a diagnostic marker for SPC with neuroendocrine differentiation in the breast.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb62a02db13cdcc737323651a537b026Test
https://doi.org/10.1111/pin.13043Test

99

High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient

المؤلفون: Elena Anghileri, Junfei Zhao, Valeria Cuccarini, Gaetano Finocchiaro, Monica Patanè, Natalia Di Ianni, Marica Eoli, Tiziana Langella, Antonio Iavarone, Serena Pellegatta, Raul Rabadan, Bianca Pollo, Rosina Paterra

المصدر: Cancer Immunology, Immunotherapy. 70:831-842

مصطلحات موضوعية: Adult, Cancer Research, Biopsy, T-Lymphocytes, T cell, Programmed Cell Death 1 Receptor, Immunology, Neuroimaging, Germline, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, Immune system, Exome Sequencing, Biomarkers, Tumor, Humans, Immunology and Allergy, Medicine, Molecular Targeted Therapy, Immune Checkpoint Inhibitors, Temozolomide, business.industry, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Combined Modality Therapy, Immunohistochemistry, Magnetic Resonance Imaging, Lynch syndrome, Treatment Outcome, medicine.anatomical_structure, Oncology, MSH2, Mutation, Retreatment, Cancer research, Female, Neoplasm Recurrence, Local, Nivolumab, Glioblastoma, business, 030215 immunology, medicine.drug

الوصف: Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91e9d6d866c397beb05c63097c4dbcb1Test
https://doi.org/10.1007/s00262-020-02769-4Test

100

دورية أكاديمية

Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis

المؤلفون: Ong C.W.M., Elkington P.T., Brilha S., Ugarte-Gil C., Tome-Esteban M.T., Tezera L.B., Pabisiak P.J., Moores R.C., Sathyamoorthy T., Patel V., Gilman R.H., Porter J.C., Friedland J.S.

المساهمون: DEPT OF MEDICINE

المصدر: Unpaywall 20191101

الوصف: 10.1371/journal.ppat.1004917 ; PLoS Pathogens ; 11 ; 5 ; e1004917

العلاقة: Ong C.W.M., Elkington P.T., Brilha S., Ugarte-Gil C., Tome-Esteban M.T., Tezera L.B., Pabisiak P.J., Moores R.C., Sathyamoorthy T., Patel V., Gilman R.H., Porter J.C., Friedland J.S. (2015). Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathogens 11 (5) : e1004917. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1004917Test; https://scholarbank.nus.edu.sg/handle/10635/161936Test

الإتاحة: https://doi.org/10.1371/journal.ppat.1004917Test
https://scholarbank.nus.edu.sg/handle/10635/161936Test

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