71 research outputs found
Diffusing Alpha-Emitters Radiation Therapy in Combination With Temozolomide or Bevacizumab in Human Glioblastoma Multiforme Xenografts
Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients
Interaction between the microbiome and TP53 in human lung cancer.
BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort.
RESULTS: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas.
CONCLUSIONS: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection
Spectrométrie de Masse d'Hétérocycles Azotés. IX—Structure des Ions [MCH2CO]+⋅ Formés à Partir des Ions Moléculaires d'Acétamido-2 Benzazoles et mixage d'Hydrogěnes avant leur Fragmentation
Electron-impact-induced fragmentation of some isomeric cyclopropyl picolyl and pyridyl ketones
Elektronenstoßinduzierte Etherspaltung durch anchimere Beteiligung von Silyl- und Germylgruppen
Fast atom bombardment and tandem mass spectrometry for structure determination: Remote site fragmentation of steroid conjugates and bile salts
Decomposition channels alternative to remote-charge fragmentations observed in mass spectrometry of alkyltrimethylammonium cations
Immunohisto(cyto)chemistry: an old time classic tool driving modern oncological therapies
In the era of precision medicine
immunohistochemistry (IHC) and immunocytochemistry
(ICC) share some of the highlights in personalized
treatment. Survival data obtained from clinical trials
shape the cut-offs and IHC scoring that serve as
recommendations for patient selection both for targeted
and conventional therapies. Assessment of Estrogen and
Progesterone Receptors along with HER2 status has
been among the first approved immunostaining assays
revolutionizing breast cancer treatment. Similarly, ALK
positivity predicts the efficacy of ALK inhibitors in
patients with non-small cell lung cancer (NSCLC). In
recent years, Programmed Death Ligand 1 (PD-L1) IHC
assays have been approved as companion or
complimentary diagnostic tools predicting the response
to checkpoint inhibitors. Anti-PD-L1 and anti-PD-1
monoclonal antibodies have inaugurated a new period in
the treatment of advanced cancers, but the path to
approval of these biomarkers is filled with
immunohistochemical challenges. The latter brings to
the fore the significance of molecular pathology as a hub
between basic and clinical research. Besides, novel
markers are translated into routine practice, suggesting
that we are at the beginning of a new exciting period.
Unraveling the molecular mechanisms involved in
cellular homeostasis unfolds biomarkers with greater
specificity and sensitivity. The introduction of GL13
(SenTraGor®) for the detection of senescent cells in
archival material, the implementation of key players of
stress response pathways and the development of
compounds detecting common mutant P53 isoforms in
dictating oncological treatments are paradigms for
precision oncology
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