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JCO Precision Oncology Jun 2024HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.
HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.
Topics: Humans; Imatinib Mesylate; Infant; HMGA2 Protein; Male; Soft Tissue Neoplasms; Female; Keratins; Giant Cell Tumor of Bone; Child; Antineoplastic Agents; Bone Neoplasms; Child, Preschool
PubMed: 38935896
DOI: 10.1200/PO.23.00659 -
PloS One 2024Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account....
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
Topics: Animals; Aniline Compounds; Acrylamides; Afatinib; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mice; Humans; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Xenograft Model Antitumor Assays; ErbB Receptors; Quinazolines; Piperazines; Female; Indoles; Pyrimidines
PubMed: 38935790
DOI: 10.1371/journal.pone.0304914 -
Proceedings of the National Academy of... Jul 2024In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited...
In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited this response using the replication inhibitor azidothymidine (AZT) and RNA-Seq analysis and identified several features. We confirm the induction of classic Save our ship (SOS) loci and identify several genes, including many of the pyrimidine pathway, that have not been previously demonstrated to be DNA damage-inducible. Despite a strong dependence on LexA, these genes lack LexA boxes and their regulation by LexA is likely to be indirect via unknown factors. We show that the transcription factor "stringent starvation protein" SspA is as important as LexA in the regulation of AZT-induced genes and that the genes activated by SspA change dramatically after AZT exposure. Our experiments identify additional LexA-independent DNA damage inducible genes, including 22 small RNA genes, some of which appear to activated by SspA. Motility and chemotaxis genes are strongly down-regulated by AZT, possibly as a result of one of more of the small RNAs or other transcription factors such as AppY and GadE, whose expression is elevated by AZT. Genes controlling the iron siderophore, enterobactin, and iron homeostasis are also strongly induced, independent of LexA. We confirm that IraD antiadaptor protein is induced independent of LexA and that a second antiadaptor, IraM is likewise strongly AZT-inducible, independent of LexA, suggesting that RpoS stabilization via these antiadaptor proteins is an integral part of replication stress tolerance.
Topics: Escherichia coli; DNA Damage; Gene Expression Regulation, Bacterial; Escherichia coli Proteins; DNA Replication; SOS Response, Genetics; Bacterial Proteins; Serine Endopeptidases
PubMed: 38935560
DOI: 10.1073/pnas.2407832121 -
AIDS (London, England) Jul 2024
Topics: Humans; Female; Pregnancy; Pyridones; HIV Infections; Pregnancy Complications, Infectious; Tenofovir; Anti-HIV Agents; Oxazines; Heterocyclic Compounds, 3-Ring; Lamivudine; Piperazines; Treatment Outcome
PubMed: 38932745
DOI: 10.1097/QAD.0000000000003911 -
Pharmaceuticals (Basel, Switzerland) Jun 2024is one of the largest families of marine sponges and stands out as an exceptional source of variable metabolites with diverse biological activities. In this study, the...
is one of the largest families of marine sponges and stands out as an exceptional source of variable metabolites with diverse biological activities. In this study, the ethyl acetate fraction (HE) of a sp. marine sponge from the Red Sea, Egypt, was analyzed for the first time using Ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) analysis. The analysis tentatively identified 29 compounds in this fraction, including the isolation and identification of six compounds (two pyrimidine nucleosides, one purine, and two pyrimidine bases in addition to one cerebroside) for the first time. The structures of the isolated compounds were established by 1D and 2D NMR (nuclear magnetic resonance), MS (mass spectrometry), and IR (infrared) spectroscopy. Furthermore, the cytotoxic, antioxidant, and antimicrobial activities of the ethyl acetate fraction were evaluated in vitro. The fraction exhibited strong DPPH scavenging activity with an IC of 78.7 µg/mL, compared to ascorbic acid as a positive control with an IC of 10.6 µg/mL. It also demonstrated significant cytotoxic activity with IC values of 13.5 µg/mL and 25.3 µg/mL against HCT-116 and HEP-2 cell lines, respectively, compared to vinblastine as a positive control with IC values of 2.34 µg/mL and 6.61 µg/mL against HCT-116 and HEP-2, respectively. Additionally, the ethyl acetate fraction displayed promising antibacterial activity against with a MIC value of 62.5 µg/mL, compared to ciprofloxacin as a positive control with MIC values of 1.56 µg/mL for Gram-positive bacteria and 3.125 µg/mL for Gram-negative bacteria. It also exhibited activity against and with MIC values of 250 µg/mL and 500 µg/mL, respectively. Briefly, this is the first report on the biological activities and secondary metabolite content of the ethyl acetate fraction of sp. marine sponge, emphasizing the potential for further research against resistant bacterial and fungal strains, as well as different cancer cell lines. The ethyl acetate fraction of sp. is a promising source of safe and unique natural drugs with potential therapeutic and pharmaceutical benefits.
PubMed: 38931391
DOI: 10.3390/ph17060724 -
Nutrients Jun 2024Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate... (Review)
Review
Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.
Topics: Humans; Folic Acid; Folic Acid Deficiency; Liver Diseases; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Liver; Animals; Liver Neoplasms; Hyperhomocysteinemia; Homocysteine; Lipid Metabolism
PubMed: 38931227
DOI: 10.3390/nu16121872 -
Molecules (Basel, Switzerland) Jun 2024Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated...
Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.
Topics: Animals; Cisplatin; Acute Kidney Injury; Pyridones; Oxidative Stress; Mice; Pyrimidinones; Disease Models, Animal; Inflammation; Male; Cell Death; Apoptosis; Kidney Tubules; Lipid Peroxidation; Cytokines; MAP Kinase Signaling System
PubMed: 38930946
DOI: 10.3390/molecules29122881 -
Journal of Personalized Medicine May 2024Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a...
Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a comparative/integrative statistical analysis of seminal immunohistochemistry (IHC) findings for Wilms' Tumor 1 antigen (WT1) and thymine dimers (TDs), emerging as atypical, yet promising, potential biomarkers for RCCs. We assessed WT1/TD reactivity in adult RCC tumor cells, tumor microenvironment (TME), and tumor-adjacent healthy renal tissue (HRT). WT1 positivity was scarce and strictly nuclear in tumor cells, whereas TD-reactive tumor tissues were prevalent. We report statistically significant positive correlations between the density of reactive RCC cellularity and the intensity of nuclear staining for both biomarkers (WT1 - rho = 0.341, -value = 0.036; TDs - rho = 0.379, -value = 0.002). RCC stromal TME TD-positivity was much more frequent than WT1 reactivity, apparently proportional to that of the proper RCC cellularity and facilitated by extensive RCC inflammatory infiltration. TDs exhibited nuclear reactivity for most TME cell lines, while RCC TME WT1 expression was rare and inconsistent. In HRTs, TDs were entirely restricted to renal tubular cells, the likely cellular progenitor of most conventional RCC subtypes. In lieu of proper validation, these early findings have significant implications regarding the origins/biology of RCCs and may inform RCC therapeutics, both accounting for the high frequency of immunotherapy-permissive frameshift indels in RCCs, but also hinting at novel predictive clinical tools for WT1-targeted immunotherapy. Overall, the current study represents a meek yet hopefully significant step towards understanding the molecular biology and potential therapeutic targets of RCCs.
PubMed: 38929778
DOI: 10.3390/jpm14060557 -
Medicina (Kaunas, Lithuania) Jun 2024Colorectal cancer is a major global health concern, with a significant increase in morbidity and mortality rates associated with metastatic stages. This study...
Influence of Biomarkers on Mortality among Patients with Hepatic Metastasis of Colorectal Cancer Treated with FOLFOX/CAPOX and FOLFIRI/CAPIRI, Including Anti-EGFR and Anti-VEGF Therapies.
Colorectal cancer is a major global health concern, with a significant increase in morbidity and mortality rates associated with metastatic stages. This study investigates the prognostic significance of various clinical and laboratory parameters in patients with metastatic CRC. A retrospective cohort of 188 CRC patients with hepatic metastasis from the OncoHelp Association in Timisoara was analyzed from January 2016 to March 2023. Data on demographics, clinical characteristics, and biomarkers, such as lymphocyte counts, as well as various inflammation indices, were examined. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier survival analysis, and ROC curve assessments. Our findings indicate significant associations between survival outcomes and several biomarkers. Higher BMI and lymphocyte counts were linked with better survival rates, while higher values of Neutrophil-Hemoglobin-Lymphocyte (NHL) score, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), and Systemic Immune-Inflammation Index (SII) were predictors of poorer outcomes. Notably, the presence of hepatic metastasis at diagnosis was a critical factor, significantly reducing overall survival. The study has expanded the current understanding of prognostic factors in CRC, advocating for a multi-dimensional approach to prognostic evaluations. This approach should consider not only the traditional metrics such as tumor stage and histological grading but also incorporate a broader spectrum of biomarkers. Future studies should aim to validate these findings and explore the integration of these biomarkers into routine clinical practice, enhancing the precision of prognostic assessments and ultimately guiding more personalized treatment strategies for CRC patients.
Topics: Humans; Colorectal Neoplasms; Male; Female; Middle Aged; Liver Neoplasms; Retrospective Studies; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Leucovorin; Organoplatinum Compounds; Camptothecin; Adult; Biomarkers, Tumor; Prognosis; ErbB Receptors; Kaplan-Meier Estimate
PubMed: 38929620
DOI: 10.3390/medicina60061003 -
Medicina (Kaunas, Lithuania) May 2024: Gemcitabine has been used to treat various solid cancers, including, since 1997, metastatic pancreatic cancer. Here, we developed an HPLC-UV method to determine serum...
: Gemcitabine has been used to treat various solid cancers, including, since 1997, metastatic pancreatic cancer. Here, we developed an HPLC-UV method to determine serum gemcitabine levels and use it in pharmacokinetic studies. : The analysis was performed after a single protein precipitation step on a reversed-phase column, isocratically eluted with sodium phosphate buffer and methanol. For the pharmacokinetic study, NOD/SCID mice received a single dose of gemcitabine at 100 mg/kg by either subcutaneous (SC) or intraperitoneal (IP) administration. Blood samples were collected at 5, 15, and 30 min and 1, 2, 4, and 6 h after the administration of gemcitabine for further analysis. : The duration of the analysis was ~12.5 min. The calibration curve was linear (r = 0.999) over the range of 1-400 μM. The mean recovery of GEM was 96.53% and the limit of detection was 0.166 μΜ. T, Tmax, Cmax, AUC, and clearance were 64.49 min, 5.00 min, 264.88 μmol/L, 9351.95 μmol/L*min, and 0.0103(mg)/(μmol/L)/min, respectively, for the SC administration. The corresponding values for the IP administration were 59.34 min, 5.00 min, 300.73 μmol/L, 8981.35 μmol/L*min and 0.0108(mg)/(μmol/L)/min (not statistically different from the SC administration). : A simple, valid, sensitive, and inexpensive method for the measurement of gemcitabine in serum has been developed. This method may be useful for monitoring gemcitabine levels in cancer patients as part of therapeutic drug monitoring.
Topics: Deoxycytidine; Gemcitabine; Chromatography, High Pressure Liquid; Animals; Mice; Reproducibility of Results; Mice, SCID; Antimetabolites, Antineoplastic; Mice, Inbred NOD
PubMed: 38929481
DOI: 10.3390/medicina60060864