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Journal of Cancer Research and Clinical... Sep 2021Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions...
PURPOSE
Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044.
METHODS
DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions.
RESULTS
A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells.
CONCLUSION
The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia; Ligands; Mitochondria; Neoplasms; Tumor Cells, Cultured
PubMed: 34213662
DOI: 10.1007/s00432-021-03679-3 -
Apoptosis : An International Journal on... Aug 2022The process of spermatogenesis features significant germ cell loss through apoptosis. Routine histology of the testes of well-studied animal models hardly discloses any... (Review)
Review
The process of spermatogenesis features significant germ cell loss through apoptosis. Routine histology of the testes of well-studied animal models hardly discloses any trace of their phagocytic clearance by the supporting Sertoli cells. This review highlights lessons learnt from the cystic, diametric testes of some seasonally migrating elasmobranchs (e.g., spiny dogfish and blue sharks) that offer unconventional investigative paradigms to study these phenomena as these organs readily disclose a pronounced apoptosis gradient affecting exclusively spermatogonial clones that each are enclosed with their own Sertoli cells in spherical structures called spermatocysts. This gradient is visible at a certain time of year in the spermatogenically active shark, and peaks in mature spermatogonial cysts as clustered deaths with sporadic, and not massive secondary necrosis. Conversely, immature spermatogonial cysts in blue sharks reveal a characteristic periluminal display of single apoptotic deaths. Tracing aberrations in the immunostaining patterns of the conserved cell cycle marker, proliferating cell nuclear antigen, the gradual progression of the death process in individual or coalesced spermatogonia in contiguous cysts becomes clear. The multiple apoptotic nuclear fragmentation morphologies inform also of a protracted death process involving three different morphological routes of nuclear fragmentation (of which some are TUNEL-positive and other TUNEL-negative) and concomitant chromatin compaction that culminate in freed apoptotic bodies (i.e., secondary necrosis). It is discussed that the staggered spermatogonial deaths and accompanying intermittent secondary necrosis in mature blue shark spermatogonial cysts may well relate to the low phagocytosis capacity of cyst's Sertoli cells that are still functionally naïve.
Topics: Animals; Apoptosis; Cysts; Elasmobranchii; Male; Necrosis; Testis
PubMed: 35672487
DOI: 10.1007/s10495-022-01733-0 -
Critical Reviews in Oncology/hematology Sep 2019Liquid biopsy can quantify and qualify cell-free (cfDNA) and tumour-derived (ctDNA) DNA fragments in the bloodstream. CfDNA quantification and mutation analysis can be... (Review)
Review
Liquid biopsy can quantify and qualify cell-free (cfDNA) and tumour-derived (ctDNA) DNA fragments in the bloodstream. CfDNA quantification and mutation analysis can be applied to diagnosis, follow-up and therapeutic management as novel oncologic biomarkers. However, some tumor-types release a low amount of DNA into the bloodstream, hampering diagnosis through standard liquid biopsy procedures. Several tumors, as such as brain, kidney, prostate, and thyroid cancer, are in direct contact with other body fluids and may be alternative sources for cfDNA and ctDNA. Non-blood sources of cfDNA/ctDNA useful as novel oncologic biomarkers include cerebrospinal fluids, urine, sputum, saliva, pleural effusion, stool and seminal fluid. Seminal plasma cfDNA, which can be analyzed with cost-effective procedures, may provide powerful information capable to revolutionize prostate cancer (PCa) patient diagnosis and management. In the near future, cfDNA analysis from non-blood biological liquids will become routine clinical practice for cancer patient diagnosis and management.
Topics: Biomarkers, Tumor; Cell-Free Nucleic Acids; Circulating Tumor DNA; DNA Mutational Analysis; Feces; Female; Gene Expression Profiling; Humans; Liquid Biopsy; Male; Medical Oncology; Neoplasms; Pathology, Clinical; Prostatic Neoplasms; Urinalysis
PubMed: 31212145
DOI: 10.1016/j.critrevonc.2019.06.005 -
Journal of Assisted Reproduction and... Oct 2018To provide a commentary on our understanding of the role that the Hippo signaling pathway may play in patients with polycystic ovarian syndrome (PCOS) and how this... (Review)
Review
PURPOSE
To provide a commentary on our understanding of the role that the Hippo signaling pathway may play in patients with polycystic ovarian syndrome (PCOS) and how this understanding may impact the diagnosis of PCOS.
METHODS
We assessed publications discussing the role of the Hippo signaling pathway in the ovary. In particular, we discuss how Hippo signaling disruption after ovarian fragmentation, combined with treating ovarian fragments with phosphatase and tensin homolog (PTEN) inhibitors and phosphoinositide-3-kinase stimulators to augment AKT signaling, has been used in treatment of patients with primary ovarian insufficiency. Furthermore, we discuss our own data on variations in Hippo signaling pathway gene expression in cumulus cells isolated from women undergoing IVF with a previous diagnosis of PCOS.
RESULTS AND CONCLUSIONS
Aberrant Hippo signaling in PCOS patients is likely a contributing mechanism to the multifactorial etiology of the disease. Given the challenge of discerning the underlying etiology of oligo-ovulation in some patients, especially those with normal body mass indices, and the need for customized stimulation protocols for PCOS patients who have an increased risk of over-response and higher percentage of immature oocyte yield, it is important to identify these patients prior to treatment. Hippo gene expression fingerprints could potentially be used to more accurately define patients with PCOS. Additionally, targeting this pathway with pharmacologic agents could lead to non-surgical therapeutic options for PCOS.
Topics: Female; Fertilization in Vitro; Hippo Signaling Pathway; Humans; Infertility, Female; Oocytes; Ovary; Polycystic Ovary Syndrome; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 30120633
DOI: 10.1007/s10815-018-1235-0 -
Disease Markers 2013Cholangiocarcinoma (CCA) is a relatively rare type of primary liver cancer that originates in the bile duct epithelium. It is an aggressive malignancy typified by... (Review)
Review
Cholangiocarcinoma (CCA) is a relatively rare type of primary liver cancer that originates in the bile duct epithelium. It is an aggressive malignancy typified by unresponsiveness to chemotherapy and radiotherapy. Despite advances in radiologic techniques and laboratory diagnostic test, the diagnosis of CCA remains highly challenging. Development in molecular techniques has led to go into the possible use of serum markers in diagnosing of cholangiocarcinoma. This review summarizes the principal characteristics of serum markers of cholangiocarcinoma. The tumour markers used frequently such as Carbohydrate antigen 19-9 (CA 19-9), Carcinogenic Embryonic antigen (CEA), and Cancer Antigen 125 have shown sufficient sensitivity and specificity to detect and monitor CCA. In particular, the combination of these tumour markers seems to increase their efficiency in diagnosing of cholangiocarcinoma. New markers such as Soluble fragment of cytokeratin 19 (CYFRA 21-1) Mucins, Tumour Markers
_{2} pyruvate-Kinase (TuM_{2-} PK) and metalloproteinase-7 (MMP-7) have been recently shown to help in the diagnosis of CCA, with in some cases a prognostic value.Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Humans; Liver Neoplasms; Prognosis
PubMed: 23396291
DOI: 10.3233/DMA-130964 -
Brazilian Journal of Medical and... Nov 2004Hepatocellular carcinomas are aggressive tumors with a high dissemination power. An early diagnosis of these tumors is of great importance in order to offer the... (Review)
Review
Hepatocellular carcinomas are aggressive tumors with a high dissemination power. An early diagnosis of these tumors is of great importance in order to offer the possibility of curative treatment. For an early diagnosis, abdominal ultrasound and serum alpha-fetoprotein determinations at 6-month intervals are suggested for all patients with cirrhosis of the liver, since this disease is considered to be the main risk factor for the development of the neoplasia. Helicoidal computed tomography, magnetic resonance and/or hepatic arteriography are suggested for diagnostic confirmation and tumor staging. The need to obtain a fragment of the focal lesion for cytology and/or histology for a diagnosis of hepatocellular carcinoma depends on the inability of imaging methods to diagnose the lesion. Several classifications are currently available for tumor staging in order to determine patient prognosis. All take into consideration not only the stage of the tumor but also the degree of hepatocellular dysfunction, which is known to be the main factor related to patient survival. Classifications, however, fail to correlate treatment with prognosis and cannot suggest the ideal treatment for each tumor stage. The Barcelona Classification (BCLC) attempts to correlate tumor stage with treatment but requires prospective studies for validation. For single tumors smaller than 5 cm or up to three nodules smaller than 3 cm, surgical resection, liver transplantation and percutaneous treatment may offer good anti-tumoral results, as well as improved patient survival. Embolization or chemoembolization are therapeutic alternatives for patients who do not benefit from curative therapies.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neoplasm Staging; Prognosis; Time Factors
PubMed: 15517086
DOI: 10.1590/s0100-879x2004001100015 -
Science Translational Medicine Jan 2023Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell...
Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC content [information-weighted fraction of aberrant fragments (iwFAF)]. We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and nine nucleotide frequencies from three positions surrounding fragment ends, we developed a machine learning model to differentiate healthy individuals from patients with cancer. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.
Topics: Humans; DNA; Neoplasms; Cell-Free Nucleic Acids; Chromatin; Nucleotides; Biomarkers, Tumor; Sequence Analysis, DNA
PubMed: 36630480
DOI: 10.1126/scitranslmed.abm6863 -
Cancer Research Mar 2014Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and...
Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88(-/-) and TRIF(-/-) hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4(-/-) mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Disease Progression; Macrophages; Male; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Neoplasms; Signal Transduction; Sleep Deprivation; Toll-Like Receptor 4
PubMed: 24448240
DOI: 10.1158/0008-5472.CAN-13-3014 -
Oncotarget Nov 2014CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4(47-70) and CXCL4L1(47-70) previously displayed angiostatic and anti-tumoral...
CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4(47-70) and CXCL4L1(47-70) previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL4(47-70) and CXCL4L1(47-70) to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL4(47-70) and CXCL4L1(47-70) was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL4(47-70) and CXCL4L1(47-70) efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL4(47-70) reduced tumor growth better than CXCL4L1(47-70). In CXCL4(47-70)-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN- γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL4(47-70) or CXCL4L1(47-70). Finally, CXCL4(47-70) and CXCL4L1(47-70) inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL4(47-70) or CXCL4L1(47-70) treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.
Topics: Angiostatic Proteins; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cattle; Cell Proliferation; Cells, Cultured; Chemotaxis; Coagulants; Cytokines; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Epidermal Growth Factor; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Inflammation Mediators; Mice; Mice, SCID; Neovascularization, Pathologic; Peptide Fragments; Platelet Factor 4; Xenograft Model Antitumor Assays
PubMed: 25373734
DOI: 10.18632/oncotarget.2538 -
Scientific Reports Feb 2022Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection,...
Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection, recent studies have been focused on understanding the non-random fragmentation pattern of cfDNA. These studies have investigated fragment sizes, genomic position of fragment end points, and fragment end motifs. Although these features have been described and shown to be aberrant in cancer patients, there is a lack of understanding of how the individual and integrated analysis of these features enrich ctDNA fraction and enhance ctDNA detection. Using whole genome sequencing and copy number analysis of plasma samples from 5 high grade serious ovarian cancer patients, we observed that (1) ctDNA is enriched not only in fragments shorter than mono-nucleosomes (~ 167 bp), but also in those shorter than di-nucleosomes (~ 240-330 bp) (28-159% enrichment). (2) fragments that start and end at the border or within the nucleosome core are enriched in ctDNA (5-46% enrichment). (3) certain DNA motifs conserved in regions 10 bp up- and down- stream of fragment ends (i.e. cleavage sites) could be used to detect tumor-derived fragments (10-44% enrichment). We further show that the integrated analysis of these three features resulted in a higher enrichment of ctDNA when compared to using fragment size alone (additional 7-25% enrichment after fragment size selection). We believe these genome wide features, which are independent of genetic mutational changes, could allow new ways to analyze and interpret cfDNA data, as significant aberrations of these features from a healthy state could improve its utility as a diagnostic biomarker.
Topics: Biomarkers, Tumor; Case-Control Studies; Circulating Tumor DNA; Female; Gene Dosage; Genetic Predisposition to Disease; Humans; Neoplasm Grading; Ovarian Neoplasms; Phenotype; Predictive Value of Tests; Whole Genome Sequencing
PubMed: 35121756
DOI: 10.1038/s41598-022-05606-z