•Aging can modify the pharmacokinetics and pharmacodynamics of drugs, as well as the tolerance of the tissues.•CGA can help identify those patients with a higher risk of toxicity.•CGA can be used to ...select drugs and therapeutic schemes that are better tolerated in the elderly.•Predictive scores are less informative than CGA, but they can help in making clinical decisions.
Although approximately 50% of cancer patients are 70 years of age or older, cancer treatment in the elderly remains a therapeutic challenge. The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, for which therapeutic decisions must be made in an individualized manner. In addition, changes in pharmacokinetics and pharmacodynamics of the drugs occur with age, as well as the tolerance of the tissues, leading to a narrowing of the therapeutic margin and an increase in toxicity.
In the general population, Performace Status (PS) has traditionally been used to estimate tolerance to chemotherapy, but in the elderly population it is not useful. In this review we summarize the current knowledge about the pharmacology of antineoplastic drugs in the elderly and the tools available to help us identify risk of chemotherapy toxicity in these patients.
Abstract
Purpose of the Study: Marine sponges have developed mechanisms to protect themselves from a hostile marine microenvironment. One of these mechanisms is the use of biologically active ...metabolites, explored nowadays for their anticancer properties. PM060184 is one of these compounds, isolated from the Madagascan sponge Lithoplocamia lithistoides. This polyketide is currently under evaluation on clinical trials, and its antitumor activity was previously reported in the preclinical setting in a panel of cell lines and subcutaneous tumor xenografts of different origin. The purpose of the study is to explore the effect of PM060184 in a panel of ovarian high-grade serous (HGS) carcinoma cell lines with different sensitivity to cisplatin and paclitaxel.
Experimental Procedures: Cell growth inhibition was analyzed by exposure of increasing concentrations of PM060184 in 96 multiwell plates for 72h, by subsequent confluence evaluation and sulphorhodamine (SRB) staining. Cell cycle experiments were done by propidium iodide (PI) staining after treatment of cell lines at their IC50 value for 72h. Three independent experiments with 6 replicates per condition were performed for both approaches. Celigo Image Cytometer platform was employed for phase contrast and viable cells discrimination with a triple staining (Hoechst, PI and calcein AM), as well as for cell cycle analyses.
Results: We have focused on the effect of this drug on a panel of HGS ovarian carcinoma cell lines, previously characterized by their response to cisplatin and paclitaxel. We have observed antiproliferative activity in a concentration-dependent manner, with IC50 values at subnanomolar concentrations in all the cell lines tested. This effect was observed in platinum-sensitive and -resistant cell lines and all of them were also more sensitive to PM060184 than paclitaxel, another tubulin-binding agent usually used for the treatment of ovarian cancer. We have evaluated cell cycle and apoptosis at the IC50 values for each cell line. We have seen that this agent disrupts the cell cycle at different phases, as DNA synthesis and mitosis, depending on the cell line. Additionally, an increase in apoptotic cell death is detected as a sub G1 peak by flow cytometry in most of the cell lines tested.
Conclusions: PM060184 is a new tubulin-binding agent with a potent antitumor activity in a panel of HGS ovarian cancer cell lines, with different ranges of sensitivity to cisplatin and paclitaxel. Additionally, this effect is more potent than that exerted by other tubulin-binding compounds, such as paclitaxel. However, the underlying mechanism of PM060184 action on ovarian HGS cell lines will need to be further elucidated.
Citation Format: Victoria Heredia-Soto, Andrés Redondo, Alejandro Gallego, María Miguel-Martín, Roberto Crespo, Alicia Hernández, David Hardisson, Jaime Feliu, Carlos Galmarini, Marta Mendiola. Exploratory testing of PM060184 compound in high-grade serous ovarian carcinoma cell lines abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5876.
Recent reports have identified distinct genomic patterns in ovarian carcinoma, including proliferative and mesenchymal-like groups, with worse outcome. The exact mechanisms driving the onset and ...progression of these tumors are still poorly understood. Additionally, researchers are concerned about the correct subtype stratification of the available cell line models, and the exploration of alternatives to monolayer culture. Identification of biomarkers to stratify cell lines, characterization of important processes as epithelial-mesenchymal transition (EMT), and the use of three-dimensional (3D) cultures as alternative models could be useful for cell line classification.
In this work, we present a descriptive analysis of 16 commonly used ovarian cancer cell lines. We have studied their morphology in 2- and 3D culture, and their response to cisplatin, observing in the majority of them an increased resistance in 3D. We have also performed an immunohistochemical analysis for proliferation marker Ki-67, and EMT related markers to establish phenotypes. Epithelial cells tend to show higher proliferative rates, and mesenchymal cells show an increase in EMT related markers, especially when cultured in 3D conditions.
We have stated the complex heterogeneity of ovarian cancer models, resembling primary tumors, agreeing with the argument that the cell line model for
experiments must be carefully chosen. Our results also support that tridimensional culture could be a very helpful alternative in ovarian cancer research. Regarding EMT, a very important process for the development of this disease, some related biomarkers might be further characterized for their role in this disease development.
Background
Endometrial cancer (EC) is the most common cancer of the female reproductive organs. Despite the good overall prognosis of most low-grade ECs, FIGO I and FIGO II patients might experience ...tumor recurrence and worse prognosis. The study of alterations related to EC pathogenesis might help to get insights into underlying mechanisms involved in EC development and progression.
Methods
Core tumoral samples were used to investigate the role of C1GALT1 in EC by immunohistochemistry (IHC). ECC-1 cells were used as endometrioid EC model to investigate the effect of C1GALT1 depletion using C1GALT1 specific shRNAs. SILAC quantitative proteomics analyses and cell-based assays, PCR, qPCR, WB, dot-blot and IHC analyses were used to identify, quantify and validate dysregulation of proteins.
Results
Low C1GALT1 protein expression levels associate to a more aggressive phenotype of EC. Out of 5208 proteins identified and quantified by LC-MS/MS, 100 proteins showed dysregulation (log
2
fold-change ≥ 0.58 or ≤-0.58) in the cell protein extracts and 144 in the secretome of C1GALT1 depleted ECC-1 cells. Nine dysregulated proteins were validated. Bioinformatics analyses pointed out to an increase in pathways associated with an aggressive phenotype. This finding was corroborated by loss-of-function cell-based assays demonstrating higher proliferation, invasion, migration, colony formation and angiogenesis capacity in C1GALT1 depleted cells. These effects were associated to the overexpression of ANXA1, as demonstrated by ANXA1 transient silencing cell-based assays, and thus, correlating C1GALT and ANXA1 protein expression and biological effects. Finally, the negative protein expression correlation found by proteomics between C1GALT1 and LGALS3 was confirmed by IHC.
Conclusion
C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
Predicting response to treatment in high-grade serous ovarian carcinoma (HGSOC) still remains a clinical challenge. The standard-of-care for first-line chemotherapy, based on a combination of ...carboplatin and paclitaxel, achieves a high response rate. However, the development of drug resistance is one of the major limitations to efficacy. Therefore, identification of biomarkers able to predict response to chemotherapy in patients with HGSOC is a critical step for prognosis and treatment of the disease. Several studies suggest that angiogenesis is an important process in the development of ovarian carcinoma and chemoresistance. The aim of this study was to identify a profile of angiogenesis-related genes as a biomarker for response to first-line chemotherapy in HGSOC.
Formalin-fixed paraffin-embedded samples from 39 patients with HGSOC who underwent surgical cytoreduction and received a first-line chemotherapy with carboplatin and paclitaxel were included in this study. Expression levels of 82 angiogenesis-related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays.
Univariate analysis identified five genes angiopoietin 1 (ANGPT1), aryl hydrocarbon receptor nuclear translocator (ARNT), CD34, epidermal growth factor (EGF) and matrix metallopeptidase 3 (MMP3) as being statistically associated with response to treatment. Multivariable analysis by Lasso-penalized Cox regression generated a model with the combined expression of seven genes angiotensinogen (AGT), CD34, EGF, erythropoietin receptor (EPOR), interleukin 8 (IL8), MMP3 and MMP7). The area under the receiver operating characteristics curve (0.679) and cross-validated Kaplan-Meier survival curves were used to estimate the accuracy of these predictors.
An angiogenesis-related gene expression profile useful for response prediction in HGSOC was identified, supporting the important role of angiogenesis in HGSOC.
Objective: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24. 2-26 deletion previously reported by our ...group to predict longer survival of high-grade serous ovarian cancer patients. Methods: In order to test if protein levels of GTF2H5 are associated with patients`` outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and logrank test were used to estimate patients’ survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 down regulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. Results: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio HR, 0. 52; 95% CI, 0. 29 to 0. 93; p=0. 024) and transcriptional level (HR, 0. 80; 95% CI, 0. 65 to 0. 97; p=0. 023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0. 55; 95% CI, 0. 38 to 0. 78;p=0. 0007) and also found an association with progression-free survival (HR, 0. 72; 95% CI, 0. 54 to 0. 96; p=0. 026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. Conclusion: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.
Hypophosphatasia (HPP) a rare disease caused by mutations in the
gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed ...condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of
results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of
gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower
ALP activity than the wild-type (WT) genotype (
-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn
binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel
gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient.
The Godelieve Denys-Struyf method (GDS) is a motor learning intervention that may be applied in group or individualized sessions.
The study objective was to compare the effectiveness of routine ...physical therapy, group GDS (GDS-G) sessions, and group and individualized GDS (GDS-I) sessions.
This was a cluster randomized controlled trial.
The study took place in 21 primary care physical therapy units ("clusters") of the Spanish National Health Service (SNHS).
The participants were 461 people with subacute and chronic low back pain (LBP).
Clusters were randomized into 3 groups. All participants received medical treatment and a 15-minute group education session on active management. Additional interventions were as follows: control (fifteen 40-minute sessions of transcutaneous electrical nerve stimulation, microwave treatment, and standardized exercises), GDS-G (eleven 50-minute group GDS sessions), and GDS-I (the same 11 sessions plus four 50-minute individualized GDS sessions).
Primary outcomes at baseline and 2, 6, and 12 months later were LBP and pain referred down the leg (separate pain intensity numeric rating scales) and disability (Roland-Morris Questionnaire RMQ). Secondary outcomes were use of medication and self-reported health (mental and physical component summaries of the 12-Item Short-Form Health Survey SF-12). Separate linear mixed models for LBP, pain referred down the leg, and disability were developed to adjust for potential confounders. Randomization, outcome assessment, and data analyses were masked.
At 12 months, disability improved 0.7 (95% confidence interval CI=-0.4, 1.8) RMQ point in the control group, 1.5 (95% CI=0.4, 2.7) RMQ points in the GDS-I group, and 2.2 (95% CI=1.2, 3.2) RMQ points in the GDS-G group. There were no differences in pain.
The amount of exercise was smaller in the control group, and GDS-I sessions were provided by junior physical therapists.
The improvement in disability was slightly higher with group GDS sessions than with the program routinely used in clusters within the SNHS. Adding individualized GDS sessions eliminated this advantage. Further studies should compare the GDS with other types of exercise.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
PDF
