46 research outputs found
Endometrial cancer : from a molecular genetic perspective
The first observations indicative of a role of genetic factors in carcinogenesis
were made as early as 1912, when Rous demonstrated that a filterable agent
(i.e. virus) could induce cancer in chicken (Rous 1965). In 1914, Boveri
postulated a "genetic" theory on carcinogenesis by hypothesizing that the
development of malignant tumor cells is caused by either the predominance
of chromosomes which promote cell division, or by the elimination of chromosomes
which inhibit cell division (Boveri, 1914).
In the last decade, research techniques in molecular biology have advanced
rapidly. As a result, biological science has recently made huge steps
forward in understanding the human genome. The disclosure of the human
genome seems imminent, as, in February 2001, two research groups (the
Human Genome Project (HGP) and Celera Genomics) published their draft
sequences of the near complete human genome (Lander, Linton et al. 2001;
Venter, Adams et al. 2001). With the knowledge of the human genome sequence
and new molecular research techniques it is now possible to monitor
gene expression levels on a genomic scale. These new data promise to enhance
the fundamental understanding of life at the molecular level.
As, in general, genetic alterations are thought to play a major role in
tumor development and tumor progression ((Fearon and Vogel stein 1990);
(Knudson 1993)), knowledge of molecular genetics seems essential in understanding
the etiology and the biological behavior of cancer
Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer
Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer
Progestogenic effects of tibolone on human endometrial cancer cells
Tibolone, a synthetic steroid acting in a tissue-specific manner and used
in hormone replacement therapy, is converted into three active
metabolites: a Delta(4) isomer (exerting progestogenic and androgenic
effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3
alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In
the present study an endometrial carcinoma cell line (Ishikawa PRAB-36)
was used to investigate the progestogenic properties of tibolone and its
metabolites. This cell line contains progesterone receptors A and B, but
lacks estrogen and androgen receptors. When tibolone was added to the
cells, complete conversion into the progestogenic/androgenic Delta(4)
isomer was observed within 6 d. Furthermore, when cells were cultured with
tibolone or when the Delta(4) isomer or the established progestagen
medroxyprogesterone acetate was added to the medium, marked inhibition of
growth was observed. Interestingly, 3 beta-OH-tibolone also induces some
inhibition of growth. These growth inhibitions were not observed in
progesterone receptor-negative parental Ishikawa cells, and
progestagen-induced growth inhibition of PRAB-36 cells could readily be
reversed using the antiprogestagen Org-31489. Upon measuring the
expression of two progesterone-regulated genes (fibronectin and
IGF-binding protein-3), tibolone, the Delta(4) isomer and
medroxyprogesterone acetate showed similar gene expression regulation.
These results indicate that tibolone, the Delta(4) metabolite, and to some
extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most
likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite
Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer
PURPOSE: In endometrial cancer, loss of progesterone receptors (PR) is
associated with more advanced disease. This study aimed to investigate the
mechanism of action of progesterone and the loss of its receptors (PRA and
PRB) in development of endometrial cancer. EXPERIMENTAL DESIGN: A
9600-cDNA microarray analysis was performed to study regulation of gene
expression in the human endometrial cancer subcell line Ishikawa PRAB-36
by the progestagen medroxy progesterone acetate (MPA). Five MPA-regulated
genes were selected for additional investigation. Expression of these
genes was studied by Northern blot and by immunohistochemistry in Ishikawa
subcell lines expressing different PR isoforms. Additionally, endometrial
cancer tissue samples were immunohistochemically stained to study the in
vivo protein expression of the selected genes. RESULTS: In the PRAB-36
cell line, MPA was found to regulate the expression of a number of
invasion- and metastasis-related genes. On additional investigation of
five of these genes (CD44, CSPG/Versican, Tenascin-C, Fibronectin-1, and
Integrin-beta 1), it was observed that expression and progesterone
regulation of expression of these genes varied in subcell lines expressing
different PR isoforms. Furthermore, in advanced endometrial cancer, it was
shown that loss of expression of both PR and E-cadherin was associated
with increased expression CD44 and CSPG/Versican. CONCLUSION: The present
study shows that progestagens exert a modulatory effect on the expression
of genes involved in tumor cell invasion. As a consequence, loss of PR
expression in human endometrial cancer may lead to development of a more
invasive phenotype of the respective tumor
Two-year neurodevelopmental outcome in children born extremely preterm:the EPI-DAF study
OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth
Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands
Background: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. Methods: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). Results: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8–2.3) and 5.4 months (95% CI, 4.0–6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0–1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. Conclusions: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. Funding: Johannes J.M. Kwakman received an unrestricted research grant from Servier
Development and measurement of guidelines-based quality indicators of caesarean section care in the Netherlands: A RAND-modified delphi procedure and retrospective medical chart review
Background
There is an ongoing discussion on the rising CS rate worldwide. Suboptimal guideline adherence may be an important contributor to this rise. Before improvement of care can be established, optimal CS care in different settings has to be defined. This study aimed to develop and measure quality indicators to determine guideline adherence and identify target groups for improvement of care with direct effect on caesarean section (CS) rates.
Method
Eighteen obstetricians and midwives participated in an expert panel for systematic CS quality indicator development according to the RAND-modified Delphi method. A multi-center study was performed and medical charts of 1024 women with a CS and a stratified and weighted randomly selected group of 1036 women with a vaginal delivery were analysed. Quality indicator frequency and adherence were scored in 2060 women with a CS or vaginal delivery.
Results
The expert panel developed 16 indicators on planned CS and 11 indicators on unplanned CS. Indicator adherence was calculated, defined as the number of women in a specific obstetrical situation in which care was performed as recommended in both planned and unplanned CS settings. The most frequently occurring obstetrical situations with low indicator adherence were: 1) suspected fetal distress (frequency 17%, adh
Mitochondrial physiology
As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery