Progesterone metabolites 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αP) have opposite effects on proliferation, apoptosis and metastasis in the breast. Evidence regarding their ...influence on ductal carcinoma in situ (DCIS) lesions is lacking.
MCF10DCIS.com cells were cultured in a 3D culture system and treated with 5αP or 3αP. After 5 and 12 days of treatment, polymerase chain reaction (PCR) of proliferation, invasion/metastasis, anti-apoptotic or other markers was performed. Cells treated with the tumor-promoting 5αP were observed under the light and confocal microscopes to reveal possible morphological changes that could indicate a transition from an in situ to an invasive phenotype. As a control, the morphology of the MDA-MB-231 invasive cell line was examined. The invasive potential after exposure to 5αP was also assessed using a detachment assay.
The PCR analysis of the chosen markers showed no statistically significant difference between naive cells and cells treated with 5αP or 3αP. DCIS spheroids retained their in situ morphology after treatment with 5αP. The detachment assay showed no increased potential for invasion after exposure to 5αP. Progesterone metabolites 5αP and 3αP do not facilitate or prohibit tumor promotion/invasion in MCF10DCIS.com cells, respectively.
As oral micronized progesterone has been proved effective for hot flushes in postmenopausal women, first in vitro data propose that progesterone-only therapy could possibly be considered for women after DCIS suffering from hot flushes.
species are important denizens of the human gut microbiome that ferment complex polysaccharides to butyrate as a terminal fermentation product, which influences human physiology and serves as an ...energy source for colonocytes. Previous comparative genomics analyses of the genus
have examined polysaccharide degradation genes. Here, we characterize the core and pangenomes of the genus
with respect to central carbon and energy metabolism, as well as biosynthesis of amino acids and B vitamins using orthology-based methods, uncovering significant differences among species in their biosynthetic capacities. Variation in gene content among
species and strains was most significant for cofactor biosynthesis. Unlike all other species of
that we analysed,
strains lacked biosynthetic genes for riboflavin or pantothenate but possessed folate biosynthesis genes. Differences in gene content for B vitamin synthesis were matched with differences in putative salvage and synthesis strategies among species. For example, we observed extended biotin salvage capabilities in
strains, which further suggest that B vitamin acquisition strategies may impact fitness in the gut ecosystem. As differences in the functional potential to synthesize components of biomass (e.g. amino acids, vitamins) can drive interspecies interactions, variation in auxotrophies of the
spp. genomes may influence
gut ecology. This study serves to advance our understanding of the potential metabolic interactions that influence the ecology of
spp. and, ultimately, may provide a basis for rational strategies to manipulate the abundances of these species.
Objectives
To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi‐national investigation of targeted prostate cancer (PCa) screening among ...men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes.
Particpants and Methods
Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36‐item short‐form health survey (SF‐36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale‐Revised, risk perception and knowledge. The results of the baseline questionnaire are presented.
Results
A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants’ perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF‐36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status.
Conclusion
This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer‐specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.
Abstract Background Men with germline breast cancer 1, early onset ( BRCA1 ) or breast cancer 2, early onset ( BRCA2 ) gene mutations have a higher risk of developing prostate cancer (PCa) than ...noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. Patient summary In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal ...outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients—from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.
•Fertility counseling and referral to a specialist in reproductive medicine should be offered to all patients at fertile age.•In view of the limited preclinical evidence, a fertility-lowering effect of the BRAF/MEK inhibitors cannot be excluded.•The treatment-related adverse events of immune checkpoint inhibitor therapy can impair fertility directly or indirectly.•Contraception shall be carried out during systemic melanoma therapy and continued for several months after the end of therapy.•In the adjuvant setting, melanoma treatment should not be started; treatment should be discontinued if pregnancy is detected.
Abstract
STUDY QUESTION
Can the differences in patients' and professionals' perspective regarding essential endometriosis care be accommodated in one set of key recommendations?
SUMMARY ANSWER
...Consensus between patients and professions on a key set of recommendations for essential endometriosis care was achieved.
WHAT IS KNOWN ALREADY
Guideline development alone will not lead to healthcare improvement. Quality indicators are needed to monitor actual care and guideline adherence. These can help with better implementation of the ESHRE guidelines in European hospitals and thereby improve the quality of endometriosis care. The first step in the development of quality indicators is to select a compact set of key recommendations.
STUDY DESIGN, SIZE AND DURATION
Using a RAND modified Delphi method, this study reports the systematic selection of key recommendations based on the ESHRE guideline ‘Management of Women with Endometriosis’ by an international expert panel of both patients and professionals during the study period of September 2015 and December 2015.
PARTICIPANTS, SETTING, METHODS
An international panel of patients (n = 10) and medical professionals (n = 11) rated and prioritized the 83 recommendations extracted from the ESHRE guideline for relevance in three rounds. A strict consensus methodology was used to select key recommendations. The main outcome measure was one set of key recommendations for endometriosis care.
MAIN RESULTS AND THE ROLE OF CHANCE
A representative set of 17 key recommendations was selected from the preliminary set of 83 recommendations. This selection covers all dimensions of endometriosis care, including diagnosis, treatment of endometriosis-associated pain, treatment of endometriosis-associated infertility and miscellaneous topics such as prevention, menopause and relationship with cancer. Of the 21 experts, 17 participated in at least one round while 16 (76.2%) participated in all 3 rounds.
LIMITATIONS, REASONS FOR CAUTION
The feasibility of the selected key recommendations was not assessed in this study. As not all panel members took part in all three rounds, some response bias may have occurred.
WIDER IMPLICATIONS OF THE FINDINGS
This set of key recommendations is the first step in the development of quality indicators for monitoring and improving endometriosis care. The set is generic and can be used in hospitals internationally. A practice test should be conducted to assess the feasibility of our key recommendations in clinical practice.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received for the conduct of this study. Members of the EndoKey study group did not receive payment. The authors and members of the EndoKey study group have no conflict of interest.
Zusammenfassung
Hintergrund
Frauen mit Brustkrebs in der Vorgeschichte leiden häufig unter klimakterischen Beschwerden. Eine menopausale Hormontherapie kann die Beschwerden zwar reduzieren, wird für ...dieses Patientenkollektiv jedoch aufgrund eines erhöhten Rezidivrisikos nicht empfohlen.
Ziel der Arbeit
Ziel ist die Darlegung der aktuellen Datenlage zur nichthormonellen Therapie für das genannte Patientenkollektiv.
Material und Methoden
In einer PubMed-Recherche wurden Studien und Metaanalysen von 1997 bis 2014 gesucht, die eine menopausale Hormontherapie mit einer nichthormonellen Therapie bei klimakterischen Symptomen nach Mammakarzinom verglichen.
Ergebnisse
Der Einsatz einer menopausalen Hormontherapie wird Frauen mit einer Brustkrebsdiagnose in der Vorgeschichte nicht empfohlen. Lebensstiländerungen sind die therapeutische Basis bei klimakterischen Beschwerden. Die tägliche Einnahme von 50–60 mg Isoflavon kann die Frequenz und Schwere von Hitzewallungen signifikant senken, wenn nicht mehr als 4 Episoden pro Tag auftreten.
Cimicifuga racemosa
mildert Hitzewallungen und depressive Symptome, zudem könnte eine Assoziation mit einem verlängerten krankheitsfreien Überleben bestehen. Die Wirksamkeit ist vergleichbar mit transdermalem Östrogen. Antidepressiva und Antikonvulsiva sind erwiesenermaßen wirksam und können als Zweitlinientherapie zum Einsatz kommen.
Schlussfolgerungen
Studien zur nichthormonellen Therapie klimakterischer Beschwerden zeigen, dass sie wirksam ist. Brustkrebspatientinnen haben also eine Therapiealternative zur Hormontherapie, die jedoch weiterhin die wirksamere Option darstellt. Weitere Studien sind notwendig, um die Effektivität und die Wirkmechanismen nichthormoneller Therapien weiter zu untersuchen.
OBJECTIVE: To study the function of miR-145, known to be dysregulated in endometriosis, and to identify its target genes in an in vitro endometriosis model. DESIGN: Experimental laboratory study. ...SETTING: University medical centers. PATIENT(S): Primary endometrial stroma cells were derived from eutopic endometrium of three American Society for Reproductive Medicine stage III endometriosis patients and from ectopic lesions of four patients with deep infiltrating endometriosis. INTERVENTION(S): The human endometriotic cell line 12Z and primary eutopic and ectopic endometrial stroma cells were transiently transfected with miR-145 precursors or anti–miR-145 inhibitors and investigated for posttranscriptional regulation of predicted target genes and changes in cell behavior. MAIN OUTCOME MEASURE(S): Predicted target expression was measured by quantitative reverse transcription–polymerase chain reaction and Western blotting, and altered cell behavior was monitored by cell proliferation assays. The 12Z cells were additionally investigated by Matrigel invasion assays, cell cycle analysis, side population analysis, and aldehyde dehydrogenase activity assays. RESULT(S): In all cells investigated, miR-145 overexpression inhibited cell proliferation and induced down-regulation of FASCIN-1, SOX2, and MSI2. In 12Z cells miR-145 upregulation increased Matrigel invasiveness and reduced side population and aldehyde dehydrogenase-1 activity. Additional down-regulated targets in 12Z cells included OCT4, KLF4, PODXL, JAM-A, and SERPINE1/PAI-1. ACTG2 and TAGLN were up-regulated upon pre–miR-145 transfection. JAM-A, FASCIN-1, and PAI-I down-regulation in 12Z cells were confirmed by Western blotting. CONCLUSION(S): miR-145 inhibits endometriotic cell proliferation, invasiveness, and stemness by targeting multiple pluripotency factors, cytoskeletal elements, and protease inhibitors.
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