Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment
A 30-year-old woman in Japan who stopped having regular periods and was thought to be infertile was able to become pregnant and give birth thanks to a new experimental fertility treatment…
Human ovaries hold follicles containing oocytes. When follicles mature, they release eggs for fertilization. Patients with primary ovarian insufficiency develop menopausal symptoms at less than 40 y of age. They have few remaining follicles and their only chance for bearing a baby is through egg donation. The researchers demonstrated that Hippo and Akt signaling pathways regulate follicle growth. Using an in vitro activation approach, they first removed ovaries from infertile patients, followed by fragmentation to disrupt Hippo signaling and drug treatment to stimulate Akt signaling. After grafting ovarian tissues back to patients, the researchers found rapid follicle growth in some patients and successfully retrieved mature eggs. After in vitro fertilization, embryo transfer and 37 weeks of pregnancy, a healthy baby boy was born.
Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation–in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.
First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer
For the first time, researchers have estimated the daily dose of radiotherapy that could be wasted in compensating for cancer cell growth that occurs overnight and during weekends in patients with early breast cancer.
The new study suggests that shorter radiotherapy schedule may:
be more effective against breast cancer recurrence
reduce the chances of side-effects on the surrounding normal tissues
Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen.
Materials and methods
Women aged ⩾50 years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50 Gy in 25 fractions versus 28.5 or 30 Gy in 5 once-weekly fractions of 5.7 or 6.0 Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance.
Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26–2.29, p < 0.001) for 30 Gy and 1.15 (0.82–1.60, p = 0.489) for 28.5 Gy versus 50 Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3–22.3%, p < 0.001) for 30 Gy and 11.1% (7.9–15.6%, p = 0.18) for 28.5 Gy compared with 9.5% (6.5–13.7%) after 50 Gy. With a median follow-up in survivors of 37.3 months, 2 local tumour relapses and 23 deaths have occurred.
At 3 years median follow-up, 28.5 Gy in 5 fractions is comparable to 50 Gy in 25 fractions, and significantly milder than 30 Gy in 5 fractions, in terms of adverse effects in the breast.
Il existe une vulnérabilité aux perturbateurs endocriniens qui dépend de notre fond génétique
“Il faut diminuer autant que possible l’exposition de la population aux perturbateurs endocriniens pour se préserver de leurs effets sanitaires“
a déclaré Delphine Batho, (ex)ministre de l’Ecologie, en ouverture du colloque international qui s’est déroulé à Paris les 10 et 11 décembre 2012 sous l’égide de l’Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES).
Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs.
Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified.
Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.
There are few illnesses as terrifying in the public consciousness as cancer. With up to a third of us getting cancer at some stage in our lives, it is almost impossible to remain untouched by the disease. As an ominous reminder of our mortality, cancer scares us to the point that discussions about it are often avoided and the language we use is couched in euphemisms.
While it would be impossible to address all the legends on the subject, David Robert Grimes – physicist and researcher at Oxford University – dispells some of the more persistent misunderstandings:
A Testimony-Case Study in a French Family Troop, 2012
Using a familial case control study, Marie-Odile Soyer-Gobillard – former director emeritus at the CNRS (French National Center for Scientific Research) – and Charles Sultan show that there are serious effects on the psychological and physical health of the descendants of women treated with synthetic hormones during their pregnancy: psychiatric illnesses are often found associated with somatic disorders which are well known to be the DES and EE signature. Synthetic hormones, acting as endocrine disturbers, are toxic for humans, especially for pregnant women and their children, probably partly in relation with their toxic degradation status. In all cases girls suffered more than boys either of somatic and/or psychiatric disorders due to the estrogen receptor alpha or beta concentration higher in female fetus than in male. It is also clear that in all the families most of the exposed children are ill while quite the unexposed are not.
2012 Study Overview:
Materials and methods: Gathering questionnaires and the evidence
An emergency £200m-a-year fund for life-enhancing cancer drugs is to continue until 2016 – after the NHS’s rationing body failed to clear any medicines sent for approval in the past year – the prime minister has announced.
The Cancer Drugs Fund (CDF) was set up in 2011 to help patients in England access certain drugs before they get approval for widespread NHS use – and/or pay for treatments denied to NHS patients by the National Institute for Health and Care Excellence (NICE).
” … if we look at the data from Europe, 77% of treatments fail. The Centre for Disease Control has it at 70% failure. But you never hear from the people who failed, which makes you think there’s something wrong with you. The reality is that the science is fragile. It is amazing that five million babies have been born because of IVF but there must be at least 10-to-15 million couples whose treatments have failed … ”
DES-exposed daughters need continued surveillance to determine whether any increases in cancer risk occur during the menopausal years
1998 Study Abstract
The association between in utero exposure to diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the vagina and cervix is well known, yet there has been no systematic study of DES-exposed daughters to determine whether they have an increased risk of other cancers. As many as 3 million women in the United States may have been exposed to DES in utero.
To determine whether women exposed to DES in utero have a higher risk of cancer after an average of 16 years of follow-up.
A cohort study with mailed questionnaires and medical record review of reported cancer outcomes.
A cohort of 4536 DES-exposed daughters (of whom 81% responded) and 1544 unexposed daughters (of whom 79% responded) who were first identified in the mid-1970s.
MAIN OUTCOME MEASURES:
Cancer incidence in DES-exposed daughters compared with population-based rates and compared with cancer incidence in unexposed daughters.
To date, DES-exposed daughters have not experienced an increased risk for all cancers (rate ratio, 0.96; 95% confidence interval [CI], 0.58-1.56) or for individual cancer sites, except for CCA. Three cases of vaginal CCA occurred among the exposed daughters, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1-126.2) in comparison with population-based incidence rates. The rate ratio for breast cancer was 1.18 (95% CI, 0.56-2.49); adjustment for known risk factors did not alter this result.
Thus far, DES-exposed daughters show no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in our study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.
Cancer risk in women prenatally exposed to diethylstilbestrol, NCBI, PMID: 9718055, 1998 Aug 19;280(7):630-4.
Full text JAMA. 1998;280(7):630-634. doi:10.1001/jama.280.7.630. link.