Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.

BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ±â€¯3·1 years old; 2 female; BMI:33·9 ±â€¯2·3 kg/m2; eGFR:27·0 ±â€¯2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

High cumulative live births in oocyte donation cycles with cryopreservation of all embryos.

BACKGROUND: Cryopreservation of all embryos in stimulated IVF cycles is occasionally necessary. Although it is known that frozen embryo transfer results in lower live birth rates per transfer, there is limited information regarding expected cumulative live birth rates for patients who are in this particular scenario. METHODS: The objective was to evaluate long-term outcomes in cycles undergoing pronuclear cryopreservation of all embryos utilizing a retrospective analysis of 154 consecutive recipients from 1995 to 2006. RESULTS: The cumulative rate of first live birth per retrieval was 66.2%, with a 36.4% live birth rate per frozen embryo transfer. Following an average 2.2 +/- 0.98 transfers, 32.6% (17/52) of patients who never delivered had remaining embryos making the cumulative first live birth rate previously stated a conservative estimate. 11.7% of recipients had sibling deliveries from a single retrieval. Over 1/3 of the delivered recipients have remaining cryopreserved embryos and could pursue an additional pregnancy. CONCLUSION: These results suggest that pronuclear cryopreservation of all embryos in an oocyte donation cycle maintains good cumulative live birth rates, as well as chances for a sibling from a single retrieval. Recipients who must delay transfer can be reassured a high potential for live birth from their first donor retrieval.

Ovarian hyperstimulation syndrome: steps to maximize success and minimize effect for assisted reproductive outcome.

OBJECTIVE: To investigate the strategies used to decrease the risk of ovarian hyperstimulation syndrome (OHSS) and their impact on pregnancy and live birth rates. DESIGN: Retrospective cohort analysis. SETTING: University hospital. PATIENT(S): One hundred eighty-eight patients undergoing fresh in vitro fertilization (IVF) cycles between 2000 and 2004, with peak serum estradiol levels >2500 pg/mL and presumed to be at risk for OHSS. INTERVENTION(S): Coasting and elective embryo cryopreservation were evaluated for their effect on OHSS and live birth rates. MAIN OUTCOME MEASURE(S): Pregnancy, live birth rates, and OHSS incidence. RESULT(S): Out of 188 patients at risk for OHSS, 21 patients had their cycles coasted (group 1), and elective embryo cryopreservation was performed in 32 patients (group 2). In 135 patients with no other risk factors, ovulation was triggered with human chorionic gonadotropin and embryo transfer was performed (group 3). The incidence in our IVF population was 38 out of 1002 (3.8%). The overall incidence of OHSS for those who had an estradiol level >2500 pg/mL was 20.2% (38 out of 188), and none of the patients in group 1 developed OHSS; 13 out of 32 patients in group 2 (40.6%) and 25 out of 135 (18.5%) patients in group 3 developed OHSS. The live birth rate was 38%, 40%, and 45% in groups 1, 2, and 3, respectively, and the cumulative live birth rate was 52%, 75%, and 59%, respectively. CONCLUSION(S): Elective cryopreservation of embryos with subsequent frozen embryo transfer and coasting are effective ways of maximizing pregnancy and limiting severe OHSS.

Frozen-thawed embryo transfer and live birth: Long-term follow-up after one oocyte retrieval.

Frozen-thawed embryos accounted for 39% (249 of 639) of live births from 931 consecutive first oocyte retrievals after median follow-up of 6.5 years with consistent use of pronuclear-stage freezing and cleavage-stage transfer. Survival after thaw was 95% (2,129 of 2,247). Implantation and live birth rates per individual frozen-thawed embryo transfered were 22% (431 of 1,937) and 18% (346 of 1,937), respectively.