Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells

Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pT alpha, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in TALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of TALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumor

Autotransplantation of cryopreserved ovarian tissue in oncological patients: recovery of ovarian function

AIM: To present preliminary results of autotransplantation of cryopreserved ovarian tissue performed at Sant'Orsola-Malpighi Hospital, Bologna, Italy. MATERIALS & METHODS: Orthotopic transplantation was performed in two women with colorectal and breast cancer, and heterotopic transplantation was performed in one Hodgkin's lymphoma woman. The presence of micrometastasis in the ovarian tissue was checked, and morphological features of ovarian tissue were evaluated before transplantation. Ovarian function was monitored by hormonal and ultrasound-color Doppler examination after transplantation. RESULTS: In all three women, no micrometastasis was found; light and transmission electron microscopy showed well-preserved thawed ovarian tissue. Ovarian function recovery was observed 2-4 months after transplantation. Spontaneous menstrual cycles occurred in two women with normal follicular densities. No periods occurred in the woman with low follicular density at the time of tissue collection. CONCLUSION: Ovarian tissue cryopreservation and transplantation is a promising approach for preserving ovarian function in women with cancer

Ovarian tissue cryopreservation and transplantation: 20 years experience in Bologna University

Objective: To report the 20-year experience in ovarian tissue cryopreservation (OTC) and ovarian tissue transplantation (OTT) of the Bologna clinical center (Bologna, Italy). Design: Retrospective cohort study. Patients: 1026 pediatrics and women aged between 2 and 38 years who underwent OTC and OTT between January 2002 to January 2022. Results: Of the 1026 patients, 238 (22.8%) were pediatrics (≤ 17 years, Group 1) and 788 (77.2%) were adult women (range 18-38 years, Group 2). In Group 1, 184 (77.3%) patients had malignant diseases and 54 (22.7%) had non-malignant diseases. In Group 2, 746 (94.7%) patients had malignant diseases and 42 (5.3%) had non-malignant diseases. No real complications were observed during surgery. In all the samples analyzed most of the follicles were in the resting stage, while only a few follicles were growing. In both fresh and thawed samples, follicular density was higher in Group 1 than in Group 2 (p < 0.01). Regardless of age, good preservation of follicles and stroma was observed in fresh and thawed ovarian tissue by histological and immunohistochemical analyses (estrogen and progesterone receptors; Ki67 and Bcl2 markers; TUNEL). To date, out of 1026 total women, 812 (79.1%) had their tissue stored. Sixty-eight (6.6%) patients died from their primary disease. Twentyfour (2.3%) women performed 33 OTTs between December 2011 and January 2022. Restoration of menstruation was observed in 15 out of 17 menopausal women. Six pregnancies were achieved, two hesitated in abortion and four in the birth of healthy babies. Conclusion: OTC is the only fertility preservation technique applicable in prepubertal/ pediatrics and in adult patients when stimulation for oocytes/embryos cryopreservation is not possible. The reported data can help future patients and physicians in their discussions and decisions about the need and possibilities of preserving ovarian function

Metroplasty in a large population of women with septate uterus.

none5STUDY OBJECTIVE: To determine the reproductive outcome after hysteroscopic metroplasty in women with septate uterus. DESIGN: Retrospective comparative single-center study (Canadian Task Force classification II-3). SETTING: University-affiliated hospital. PATIENTS: Two hundred forty-six patients with septate uterus undergoing hysteroscopic metroplasty between January 1998 and December 2007. The diagnosis was based on hysteroscopy and 3-dimensional ultrasonography. In the most cases laparoscopy was also available. The subjects were divided into 2 age-matched groups. Group 1 consisted of 108 women with unexplained infertility, and group 2 consisted of 138 women suffering from recurrent abortion. INTERVENTIONS: Patients underwent hysteroscopic metroplasty by use of resectoscopy with an equatorial semicircular loop cutting at 0 degree with monopolar energy. All septa were completely removed without complications of bleeding, infection, risk of perforation, visceral injury, or uterine dehiscence during pregnancy. MEASUREMENT AND MAIN RESULTS: The 2 groups were compared in terms of reproductive performance in mean ± SD follow-up of 37 ± 18 months. In group 1, 61 (56.5%) patients achieved pregnancy. Seventy-one pregnancies ensued, including 1 twin gestation. Fourteen of the 71 pregnancies (19.7%) ended in miscarriage. In group 2, 90 (65.3%) patients achieved pregnancy. One hundred twenty-nine pregnancies ensued, including 2 twin gestations. Forty-four of the 129 pregnancies (34.1%) ended in miscarriage. The 2 groups have no significant differences in terms of reproductive outcome after surgery, except for the number of abortions, which was higher in group 2 (pmixedParadisi R.; Barzanti R.; Natali F.; Battaglia C.; Venturoli S.Paradisi R.; Barzanti R.; Natali F.; Battaglia C.; Venturoli S

Sexuality and psychopathological aspects in premenopausal women with metabolic syndrome.

none9noINTRODUCTION: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that have been suggested to impact female sexual function. AIMS: This study aims to assess the prevalence of female sexual dysfunction (FSD) in premenopausal women with MetS compared with healthy controls (HC). Psychopathological aspects and the relationship to FSD were also evaluated in both groups. METHODS: Two hundred four premenopausal women, of whom 98 had diagnosis of MetS, were asked to complete the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), and the Middlesex Hospital Questionnaire (MHQ). Routine laboratory tests and anthropometric measurements were routinely performed. MAIN OUTCOME MEASURES: FSFI and FSDS questionnaires, prevalence of FSD, and MHQ scores. RESULTS: In the MetS group compared with the HC group, we found: a lower global FSFI score (P=0.005), higher prevalence of pathological scores compared with HC group, and lower scores in the desire, arousal, lubrication, and orgasm domains. An inverse correlation between the FSFI score and the number of risk factors for MetS was detected. MetS women reported significantly higher total scores in the somatization and depression domains when compared with the HC group. The logistic regression showed that high triglycerides (odds ratio [OR] 3.097; 95% confidence interval [CI] 1.272-7.542; P=0.026) and somatization (OR 7.068; CI 95% 2.291-21.812; P=0.001) are independently associated with FSD in premenopausal women. CONCLUSIONS: Our results indicate a higher prevalence of sexual dysfunction in MetS women. A number of risk factors for MetS are positively associated with FSD and higher triglycerides seem to be the strongest predictors of sexual dysfunction. Psychopathological dimensions such as somatization are strongly associated with sexual dysfunction.openAlvisi S; Baldassarre M; Lambertini M; Martelli V; Berra M; Moscatiello S; Marchesini G; Venturoli S; Meriggiola MC.Alvisi S; Baldassarre M; Lambertini M; Martelli V; Berra M; Moscatiello S; Marchesini G; Venturoli S; Meriggiola MC