Study of novel androgen receptor V770 variant in androgen insensitivity syndrome patients reveals the transitional state of the androgen receptor ligand binding domain homodimer.

We report the discovery of the androgen receptor missense mutation V770D, that was found in two sisters suffering from complete androgen insensitivity. Experimental validation of AR V770 variants demonstrated that AR V770D was transcriptionally inactive due to the inability to dimerize and a reduced ligand binding affinity. The more conservative AR V770A variant showed a dimerization defect at low levels of DHT with a partial recovery of the transcriptional activity and of the receptor's ability to dimerize when increasing the DHT levels. With V770 located outside of the proposed LBD dimerization interface of the AR LBD homodimer crystal structure, the effects of the V770A mutation on AR dimerization were unexpected. We therefore explored whether the AR LBD dimerization interface would be better described by an alternative dimerization mode based on available human homodimeric LBD crystal structures of other nuclear receptors. Superposition of the monomeric AR LBD in the homodimeric crystal structures of GR, PR, ER, CAR, TRß, and HNF-4α showed that the GR-like LBD dimer model was energetically the most stable. Moreover, V770 was a key energy residue in the GR-like LBD dimer while it was not involved in the stabilization of the AR LBD homodimer according to the crystal structure. Additionally, the observation that 4 AIS mutations impacted the stability of the AR LBD dimer while 16 mutations affected the GR-like LBD dimer, suggested that the AR LBD dimer crystal is a snapshot of a breathing AR LBD homodimer that can transition into the GR-like LBD dimer model.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

PURPOSE: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. METHODS: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. RESULTS: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. CONCLUSION: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

[Treatment of inguinal hernia: a prospective study comparing Bassini's procedure, the inguinal pre-peritoneal prosthesis and the Lichtenstein technique]. / Trattamento dell'ernia inguinale. Studio prospettico: Bassini vs protesi peritoneale per via inguinale vs Lichtenstein.

Inguinal hernia surgery has aroused considerable interest in recent years, with numerous advances being proposed to treat these disorders. Bassini's procedure, based on the importance of the transversalis fascia as a fundamental containment mechanism, was for many years the treatment of choice for inguinal hernia. In our study, covering eight years of activity, we focused our attention on this principle, comparing repair procedures such as Bassini's and those with a preperitoneal mesh, in which the repair involves the transversalis fascia, with procedures based on Lichtenstein's technique in which the fascia is left intact. The investigation protocol was thus based on the performance of the three techniques in parallel by the same surgical team. The parameters of immediate complications, lasting pain and recurrence were used to evaluate the results. The first two occurred infrequently in all groups (a greater incidence was seen with mesh procedures). Recurrence rates after preperitoneal mesh techniques were extremely low, confirming the paramount functional importance of the transversalis fascia. The results of our analysis substantiate the advantage of employing the preperitoneal mesh technique, which opens up new horizons for the treatment of recurrent hernia.

[Anatomical thyroid abnormalities. Quadrilobate thyroid gland: a case report and review of the literature]. / Anomalie anatomiche della tiroide. Su un caso di tiroide quadrilobata e revisione della letteratura.

Abnormalities of the thyroid gland and of some adjacent structures arouse interest because of their surgical implications. One need only think of a non-recurrent laryngeal nerve, of thyroid hemiagenesis or of a quadrilobate thyroid gland, as in the case described here. To the best of the authors' knowledge, no similar reports of such a case are present in the medical literature. The patient was a 37-year-old woman suffering from Graves' disease. The abnormality was detected only during surgical examination and consisted in two lobes divided by a cleft on each side and joined by an isthmus. After a number of considerations regarding the anatomical details of this case and a review of the literature, the authors attempt to give an embryological interpretation and formulate the hypothesis that the second lateral lobe could be a development of the widely studied and controversial embryological anlage, the so-called "lateral thyroid".