The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants.

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.

Effects of nitric oxide donor N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine on the expression of interferon-gamma in tumor infiltrating lymphocytes.

Nitric oxide (NO) has been proven to be a key regulator in the mammalian immune response, such as the innate and adaptive immune responses to tumors. The messenger NO involves T helper cell differentiation and lymphocyte biofunctions. In this study, we employed N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine as NO donor and released NO around tumor infiltrating lymphocytes in vitro by short-time blue light irradiation. The interferon-γ secretion of tumor infiltrating lymphocytes was investigated to study the functional changes caused by the accurate spatio-temporal delivery of NO. The downregulation of interferon-γ in tumor infiltrating lymphocytes after NO treatment indicates promising biological applications to potentially play a role in the treatment of autoimmune diseases. The study was approved by the Medical Ethics Committee of the Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, China (approved No. 065) on February 12, 2018.

Incidence and Causes of Intentional Fetal or Neonatal Demise in Twin-Twin Transfusion Syndrome.

INTRODUCTION: The aim of this study is to evaluate the incidence and causes of intentional fetal and neonatal demise in twin-twin transfusion syndrome (TTTS). MATERIAL AND METHODS: All TTTS pregnancies managed at our centre between 2000 and 2014 were included. We evaluated incidence and causes of intentional fetal/neonatal demise, defined as termination of pregnancy, selective fetal reduction, or withdrawal of neonatal intensive care. RESULTS: Intentional fetal/neonatal demise occurred in 9.8% (110/1,122) of fetuses and was due to termination of pregnancy (2.2%), selective fetal reduction (4.2%), or withdrawal of neonatal intensive care (3.4%). Reasons for termination of pregnancy included complications of laser treatment (72.0%), severe fetal anomaly (20.0%), and unwanted pregnancy (8.0%). Reasons for selective fetal reduction were technical difficulties to perform laser surgery (51.1%), fetal complications (38.3%), and parental preference for fetal reduction rather than laser treatment (10.6%). Reasons for withdrawal of neonatal intensive care treatment were severe cerebral injury (47.4%), severe pulmonary complications (15.8%), birth asphyxia (5.3%), multiple complications of TTTS and/or prematurity combined (21.1%), or other (10.5%). CONCLUSIONS: Intentional fetal or neonatal demise in TTTS occurs frequently and is often due to complications after laser surgery and/or severe (cerebral) injury in affected fetuses or neonates.

Discordance of cord insertions as a predictor of discordant fetal growth in monochorionic twins.

INTRODUCTION: The type of cord insertion within monochorionic twin pairs could be different. The purpose of study is to evaluate the association of different combinations of placental umbilical cord insertions with birth weight discordance in a large cohort of monochorionic twins. METHODS: All consecutive monochorionic placentas from either uncomplicated twin pregnancies or with fetal weight discordance examined and injected with color dye at our centers were included in this study (n = 374). Marginal or velamentous cord insertions were defined as abnormal. Placentas were categorized as concordant when the cord insertions of both fetuses were either normal-normal or abnormal-abnormal, and as discordant when they were normal-abnormal. Birth weight discordance was defined as a difference in birth weight of each twin ≥25%. The association of different cord insertion combinations with birth weight discordance was analyzed. RESULTS: The rate of discordant cord insertions was 55% (204/374) in monochorionic twins. A highly significant association between discordant cord insertions and discordant birth weight was observed (p < 0.01). The odds ratios (OR) for birth weight discordance in the discordant cord insertion group compared with the concordant group were 2.3 (95% CI: 1.2-4.4) for the normal-marginal and 5.9 (95% CI: 3.8-10.4) for the normal-velamentous cord insertion subgroup. Discordant cord insertions are associated with the occurrence of unequal placental sharing (OR 4.3, 95%CI 2.7-6.9). DISCUSSION: Discordance of cord insertions is associated with discordance of birth weight and may therefore be an important indicator of adverse outcome in monochorionic twins.

[Experimental study of angiography using vascular interventional robot-2(VIR-2)].

OBJECTIVE: To verify the feasibility and safety of new vascular interventional robot system used in vascular interventional procedures. METHODS: Vascular interventional robot type-2 (VIR-2) included master-slave parts of body propulsion system, image navigation systems and force feedback system, the catheter movement could achieve under automatic control and navigation, force feedback was integrated real-time, followed by in vitro pre-test in vascular model and cerebral angiography in dog. Surgeon controlled vascular interventional robot remotely, the catheter was inserted into the intended target, the catheter positioning error and the operation time would be evaluated. RESULTS: In vitro pre-test and animal experiment went well; the catheter can enter any branch of vascular. Catheter positioning error was less than 1 mm. The angiography operation in animal was carried out smoothly without complication; the success rate of the operation was 100% and the entire experiment took 26 and 30 minutes, efficiency was slightly improved compared with the VIR-1, and the time what staff exposed to the DSA machine was 0 minute. The resistance of force sensor can be displayed to the operator to provide a security guarantee for the operation. No surgical complications. CONCLUSIONS: VIR-2 is safe and feasible, and can achieve the catheter remote operation and angiography; the master-slave system meets the characteristics of traditional procedure. The three-dimensional image can guide the operation more smoothly; force feedback device provides remote real-time haptic information to provide security for the operation.