Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling:results of a GITMO/EBMT randomized trial

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)

GTPase activity of dynamin and resulting conformation change are essential for endocytosis

Dynamin is a large GTPase with a relative molecular mass of 96,000 (Mr 96K) that is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Although its function is apparently essential for scission of newly formed vesicles from the plasma membrane, the nature of dynamin's role in the scission process is still unclear. It has been proposed that dynamin is a regulator (similar to classical G proteins) of downstream effectors. Here we report the analysis of several point mutants of dynamin's GTPase effector (GED) and GTPase domains. We show that oligomerization and GTP binding alone, by dynamin, are not sufficient for endocytosis in vivo. Rather, efficient GTP hydrolysis and an associated conformational change are also required. These data argue that dynamin has a mechanochemical function in vesicle scission.

Multiuser relaying over mixed RF/FSO links

A multiuser dual-hop relaying system over mixed radio frequency/free-space optical (RF/FSO) links is investigated. Specifically, the system consists of m single-antenna sources, a relay node equipped with n≥ m receive antennas and a single photo-aperture transmitter, and one destination equipped with a single photo-detector. RF links are used for the simultaneous data transmission from multiple sources to the relay. The relay operates under the decode-and-forward protocol and utilizes the popular V-BLAST technique by successively decoding each user's transmitted stream. Two common norm-based orderings are adopted, i.e., the streams are decoded in an ascending or a descending order. After V-BLAST, the relay retransmits the decoded information to the destination via a point-to-point FSO link in m consecutive timeslots. Analytical expressions for the end-to-end outage probability and average symbol error probability of each user are derived, while closed-form asymptotic expressions are also presented. Capitalizing on the derived results, some engineering insights are manifested, such as the coding and diversity gain of each user, the impact of the pointing error displacement on the FSO link and the V-BLAST ordering effectiveness at the relay.

Rapid, objective detection of cataract-induced blur using a bull's eye photodetector.

PURPOSE: To determine whether optical aberrations caused by cataract can be detected and quantified objectively using a newly described focus detection system (FDS). SETTING: The Wilmer Opthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. METHODS: The FDS uses a bull's eye photodetector to measure the double-pass blur produced from a point source of light. To determine the range and level of focus, signals are measured with a series of trial lenses in the light path selected to span the point of best focus to generate focus curves. The best corrected visual acuity (BCVA), refractive error, lens photograph grades, and FDS signals were obtained in 18 patients scheduled to have cataract surgery. The tests were repeated 6 weeks after surgery. RESULTS: The mean FDS outcome measures improved after cataract surgery, with increased peak height (P=.001) and decreased peak width (P=.001). Improvement in signal strength (integral of signal within +/-1.5 diopters of the point of best focus) strongly correlated with improvement in peak height (R(2)=.88, P<.0001) and photographic cataract grade (R(2)=.72, P<.0001). The mean BCVA improved from 20/50 to 20/26 (P<.0001). The improvement in BCVA correlated more closely with FDS signal strength (R(2)=.44, P=.001) than with cataract grade (R(2)=.25, P=.06). CONCLUSIONS: Improvement in FDS outcome measures correlated with cataract severity and improvement in visual acuity. This objective approach may be useful in long-term studies of cataract progression.

Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer

: High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents.

IMPLICATIONS FOR PRACTICE: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), with a second agent (rucaparib) likely to be approved in the near future. However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.