Phase II Study of Concurrent Capecitabine and External Beam Radiotherapy for Pain Control of Bone Metastases of Breast Cancer Origin

Background

Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer.

Methodology/Principal Findings

Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m² twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%).

Conclusions/Significance

External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted.

Trial Registration

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The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome

MDC1 (NFBD1), a mediator of the cellular response to DNA damage, plays an important role in checkpoint activation and DNA repair. Here we identified a cross-talk between the DNA damage response and cell cycle regulation. We discovered that MDC1 binds the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls the cell cycle. The interaction is direct and is mediated by the tandem BRCA1 C-terminal domains of MDC1 and the C terminus of the Cdc27 (APC3) subunit of the APC/C. It requires the phosphorylation of Cdc27 and is enhanced after induction of DNA damage. We show that the tandem BRCA1 C-terminal domains of MDC1, known to directly bind the phosphorylated form of histone H2AX (gamma-H2AX), also bind the APC/C by the same mechanism, as phosphopeptides that correspond to the C termini of gamma-H2AX and Cdc27 competed with each other for the binding to MDC1. Our results reveal a link between the cellular response to DNA damage and cell cycle regulation, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the APC/C.     

Solid-state NMR evidence for an antibody-dependent conformation of the V3 loop of HIV-1 gp120

Solid-state NMR measurements have been carried out on frozen solutions of the complex of a 24-residue peptide derived from the third variable (V3) loop of the HIV-1 envelope glycoprotein gp120 bound to the Fab fragment of an anti-gp120 antibody. The measurements place strong constraints on the conformation of the conserved central GPGR motif of the V3 loop in the antibody-bound state. In combination with earlier crystal structures of V3 peptide-antibody complexes and existing data on the cross-reactivity of the antibodies, the solid-state NMR measurements suggest that the Gly-Pro-Gly-Arg (GPGR) motif adopts an antibody-dependent conformation in the bound state and may be conformationally heterogeneous in unbound, full-length gp120. These measurements are the first application of solid-state NMR methods in a structural study of a peptide-protein complex.     

Follicular dynamics and concentrations of steroids and gonadotropins in lactating cows and nulliparous heifers

Differences in follicular development and circulating hormone concentrations, between lactating cows and nulliparous heifers, that may relate to differences in fertility between the groups, were examined. Multiparous, cyclic, lactating Holstein cows (n=19) and cyclic heifers (n=20) were examined in the winter, during one estrous cycle. The examinations included ultrasound monitoring and daily blood sampling. Distributions of two-wave and three-wave cycles were similar in the two groups: 79 and 21% in cows, 70 and 30% in heifers, respectively. Cycle lengths were shorter by 2.6 days in heifers than in cows, and in two-wave than in three-wave cycles. The ovulatory follicle was smaller in heifers than in cows (13.0+/-0.3 mm versus 16.5+/-0.05 mm). The greater numbers of large follicles in cows than in heifers corresponded well to the higher concentrations of FSH in cows. The duration of dominance of the ovulatory follicle tended to be longer in cows than in heifers. Estradiol concentrations around estrus and the preovulatory LH surge were higher in heifers than in cows (20 versus 9 ng/ml). Progesterone concentrations were higher in heifers than in cows from Day 3 to Day 16 of the cycle. Circulating progesterone did not differ between two-wave and three-wave cycles. The results revealed differences in ovarian follicular dynamics, and in plasma concentrations of steroids and gonadotropins; these may account for the differences in fertility between nulliparous heifers and multiparous lactating cows.     

Multiple origins of replication in archaea

Until recently, the only archaeon for which a bona fide origin of replication was reported was Pyrococcus abyssi, where a single origin was identified. Although several in silico analyses have suggested that some archaeal species might contain more than one origin, this has only been demonstrated recently. Two studies have shown that multiple origins of replication function in two archaeal species. One study identified two origins of replication in the archaeon Sulfolobus solfataricus, whereas a second study used a different technique to show that both S. solfataricus and Sulfolobus acidocaldarius have three functional origins. These are the first reports of archaea having multiple origins. This finding has implications for research on the mechanisms of DNA replication and evolution.