The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number, NCT00540358.).

Studies of menstrual cycle length in large populations demonstrated that there is a striking increase in the variability of intermenstrual intervals just before menopause. The changes in serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P) during menstrual cycles in a group of perimenopausal women were compared with the findings in young normal women. In 8 women, 46-56 years old with regular cycles, cycle length was shorter and the mean E2 concentration was lower than in younger women. There was a striking increase in FSH concentration throughout the cycle while LH remained in the normal range. In 2 women, 14 cycles of variable length were studied during 2 years of the menopausal transition. In some instances, hormonal changes associated with follicular maturation and corpus luteum function occurred in the presence of high, menopausal levels of LH and FSH with a diminished secretion of E2 and P. In others vaginal bleeding occurred during a fall in serum E2 with no associated rise in P. Cycles of variable length during the menopausal transition may be due either to irregular maturation of residual follicles with diminished responsiveness to gonadotropin stimulation, or to anovulatory vaginal bleeding that may follow estrogen withdrawal without evidence of corpus luteum function. The observation of elevated FSH concentrations and normal LH levels in perimenopausal women emphasizes the complexity of the hypothalamic-pituitary-ovarian regulatory system and suggests that LH and FSH are modulated independently at the level of the pituitary.

IntroductionPoly (ADP-ribose) polymerase-1 (PARP1) is a chromatinassociated enzyme with key functions in the regulation of transcription, cell cycle, tumorigenesis, and cellular response to DNA damage. 1 PARP1 is activated by DNA damage and has important roles in DNA base excision repair (BER), functioning as a nick sensor, recruiter, and modulator of key DNA repair molecules.2 Upon activation, PARP1 synthesizes poly (ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD + ) as a substrate and covalently transfers PAR to nuclear proteins, including nucleosomal core histones, topoisomerases I and II, high mobility group (HMG) proteins, and p53. 3 Loss of PARP1 activity can lead to enhanced cancer cell death, following treatment with PARP inhibitors, both as single agents and in combination with DNA-damaging agents. Impairing PARP1-dependent BER can elicit DNA double-strand breaks (DSBs) following collapse of the replication fork, particularly in cells whose homologous recombination (HR)-dependent DSB repair is already defective due to mutations in breast cancer 1 and 2 genes (BRCA1 and BRCA2); these defects are found frequently in familial breast and ovarian cancers and can elicit profound sensitization to PARP inhibitors, resulting in cytotoxic effects. 4,5 Over 80% of BRCA-associated breast cancers are negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). 6,7 These "triple-negative" breast cancers, which comprise 15% to 20% of all breast cancers, 8,9 are among the most aggressive breast cancer subtypes. Importantly, over 60% AbstractPoly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin's lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an indep...

We evaluated the effects of recombinant human GH (rhGH) in 16 men and women more than 60 yr of age. After 10 days of dietary equilibration and control collections, subjects were randomly assigned to receive 0.03, 0.06, or 0.12 mg/kg rhGH by daily injection for 7 days. A brisk rise in circulating somatomedin-C (insulin-like growth factor-I) occurred in all subjects, and this rise was dose dependent. rhGH produced striking changes in nitrogen retention, sodium excretion, and the parathyroid-vitamin D axis. Twenty-four-hour urinary nitrogen excretion decreased from 8.00 +/- 0.33 to 5.01 +/- 0.33 g (P less than 0.001), and sodium excretion decreased from 45.9 +/- 2.96 to 21.2 +/- 3.48 mmol/day (P less than 0.001). Serum calcium concentrations did not change, but serum inorganic phosphorus levels of 1.08 +/- 0.04 mmol/L at baseline increased significantly after rhGH treatment to 1.33 +/- 0.04 mmol/L (P less than 0.001). Increases were also observed in circulating PTH (53.2 +/- 6 vs. 39.5 +/- 4.2 ng/L; P less than 0.01) and calcitriol (82.8 vs. 65.8 pmol/L; P less than 0.05). A rise in serum osteocalcin (10.3 +/- .86 vs. 8.0 +/- 0.5 micrograms/L; P less than 0.05) was accompanied by increased urinary excretion of hydroxyproline (628 +/- 63 vs. 406 +/- 44 mumol/day; P less than 0.01). Despite the reduction in sodium excretion, marked increases were observed in urinary calcium (6.04 +/- 0.97 vs. 3.27 +/- 0.40 mmol/day; P less than 0.01). rhGH significantly impaired oral glucose tolerance and reduced insulin sensitivity, but was otherwise well tolerated and produced no systematic changes in weight or blood pressure. The results of this study indicate that rhGH requires further study as a potential agent for attenuating or reversing the loss of muscle and bone in elderly people.