Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation.The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.Certain solid tumors, such as breast and prostate cancer, have a propensity to metastasize to bone and cause osteolysis and abnormal new bone formation (1, 2). The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. In fact, bone metastases are heterogeneous: data gleaned from a rapid autopsy program indicate that the same prostate cancer patient often has evidence of osteolytic and osteoblastic disease as shown by histologic examination (3). The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone, illustrated in Fig. 1. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases. Breast Cancer: The Prototypic OsteolyticTumorBreast cancer commonly metastasizes to and destroys bone, causing pain and fracture. Tumors produce many factors that stimulate osteolysis: parathyroid hormone-related protein (PTHrP), interleukin (IL)-11, IL-8, IL-6, and receptor activator of nuclear factor-nB ligand (RANKL;. Substantial data support a role for bone-derived transforming growth factor-h (TGF-h) and tumor-derived osteolytic factors, such as PTHrP, in a vicious cycle of local bone destruction in osteolytic metastases. Bone matrix stores several immobilized growth factors, particularly TGF-h, which is released in active form during osteoclastic resorption (10) and stimulates PTHrP production by tumor cells. PTHrP in turn mediates bone destruction by stimulating osteoclasts. A dominant-negative mutant of the type II TGF-h receptor inhibited TGF-h-induced PTHrP secretion in vitro and development of bone metastases in an MDA-MB-231 experimental metastasis model (5, 6). In addition, TGF-h regulates several genes that are responsible for enhanced bone metastases in MDA-MB-231: IL-11 and connective tissue growth factor (CTGF; refs. 8, 9). Collectively, these studies provided proof of principle to support a role for TGF-h blockade in the treatment of breast cancer bone metastases.SD-20...

ABSTRACT

Tracheal resection is usually successful and has a low mortality. Anastomotic complications are uncommon, and important risk factors are reoperation, diabetes, lengthy resections, laryngotracheal resections, young age (pediatric patients), and the need for tracheostomy before operation.

ABSTRACT

During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-β has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-β signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-β signaling on bone remain unclear. To examine the role of TGF-β in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-β type I receptor (TβRI) kinase on bone mass, architecture and material properties. Inhibition of TβRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TβRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TβRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TβRI inhibitors may be effective in treating conditions of skeletal fragility.

Ran, a Ras‐like GTPase, has been implicated in controlling the movement of proteins and RNAs in and out of the nucleus. We have constructed strains of Saccharomyces cerevisiae which produce fusion proteins containing glutathione‐S‐transferase (GST) fused to Gsp1p, which encodes the essential yeast Ran homolog, and a mutant form of Gsp1p that mimics the GTP‐bound state. A major protein with the apparent size of 34 kDa co‐purifies with the GTP‐bound form of Gsp1p. This protein was identified as Yrb1p (Yeast Ran Binding Protein) and stimulates GTP hydrolysis by Gsp1p in the presence of Rna1p, the Gsp1 GTPase activating protein. Yrb1p is located in the cytoplasm with some concentration at the nuclear periphery. Temperature‐sensitive yrb1 mutants are defective in nuclear protein import and RNA export. A mutation in the highly conserved Ran binding region of Yrb1p reduces its ability to interact with Gsp1p. These data indicate that Yrb1p functions with Gsp1p and suggest that together they can control transport of macromolecules across the nuclear envelope.

Introduction Erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) commonly coexist in aging men. Tadalafil, a phosphodiesterase type 5 inhibitor approved for treating ED, is currently being evaluated for treating BPH-LUTS. Aims This multinational Phase 3 study assessed effects of tadalafil 2.5 or 5 mg once daily on ED and BPH-LUTS in men with both conditions during 12 weeks of double-blinded therapy. Methods Men were ≥45 years old, sexually active, and experiencing ED for ≥3 months and BPH-LUTS for >6 months. Randomization (baseline) followed a 4-week placebo lead-in; changes from baseline were assessed via analysis of covariance and compared to placebo. A gatekeeping procedure controlled for multiple comparisons of co-primary and key secondary measures at end point (last post-baseline observation). Main Outcome Measures The co-primary measures were the International Index of Erectile Function-erectile function (IIEF-EF) domain and International Prostate Symptom Score (IPSS) score; key secondary measures were the Sexual Encounter Profile Question 3 (SEP Q3) and BPH Impact Index (BII). Treatment-emergent adverse events, serious adverse events, orthostatic vital signs, clinical laboratory and uroflowmetry parameters, and postvoid residual volume were assessed. Results Tadalafil 2.5 mg (N = 198) and 5 mg (N = 208) significantly improved IIEF-EF domain scores (both P < 0.001) vs. placebo (N = 200) at end point. For IPSS, improvements were significant with tadalafil 5 mg (P < 0.001), but not 2.5 mg, for observations from 2 weeks through end point (least-squares mean ± standard error change from baseline at end point, placebo −3.8 ± 0.5, tadalafil 2.5 mg −4.6 ± 0.4, and 5 mg −6.1 ± 0.4). Tadalafil 5 mg significantly improved SEP Q3 and BII (P < 0.001). Overall, tadalafil was well tolerated with no clinically adverse changes in orthostatic vital signs or uroflowmetry parameters. Conclusions Tadalafil 5 mg significantly improved both ED and BPH-related outcomes through 12 weeks and was well tolerated.

Oxidized abasic residues in DNA constitute a major class of radiation and oxidative damage. Free radical attack on the nucleotidyl C-1 carbon yields 2-deoxyribonolactone (dL) as a significant lesion. Although dL residues are efficiently incised by the main human abasic endonuclease enzyme Ape1, we show here that subsequent excision by human DNA polymerase ␤ is impaired at dL compared with unmodified abasic sites. This inhibition is accompanied by accumulation of a protein-DNA cross-link not observed in reactions of polymerase ␤ with unmodified abasic sites, although a similar form can be trapped by reduction with sodium borohydride. The formation of the stably cross-linked species with dL depends on the polymerase lysine 72 residue, which forms a Schiff base with the C-1 aldehyde during excision of an unmodified abasic site. In the case of a dL residue, attack on the lactone C-1 by lysine 72 proceeds more slowly and evidently produces an amide linkage, which resists further processing. Consequently dL residues may not be readily repaired by "shortpatch" base excision repair but instead function as suicide substrates in the formation of protein-DNA crosslinks that may require alternative modes of repair.Mutagenesis and disruption of the cell cycle caused by DNA damage is counteracted by DNA repair systems. In the base excision repair pathway (1-3), DNA glycosylases eliminate damaged bases to generate abasic (AP) 1 sites, which are also formed in large numbers by spontaneous depurination (2). In either case, AP sites are incised by an AP endonuclease to allow subsequent DNA repair synthesis and excision of the abasic residue. In mammalian cells, incision is carried out by the major AP endonuclease Ape1 protein (also called Apex, Hap1, or Ref1), while the excision step for regular abasic residues is thought to be mainly carried out by DNA polymerase ␤ (Pol␤) using a ␤-elimination mechanism. A distinct branch of the base excision pathway involves strand displacement repair synthesis and excision of the displaced, damaged strand by the FEN1 nuclease (4 -6). Still another variation is potentiated by the initial DNA glycosylase (7) because some of these enzymes carry out a second reaction to cleave at the abasic site by ␤- elimination (1, 3). The resulting 3Ј-blocked products must then be removed by an enzyme such as Ape1 before repair synthesis can proceed (1).Base excision repair acts on a wide variety of deaminated, alkylated, or oxidized bases (2, 3). However, oxidative damage to DNA also produces various modified abasic residues that may complicate the repair scenario (1). For example, free radical attack forms strand breaks with fragmentary or oxidized products of deoxyribose; when these are present at the 3Ј terminus, removal by Ape1 may be the rate-limiting repair step (8, 9). Oxidized abasic residues without direct strand breakage (10) include 2-deoxypentos-4-ulose residues (a major lesion produced by the antitumor drug bleomycin) and 2-deoxyribonolactone (dL) residues (formed by diverse oxidative agents). 2-D...