Inhibiting activin‐A signaling stimulates bone formation and prevents cancer‐induced bone destruction in vivo

Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis (p < .01), promotes bone formation (p < .01) and increases bone mass in vivo (p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < .05) and suppression of bone formation (p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis (p < .01), prevents myeloma‐induced suppression of bone formation (p < .05), blocks the development of osteolytic bone lesions (p < .05), and increases survival (p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction (p < .001) and inhibits bone metastases (p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. © 2010 American Society for Bone and Mineral Research.     

Angiotensin-converting enzyme inhibition attenuates renal platelet-derived growth factor gene expression and cell proliferation in subtotal nephrectomy

Cell proliferation, matrix accumulation and cell infiltration are characteristic features of progressive glomerulosclerosis and tubulointerstitial fibrosis. Platelet‐derived growth factor (PDGF), a cytokine which has proliferative, prosclerotic and chemokine properties, has been shown to be upregulated in the rat remnant kidney model. Inhibition of the renin–angiotensin system by angiotensin‐converting enzyme (ACE) inhibitors has a beneficial effect on renal function and morphology, but the effect of ACE inhibition on PDGF gene expression and PDGF‐mediated cellular proliferation in subtotal nephrectomy has not been studied in detail. Twelve rats were subtotally nephrectomized (STNx) and received either the ACE inhibitor perindopril or a placebo for 12 weeks. Five sham‐operated rats served as controls. Subtotal nephrectomy was associated with hypertension, proteinuria, elevated plasma creatinine and increased kidney weight. After 12 weeks, PDGF B‐chain mRNA was significantly upregulated in the glomeruli and tubulointerstitium of subtotally nephrectomized rats. ACE inhibition attenuated PDGF mRNA expression in association with a reduction in tubular and glomerular proliferation, as assessed by staining for proliferating cell nuclear antigen. In the context of the known in vitro and in vivo effects of PDGF, it is postulated that the renoprotective action of ACE inhibitors may be partially related to PDGF‐mediated antiproliferative mechanisms.     

The validation of the patient perception of bladder condition (PPBC): a single-item global measure for patients with overactive bladder

OBJECTIVES: The purpose of this study was to evaluate the validity and responsiveness of a global measure for overactive bladder (OAB), the Patient Perception of Bladder Condition (PPBC). METHODS: Post-hoc analyses were conducted on two 12-wk clinical trials for OAB (Study 1: n = 865; Study 2: n = 520). In addition to the PPBC, patients completed two condition-specific health-related quality of life (HRQL) measures, the Overactive Bladder Questionnaire (OAB-q) and King's Health Questionnaire (KHQ), and bladder diaries at baseline and 12 wk. Validity of the PPBC was evaluated through correlations with baseline diaries, OAB-q, and KHQ. The responsiveness of the PPBC was evaluated using correlations and general linear models to assess the degree of association between change in PPBC and change in the diaries, OAB-q, and KHQ. RESULTS: Both samples were primarily women and white with mean ages of 61.0 and 58.8 yr. The majority of patients were incontinent (75.3% and 80.4%) with the greatest proportion of patients indicating that they had "moderate problems" (47.5% and 51.2%) on the PPBC at baseline. Significant correlations were present at baseline and among change scores between the PPBC and the bladder diaries (p < 0.001), OAB-q (p < 0.001), and KHQ (p < 0.01). In both studies, patients with major PPBC improvement had significantly greater reductions in frequency, urgency episodes, incontinence episodes, and Symptom Bother and significantly greater improvements in HRQL than patients with only a minor PPBC improvement. CONCLUSION: The PPBC, a global patient-reported measure of bladder condition, demonstrated good construct validity and responsiveness to change. These findings support the use of the PPBC as a global assessment of bladder condition among patients with OAB.     

Local and transient inhibition of p21 expression ameliorates age‐related delayed wound healing

Nonhealing chronic wounds in the constantly growing elderly population represent a major public health problem with high socioeconomic burden. Yet, the underlying mechanism of age‐related impairment of wound healing remains elusive. Here, we show that the number of dermal cells expressing cyclin‐dependent kinase inhibitor p21 was elevated upon skin injury, particularly in aged population, in both man and mouse. The nuclear expression of p21 in activated wound fibroblasts delayed the onset of the proliferation phase of wound healing in a p53‐independent manner. Further, the local and transient inhibition of p21 expression by in vivo delivered p21‐targeting siRNA ameliorated the delayed wound healing in aged mice. Our results suggest that the increased number of p21⁺ wound fibroblasts enforces the age‐related compromised healing, and targeting p21 creates potential clinical avenues to promote wound healing in aged population.     

The importance of stromal inflammation in squamous cell carcinoma of the tongue

J Oral Pathol Med (2012) 41 : 379–383 Background: Histological risk assessment evaluating worst pattern of tumour invasion (WPOI), and lymphocytic response (LR), has previously been shown to be of prognostic significance in squamous cell carcinomas of the head and neck (SCCHN). SCCHN is a heterogeneous group of tumours including tumours located in the oral cavity, of which the majority is located in the tongue. Methods: Haematoxylin/eosin–stained slides from diagnostic biopsies from 94 cases of SCC on the tongue were evaluated for WPOI and LR. Within the inflammatory infiltrate, the percentage of eosinophilic granulocytes was also estimated. Results were correlated with clinical data such as response to treatment and recurrence. Results: For WPOI the majority of patients, 84%, showed small invasive tumours islands with a size <15 cells (grade 4). No correlation with survival, response to treatment or recurrence was seen for WPOI. More than half of the patients showed a dense lymphocytic infiltrate, a factor that was significantly correlated with complete response to radio therapy. Of the patients with dense lymphoid infiltrate, the majority, 63%, did not either have a recurrence. No significant correlation with recurrence, response to treatment or any other factor was seen for presence of eosinophils. Conclusions: Data clearly showed that tongue tumours have a split invasive growth pattern and an intense inflammatory response at the tumour interface. Results also indicated that evaluation of the intensity of the inflammatory infiltrate at the tumour interface in tongue SCC could provide information of potential importance for choice of treatment and prognosis.     

Peel bond strength of resilient liner modified by the addition of antimicrobial agents to denture base acrylic resin

In order to prolong the clinical longevity of resilient denture relining materials and reduce plaque accumulation, incorporation of antimicrobial agents into these materials has been proposed. However, this addition may affect their properties.

Objective

This study evaluated the effect of the addition of antimicrobial agents into one soft liner (Soft Confort, Dencril) on its peel bond strength to one denture base (QC 20, Dentsply).

Material and Methods

Acrylic specimens (n=9) were made (75x10x3 mm) and stored in distilled water at 37ºC for 48 h. The drug powder concentrations (nystatin 500,000U - G2; nystatin 1,000,000U - G3; miconazole 125 mg - G4; miconazole 250 mg - G5; ketoconazole 100 mg - G6; ketoconazole 200 mg - G7; chlorhexidine diacetate 5% - G8; and 10% chlorhexidine diacetate - G9) were blended with the soft liner powder before the addition of the soft liner liquid. A group (G1) without any drug incorporation was used as control. Specimens (n=9) (75x10x6 mm) were plasticized according to the manufacturers'' instructions and stored in distilled water at 37ºC for 24 h. Relined specimens were then submitted to a 180-degree peel test at a crosshead speed of 10 mm/min. Data (MPa) were analyzed by analysis of variance (α=0.05) and the failure modes were visually classified.

Results

No significant difference was found among experimental groups (p=0.148). Cohesive failure located within the resilient material was predominantly observed in all tested groups.

Conclusions

Peel bond strength between the denture base and the modified soft liner was not affected by the addition of antimicrobial agents.     

Dimethylfumarate induces apoptosis in human mast cells

Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC‐1 and in primary cord blood‐derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca‐MF). Our data show that only DMF potently induces apoptotic cell death in HMC‐1 cells and CBMCs. DMF‐mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase‐9 and caspase‐6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL‐ and dexamethasone‐induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.     

Association Between Open-Angle Glaucoma and Gene Polymorphism for Heat-Shock Protein 70-1

Purpose

Heat-shock proteins (HSPs) or antibodies against them may contribute to glaucomatous optic neuropathy. We investigated the associations of HSP70-1 polymorphisms with open-angle glaucoma (OAG) in a Japanese population.

Methods

In 241 normal Japanese controls and 501 Japanese OAG patients, including 211 with primary open-angle glaucoma (POAG) and 290 with normal-tension glaucoma (NTG), two single-nucleotide polymorphisms, A?110C and G+190C, of HSP70-1 were identified by using an Invader assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype distributions were compared between controls and OAG patients. Age at diagnosis, untreated maximum intraocular pressure, and visual field defects at diagnosis were examined for associations with the polymorphisms.

Results

Distribution of the A?110C genotype (AA versus AC+CC) differed significantly between controls and OAG patients (P = 0.007), POAG patients (P = 0.007), or NTG patients (P = 0.032). The genotype distribution of the G+190C polymorphism did not differ significantly between the controls and any patient group. No significant differences in the clinical characteristics of the patients were detected between genotype-defined groups by logistic regression analysis.

Conclusion

The A?110C polymorphism of HSP70-1 may be associated with OAG pathogenesis in Japanese patients.?Jpn J Ophthalmol 2007;51:417–423 © Japanese Ophthalmological Society 2007