Vicious Cycle Hypothesis Research Articles

Bidding despite corruption: evidence from Honduras

PurposeIn addition to lower value for money and the loss of trust in government, procurement corruption threatens to produce a vicious cycle whereby honest firms self-select out of public procurements, further increasing corruption and decreasing value for money. This paper aims to explore this vicious cycle hypothesis.Design/methodology/approachThis paper uses a survey of businesses registered with the procurement regulator in Honduras, a country with high grand corruption but low levels of administrative procurement corruption. The study uses the survey to test the effects of experiences and perceptions of corruption and personal connections on perceptions of fairness and intention to bid on future procurements.FindingsThis study finds that experiences with bribery and the perceived importance of personal and party connections undermine perceptions of fairness, particularly for firms bidding with Honduras’s public works agency. While firms that have not bid recently view the process as less merit-based than those that have, the study does not find that perceptions of fairness influence intention to bid in the future as the vicious cycle hypothesis would suggest.Social implicationsThis research suggests that even firms that are frustrated with procurement irregularities are willing to tolerate them to access government markets.Originality/valueThe study benefits from a unique survey of businesses on issues of corruption and connections in a challenging procurement environment.

Victims, perpetrators, or both? The vicious cycle of disrespect and cynical beliefs about human nature.

We tested how cynicism emerges and what maintains it. Cynicism is the tendency to believe that people are morally bankrupt and behave treacherously to maximize self-interest. Drawing on literatures on norms of respectful treatment, we proposed that being the target of disrespect gives rise to cynical views, which predisposes people to further disrespect. The end result is a vicious cycle: cynicism and disrespect fuel one another. Study 1's nationally representative survey showed that disrespect and cynicism are positively related to each other in 28 of 29 countries studied, and that cynicism's associations with disrespect were independent of (and stronger than) associations with lacking social support. Study 2 used a nationally representative longitudinal dataset, spanning 4 years. In line with the vicious cycle hypothesis, feeling disrespected and holding cynical views gave rise to each other over time. Five preregistered experiments (including 2 in the online supplemental materials) provided causal evidence. Study 3 showed that bringing to mind previous experiences of being disrespected heightened cynical beliefs subsequently. Studies 4 and 5 showed that to the extent that people endorsed cynical beliefs, others were inclined to treat them disrespectfully. Study 6's weeklong daily diary study replicated the vicious cycle pattern. Everyday experiences of disrespect elevated cynical beliefs and vice versa. Moreover, cynical individuals tended to treat others with disrespect, which in turn predicted more disrespectful treatment by others. In short, experiencing disrespect gives rise to cynicism and cynicism elicits disrespect from others, thereby reinforcing the worldview that caused these negative reactions in the first place. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Abstract A67: Microbial polyamines and early detection of pancreatic cancer

Abstract The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we present the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. A combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC) showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were found to be significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation, validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to promote inflammation and release metabolites that foster host tumorigenesis, thereby fulfilling the “vicious cycle hypothesis” of the role of the microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which will result in improved outcomes. Citation Format: Roberto Mendez, Kousik Kesh, Nivedita Arora, Leá Di Martino, Florencia McAllister, Nipun Merchant, Sulagna Banerjee, Santanu Banerjee. Microbial polyamines and early detection of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A67.

The biology of pulmonary exacerbations in bronchiectasis.

Bronchiectasis is a heterogeneous chronic disease. Heterogeneity characterises bronchiectasis not only in the stable state but also during exacerbations, despite evidence on clinical and biological aspects of bronchiectasis, exacerbations still remain poorly understood.Although the scientific community recognises that bacterial infection is a cornerstone in the development of bronchiectasis, there is a lack of data regarding other trigger factors for exacerbations. In addition, a huge amount of data suggest a primary role of neutrophils in the stable state and exacerbation of bronchiectasis, but the inflammatory reaction involves many other additional pathways. Cole's vicious cycle hypothesis illustrates how airway dysfunction, airway inflammation, infection and structural damage are linked. The introduction of the concept of a "vicious vortex" stresses the complexity of the relationships between the components of the cycle. In this model of disease, exacerbations work as a catalyst, accelerating the progression of disease. The roles of microbiology and inflammation need to be considered as closely linked and will need to be investigated in different ways to collect samples. Clinical and translational research is of paramount importance to achieve a better comprehension of the pathophysiology of bronchiectasis, microbiology and inflammation both in the stable state and during exacerbations.

Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.

The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.

Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis.

Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF.

MiR-221 to modulate tumor growth in vivo and as a regulator of TGF.

e23008 Background: Despite the advances in cancer therapy, when Prostate Cancer (PCa) progress to castration resistant phase, patients develop incurable bone metastases. Understanding the processes that regulate homing and survival of metastatic cancer cells in the bone is crucial for the identification of new therapies. TGF-β signaling plays a major role in bone remodeling and according to the “vicious cycle hypothesis” is a master regulator of maintenance of prostate cancer cells in lytic bone lesions. microRNAs (miRs) are a class of small non-coding RNAs that regulates many biological process. miR-221 expression has been previously associated with prostate cancer progression. Here we studied the effect of miR-221 on TGF-β signaling and the impact of miR-221 on tumor growth in vivo Methods: miR-221 was overexpressed in PC3 and RWPE-1 cells and PMEPA was monitored by RT-qPCR and western blot. Expression of miR-221 in PC3 and RWPE-1 cells was assessed by RT-qPCR. Luciferase assay was used to investigate the interaction between miR-221 and PMEPA1. For zebrafish experiment, fluorescently labelled PC-3M-Pro4 cells overexpressing miR-221 were injected in the Duct of Cuvier (DC) of zebrafish embryos. Results: miR-221 overexpression resulted in decreased PMEPA1 mRNA and protein in PC-3 cells. Luciferase reporter assay indicated that miR-221 can directly interact with PMEPA1 3’ UTR. We show an enhancement of the proliferative effect of TGF-β in PC-3 cells, following miR-221 overexpression. In conclusion, we observed increased Smad2 activation upon TGF-β treatment in miR-221 overexpressing PC-3 cells. Inoculation of PC-3M-Pro4 cells overexpressing miR-221 in the DC of zebrafish embryos resulted reduced tumor burden compared to control. Finally, we observed inverse correlation between miR-221 and PMEPA1 expression in normal vs. tumor tissue collected from PCa patients. Conclusions: Our results indicate that miR-221 is a regulator of TGF-β signaling via modulation of PMEPA1 and miR-221 overexpression can reduce tumor growth in vivo.

Prolonged antibiotics for non-cystic fibrosis bronchiectasis in children and adults.

The vicious cycle hypothesis for bronchiectasis predicts that bacterial colonisation of the respiratory tract perpetuates inflammatory change. This damages the mucociliary escalator, preventing bacterial clearance and allowing persistence of pro-inflammatory mediators. Conventional treatment with physiotherapy and intermittent antibiotics is believed to improve the condition of people with bronchiectasis, although no conclusive data show that these interventions influence the natural history of the condition. Various strategies have been tried to interrupt this cycle of infection and inflammation, including prolonging antibiotic treatment with the goal of allowing the airway mucosa to heal. To determine the benefits of prolonged antibiotic therapy in the treatment of patients with bronchiectasis. We searched the Cochrane Airways Group Trials Register and reference lists of identified articles. Searches were current as of February 2014. Randomised trials examining the use of prolonged antibiotic therapy (for four or more weeks) in the treatment of bronchiectasis compared with placebo or usual care. Two review authors independently assessed trial quality and extracted data. We contacted study authors to ask for missing information. Eighteen trials met the inclusion criteria, randomly assigning a total of 1157 participants. Antibiotics were given for between four weeks and 83 weeks. Limited meta-analysis was possible because of the diversity of outcomes reported in these trials. Based on the number of participants with at least one exacerbation, the meta-analysis showed significant effects in favour of the intervention (odds ratio (OR) 0.31, 95% confidence interval (CI) 0.19 to 0.52; P value < 0.00001), with events occurring in 271 per 1000 people in the intervention arm (95% CI 126 to 385) and in 546 per 1000 in the control population, based on evidence of moderate quality. A non-statistically significant reduction in hospitalisation favoured the use of prolonged antibiotics with a moderate quality grade of supporting evidence (37 per 1000 in the intervention arm (95% CI 13 to 96) and 87 per 1000 in control (OR 0.40, 95% CI 0.14 to 1.11; P value = 0.08). Drug resistance developed in 36 of 220 participants taking antibiotics compared with 10 of 211 participants given placebo or standard therapy (OR 3.48, 95% CI 1.20 to 10.07; P value = 0.02), translating to natural frequencies of 155 per 1000 in the intervention arm (95% CI 59 to 346) and 50 per 1000 in the control arm. The intervention was well tolerated with no overall significant difference in withdrawal between treatment and placebo groups (OR 0.91, 95% CI 0.56 to 1.49). Diarrhoea was commonly reported as an adverse event, particularly with an oral intervention. Available evidence shows benefit associated with use of prolonged antibiotics in the treatment of patients with bronchiectasis, at least halving the odds of exacerbation (with 275 fewer exacerbations per every 1000 people treated in the antibiotic arm compared with the control arm) and hospitalisation (50 fewer hospitalisations per 1000 people in the antibiotic arm compared with the control arm). However, the risk of emerging drug resistance is increased more than threefold. This review is limited by diversity of trials and by evidence of moderate to low quality. Further randomised controlled trials with adequate power and standardised end points are required.

Income inequality and social preferences for redistribution and compensation differentials

Countries with greater inequality typically exhibit less support for redistribution and greater acceptance of inequality (e.g., U.S. versus Western Europe). If individual nations evolve along this pattern, a vicious cycle could form with reduced social concern amplifying primal increases in inequality. Exploring movements around these long-term levels, however, this study finds mixed evidence regarding the vicious cycle hypothesis. Larger compensation differentials are accepted as inequality grows. Weighing against this, growth in inequality is met with greater support for government-led redistribution. Inequality shocks can be reinforced in the labor market but do not result in weaker political preferences for redistribution.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis

Cystic fibrosis (CF) is an autosomal recessive disease characterized by an elevated sweat chloride level, diffuse bronchiectasis, and pancreatic exocrine deficiency. It is the most common lethal inherited disease in whites. Most patients present at birth or early childhood, although later diagnoses are not infrequent. Once CF was uniformly fatal at an early age, but advances in nutrition, airway clearance, and infection management have led to an average survival of 37 years. The newest aspect of care is the advent of protein modulators, which may increase life expectancy even further. This chapter discusses the epidemiology, genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, and treatment of CF. The definition, epidemiology, etiology, pathogenesis, diagnosis, management, and prognosis of non-CF bronchiectasis are also covered. Figures illustrate normal and abnormal CF transmembrane conductance regulators, the vicious cycle hypothesis of lung injury, rates of respiratory germs by age, the diagnosis of CF, the therapeutics pipeline for CF, forced expiratory volume in 1 second lung function percent predicted versus body mass index, and the median predicted survival age of patients with CF. A chest x-ray and chest computed tomographic scan of CF are also provided. Tables outline the most common CF mutations in 2011, class mutations of CF, a mnemonic for acute exacerbations of CF, the diagnosis of CF-related diabetes in a stable patient, sweat test values, and the differential diagnosis of bronchiectasis.This chapter contains 9 highly rendered figures, 6 tables, 143 references, 1 teaching slide set, and 5 MCQs.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis

Cystic fibrosis (CF) is an autosomal recessive disease characterized by an elevated sweat chloride level, diffuse bronchiectasis, and pancreatic exocrine deficiency. It is the most common lethal inherited disease in whites. Most patients present at birth or early childhood, although later diagnoses are not infrequent. Once CF was uniformly fatal at an early age, but advances in nutrition, airway clearance, and infection management have led to an average survival of 37 years. The newest aspect of care is the advent of protein modulators, which may increase life expectancy even further. This chapter discusses the epidemiology, genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, and treatment of CF. The definition, epidemiology, etiology, pathogenesis, diagnosis, management, and prognosis of non-CF bronchiectasis are also covered. Figures illustrate normal and abnormal CF transmembrane conductance regulators, the vicious cycle hypothesis of lung injury, rates of respiratory germs by age, the diagnosis of CF, the therapeutics pipeline for CF, forced expiratory volume in 1 second lung function percent predicted versus body mass index, and the median predicted survival age of patients with CF. A chest x-ray and chest computed tomographic scan of CF are also provided. Tables outline the most common CF mutations in 2011, class mutations of CF, a mnemonic for acute exacerbations of CF, the diagnosis of CF-related diabetes in a stable patient, sweat test values, and the differential diagnosis of bronchiectasis.This chapter contains 9 highly rendered figures, 6 tables, 143 references, 1 teaching slide set, and 5 MCQs.

Income Inequality and Social Preferences for Redistribution and Compensation Differentials

In cross-sectional studies, countries with greater income inequality typically exhibit less support for government-led redistribution and greater acceptance of wage inequality (e.g., United States versus Western Europe). If individual nations evolve along this pattern, a vicious cycle could form with reduced social concern amplifying primal increases in inequality due to forces like skill-biased technical change. Exploring movements around these long-term levels, however, this study finds mixed evidence regarding the vicious cycle hypothesis. On one hand, larger compensation differentials are accepted as inequality grows. This growth in differentials is of a smaller magnitude than the actual increase in inequality, but it is nonetheless positive and substantial in size. Weighing against this, growth in inequality is met with greater support for government-led redistribution to the poor. These patterns suggest that short-run inequality shocks can be reinforced in the labor market but do not result in weaker political preferences for redistribution.

Income Inequality and Social Preferences for Redistribution and Compensation Differentials

In cross-sectional studies, countries with greater income inequality typically exhibit less support for government-led redistribution and greater acceptance of wage inequality (e.g., United States versus Western Europe). If individual nations evolve along this pattern, a vicious cycle could form with reduced social concern amplifying primal increases in inequality due to forces like skill-biased technical change. Exploring movements around these long-term levels, however, this study finds mixed evidence regarding the vicious cycle hypothesis. On one hand, larger compensation differentials are accepted as inequality grows. This growth in differentials is of a smaller magnitude than the actual increase in inequality, but it is nonetheless positive and substantial in size. Weighing against this, growth in inequality is met with greater support for government-led redistribution to the poor. These patterns suggest that short-run inequality shocks can be reinforced in the labor market but do not result in weaker political preferences for redistribution.

Short- and Long-Term Antibiotic Treatment Reduces Airway and Systemic Inflammation in Non–Cystic Fibrosis Bronchiectasis

The vicious cycle hypothesis of bronchiectasis argues that bacterial colonization leads to airway inflammation and progressive lung damage. The logical extension of this hypothesis is that acute or chronic antibiotic therapy should improve airway inflammation and clinical outcome. There are little data to support this hypothesis in patients with non-cystic fibrosis (CF) bronchiectasis. To determine whether acute or chronic antibiotic therapy improves airway inflammation and clinical outcome in non-CF bronchiectasis. The relationship between bacterial load and airway and systemic inflammation was investigated in 385 stable patients, 15 stable patients treated with intravenous antibiotics, and 34 patients with an exacerbation of bronchiectasis treated with intravenous antibiotics. Long-term antibiotic therapy was investigated using samples from a 12-month controlled trial of nebulized gentamicin. In stable patients, there was a direct relationship between airway bacterial load and markers of airway inflammation (P < 0.0001 for all analyses). High bacterial loads were associated with higher serum intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 (P < 0.05 above bacterial load ≥1 × 10(7) cfu/ml). In stable patients, there was a direct relationship between bacterial load and the risk of subsequent exacerbations (odds ratio, 1.20; 95% confidence interval, 1.11-1.29; P < 0.0001) and severe exacerbations (odds ratio, 1.11; 95% confidence interval, 1.01-1.21; P = 0.02). Short- and long-term antibiotic treatments were associated with reductions in bacterial load, airways, and systemic inflammation. High airway bacterial loads in non-CF bronchiectasis are associated with airway and systemic inflammation and a greater risk of exacerbations. Short- and long-term antibiotic therapy reduce markers of airways and systemic inflammation.

Pathogenesis of idiopathic scoliosis: A review

Idiopathic scoliosis is a three-dimensional deformation of the spine. As its name suggests, its pathogenesis remains poorly understood. Enhanced comprehension of its pathogenesis would be likely to improve current therapeutic results. While the hereditary and genetic origin of scoliosis appears unassailable and several chromosomes are known to be involved in transmission, the role assumed by each individual chromosome remains uncertain, and the mechanisms leading to the expression of scoliosis have yet to be determined. Even though a large number of pathogenetic hypotheses have been put forward and numerous studies carried out, none of these hypotheses have won unanimous approval, and the controversy remains persistent. ObjectiveThe objective of this paper is to identify the existing hypotheses and to group them within large-scale etiological categories. MethodsWe examined the Pubmed and Goggle databases using as keywords “idiopathic scoliosis” and “pathogenesis”. The search was limited to articles in English and French. ResultsThe vicious cycle hypothesis is markedly preponderant. However, no existing pathogenetic model adequately accounts for the formation of scolioses. ConclusionWe are proposing four main pathogenetic mechanisms: asymmetric bone growth dysregulation, susceptibility of bones to deformation, abnormal passive spinal system maintenance and disturbed active spinal system maintenance.

Preverbal error-monitoring in stutterers and fluent speakers

This study was designed to characterize the brain system that monitors speech in people who stutter and matched controls. We measured two electrophysiological peaks associated with action-monitoring: the error-related negativity (ERN) and the error positivity (Pe). Both the ERN and Pe were reliably observed after errors in a rhyming task and a nonverbal flanker task, replicating previous reports of a language-monitoring ERN and demonstrating that the Pe can also be elicited by phonological errors. In the rhyming task, stutterers showed a heightened ERN peak regardless of whether they actually committed an error. Similar results, though only marginally significant, were obtained from the flanker task. These results support the vicious cycle hypothesis, which posits that stuttering results from over-monitoring the speech plan. The elevation of the ERN in stutterers and the similarity of the results between the flanker and rhyming tasks implies that speech-monitoring may rely on the same neural substrate as action-monitoring.

The impact of successor characteristic on stock returns

To find out effects of top managers’ turnover on stock returns, this study utilizes the market model to analyze the wealth effects of top executive turnover in Taiwanese listed electronic companies. Results in this study show that in the case of insider successor condition, it supports the ritual scapegoating theory for top executives (R&amp;D Managers and CEOs). The results of chairmans are more consistent with vicious cycle hypothesis. On the other hand, the case of outsider successor condition shows that the ritual scapegoating theory is more suitable for CEOs and chairmans. The common sense theory is more valid when the new outsider successors are R&amp;D Managers. The results of this study show that selecting the chairman of board is a critical decision when new successors of chairman of board are insider. The results also show the turnovers of R&amp;D managers have positive stock reactions when new successors are outsiders

Government Deficits and Inflation in Brazil: The Experience During 1948-1964

A re-examination of the Aghevli-Khan model developed at the International Monetary Fund (IMF) revealed that the specification of the money supply function provided an unconvincing test of the link between government deficits and monetary growth. Their specification of the money supply function was found to be, for all practical purposes, an identity thereby explaining little. Furthermore, they also assumed that the impact of changes in the fiscal deficit on the monetary base was independent of other variables in the money supply function which were therefore treated as exogenous by the model. We respecified the model casting the money supply equation as a function of the fiscal deficit only -- a formulation testing the hypothesis that deficits were largely financed through money creation. This confirmed the thesis that in a period characterized by financial repression, the government could not tap domestic savings adequately to be able to finance the deficits in a non-inflationary manner. Instead, the government had to rely almost exclusively on credits from the monetary authorities to finance its budget deficits. The reformulated dynamic simulation model confirmed that the inflation thus generated further widened the deficits due to the asymmetrical adjustment of government expenditures and revenues to inflation. This vindicated the IMF model but that vindication only held under the limiting condition of the pure money finance of government deficits. Non-inflationary financing of government deficits would break the vicious-cycle hypothesis not only for Brazil but for other countries as well.

Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis

Bone metastases cause severe skeletal complications and are associated with osteoclast-mediated bone destruction. RANKL is essential for osteoclast formation, function, and survival, and is the primary effector of tumor-induced osteoclastogenesis and osteolysis. RANKL inhibition by its soluble decoy receptor osteoprotegerin (OPG) prevents tumor-induced osteolysis and decreases skeletal tumor burden. Because osteoclast-mediated bone resorption releases growth factors from the bone matrix, the host bone microenvironment induces a vicious cycle of bone destruction and tumor proliferation and survival. A prediction of this vicious cycle hypothesis is that targeting the host bone microenvironment by osteoclast inhibition would reduce tumor growth and survival and may enhance the anti-tumor effects of targeted therapies. The epidermal growth factor receptor (EGFR) pathway regulates critical processes such as cell growth and survival, and anti-EGFR therapies can cause tumor cell arrest and apoptosis. We evaluated whether reduction of osteolysis by RANKL inhibition could enhance the anti-tumor effects of an anti-EGFR antibody (panitumumab) in a novel murine model of human A431 epidermoid carcinoma bone metastasis. Skeletal tumor progression was assessed longitudinally by bioluminescence imaging. RANKL inhibition by OPG-Fc treatment resulted in a reduction in tumor progression in bony sites. OPG-Fc treatment also caused a dose-dependent reduction in tumor-induced osteolysis, supporting the essential role of RANKL in this process. In combination, RANKL inhibition increased the anti-tumor efficacy of an anti-EGFR antibody, and completely blocked tumor-induced bone breakdown, demonstrating that addition of the indirect anti-tumor effect of RANKL inhibition increases the anti-tumor efficacy of panitumumab, a targeted anti-EGFR antibody.

Biomechanical spinal growth modulation and progressive adolescent scoliosis--a test of the 'vicious cycle' pathogenetic hypothesis: summary of an electronic focus group debate of the IBSE.

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr Ian A Stokes. It evaluates the hypothesis that in progressive scoliosis vertebral body wedging during adolescent growth results from asymmetric muscular loading in a "vicious cycle" (vicious cycle hypothesis of pathogenesis) by affecting vertebral body growth plates (endplate physes). A frontal plane mathematical simulation tested whether the calculated loading asymmetry created by muscles in a scoliotic spine could explain the observed rate of scoliosis increase by measuring the vertebral growth modulation by altered compression. The model deals only with vertebral (not disc) wedging. It assumes that a pre-existing scoliosis curve initiates the mechanically-modulated alteration of vertebral body growth that in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically 'normal' The results provide quantitative data consistent with the vicious cycle hypothesis. Dr Stokes' biomechanical research engenders controversy. A new speculative concept is proposed of vertebral symphyseal dysplasia with implications for Dr Stokes' research and the etiology of AIS. What is not controversial is the need to test this hypothesis using additional factors in his current model and in three-dimensional quantitative models that incorporate intervertebral discs and simulate thoracic as well as lumbar scoliosis. The growth modulation process in the vertebral body can be viewed as one type of the biologic phenomenon of mechanotransduction. In certain connective tissues this involves the effects of mechanical strain on chondrocytic metabolism a possible target for novel therapeutic intervention.