Targeting selectins for the treatment of inflammatory diseases.

Expert Opin Ther Targets. 2013 Sep 27;

Authors: Impellizzeri D, Cuzzocrea S

Abstract
Introduction: Selectins mediate tethering and rolling of leukocytes to the vascular endothelium, the first adhesive step in the recruitment of immune cells to inflamed tissues. Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic, brain, lung, heart and skin inflammation, atherosclerosis and cancer progression. Because blockade of the steps of leukocyte recruitment has been predicted to interrupt leukocyte extravasation, pharmacological interference with the function of key molecules in the multistep recruitment cascade represents a promising strategy for therapeutic intervention in inflammatory disorders. Selectin-neutralizing monoclonal antibodies, recombinant soluble P-selectin glycoprotein ligand 1 and small-molecule inhibitors of selectins have been tested in preclinical and clinical studies associated with inflammation. Areas covered: This article explores the experimental studies describing the beneficial effects of selectin modulators in the treatment of inflammatory diseases. Expert opinion: Many of the selectin-directed compounds have not held up to the high expectations, in some cases due to overlapping and mutually compensating functions of selectins or suboptimal pharmacokinetic properties of the compounds, while other agents appear to be more promising candidates and have already entered clinical trials.

PMID: 24074033 [PubMed - as supplied by publisher]

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Targeting Interleukin-6 in Inflammatory Autoimmune Diseases and Cancers.

Pharmacol Ther. 2013 Sep 26;

Authors: Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y

Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases.

PMID: 24076269 [PubMed - as supplied by publisher]

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Radiotherapy for Postoperative Thoracic Lymph Node Recurrence of Non-Small-Cell Lung Cancer Provides Better Outcomes If the Disease Is Asymptomatic and a Single-Station Involvement.

J Thorac Oncol. 2013 Sep 26;

Authors: Okami J, Nishiyama K, Fujiwara A, Konishi K, Kanou T, Tokunaga T, Teshima T, Higashiyama M

Abstract
OBJECTIVE:: Thoracic lymph node recurrence after complete resection is common in non-small-cell lung cancer but it mostly occurs along with distant metastases. The recurrent disease might be localized and curative intent radiation therapy is the treatment of choice if no evidence of hematogenous metastasis is observed. We sought to describe the outcomes of thoracic radiotherapy for thoracic lymph node recurrences.
METHODS:: Fifty patients who had developed thoracic lymph node recurrence after complete resection received curative intent radiotherapy between 1997 and 2009. The clinical endpoints included the tumor response, overall survival, progression-free survival, locoregional recurrence within the irradiated field, and any other recurrence.
RESULTS:: The planned total radiotherapy was completed in 49 patients with minor toxicity. The median follow-up time after radiotherapy was 41 (19-98) months among the survivors. The response to treatment was complete response in 65%, partial response in 24%, and progressive disease in 10% of the evaluated patients. The median overall survival after radiotherapy was 37.3 months. The 5-year overall survival, progression-free survival, and local control rate were 36.1%, 22.2%, and 61.1%, respectively. A multivariate analysis revealed that the absence of symptoms and the involvement of a single lymph node station were significant factors associated with a better overall survival.
CONCLUSIONS:: Radiation therapy for thoracic lymph node recurrence after complete resection is safe and provides acceptable disease control. This treatment provides a better outcome if the disease is asymptomatic and has a single-station involvement. Early detection of the recurrence may thus improve the effectiveness of this treatment.

PMID: 24077458 [PubMed - as supplied by publisher]

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The hazards of death by smoking in middle-aged women.

Eur J Epidemiol. 2013 Sep 29;

Authors: Gram IT, Sandin S, Braaten T, Lund E, Weiderpass E

Abstract
Recent studies have found that the risk of death continues to increase among female smokers, as compared with women who have never smoked. We wanted to examine the effect of smoking on all-cause and cause-specific mortality and calculate the corresponding population attributable fraction (PAF) of mortality in the Norwegian women and cancer study; a nationally representative prospective cohort study. We followed 85,320 women, aged 31-70 years, who completed a questionnaire in 1991-1997, through linkages to national registries through December 2008. Questionnaire data included information on lifestyle factors, including lifetime history of smoking. Poisson regression models were fitted to estimate relative risks (RRs) with 95 % confidence intervals (CIs) adjusting for age, birth cohort, education, postmenopausal status, alcohol consumption and body mass index, all at enrollment. During a mean follow-up time of 14 years 2,842 deaths occurred. Compared with that of never smokers, current smokers had a mortality rate that was double (RR = 2.34; 95 % CI 2.13-2.62) from deaths overall, triple (RR = 3.30; 95 % CI 2.21-4.82) from cerebrovascular disease and myocardial infarction (RR = 3.65; 95 % CI 2.18-6.15), 12 times (RR = 12.16; 95 % CI 7.80-19.00) from lung cancer and seventeen times (RR = 17.00; 95 % CI 5.90-48.78) from chronic obstructive pulmonary diseases. The PAF of mortality due to smoking was 34 % (CI 30-39). In summary, one in three deaths among middle aged women in Norway could have been prevented if the women did not smoke. More middle-aged women, than ever before, are dying prematurely due to smoking in Norway.

PMID: 24078008 [PubMed - as supplied by publisher]