Human Galectins Induce Conversion of Dermal Fibroblasts into Myofibroblasts and Production of Extracellular Matrix: Potential Application in Tissue Engineering and Wound Repair

Members of the galectin family of endogenous lectins are potent adhesion/growth-regulatory effectors. Their multi-functionality opens possibilities for their use in bioapplications. We studied whether human galectins induce the conversion of human dermal fibroblasts into myofibroblasts (MFBs) and the production of a bioactive extracellular matrix scaffold is suitable for cell culture. Testing a panel of galectins of all three subgroups, including natural and engineered variants, we detected activity for the proto-type galectin-1 and galectin-7, the chimera-type galectin-3 and the tandem-repeat-type galectin-4. The activity of galectin-1 required the integrity of the carbohydrate recognition domain. It was independent of the presence of TGF-beta 1, but it yielded an additive effect. The resulting MFBs, relevant, for example, for tumor progression, generated a matrix scaffold rich in fibronectin and galectin-1 that supported keratinocyte culture without feeder cells. Of note, keratinocytes cultured on this substratum presented a stem-like cell phenotype with small size and keratin-19 expression. In vivo in rats, galectin-1 had a positive effect on skin wound closure 21 days after surgery. In conclusion, we describe the differential potential of certain human galectins to induce the conversion of dermal fibroblasts into MFBs and the generation of a bioactive cell culture substratum. Copyright (C) 2011 S. Karger AG, Base

Modulation of N-methyl-N-nitrosourea induced mammary tumors in Sprague–Dawley rats by combination of lysine, proline, arginine, ascorbic acid and green tea extract

INTRODUCTION: The limited ability of current treatments to control metastasis and the proposed antitumor properties of specific nutrients prompted us to examine the effect of a specific formulation (nutrient supplement [NS]) of lysine, proline, arginine, ascorbic acid, and green tea extract in vivo on the development of N-methyl-N-nitrosourea (MNU)-induced mammary tumors in rats. METHODS: A single intraperitoneal dose of MNU was injected into each of 20 female Sprague–Dawley rats (aged 50 days) to induce tumors. Two weeks after MNU treatment, a time by which the animals had recovered from MNU-induced toxicity, the rats were divided into two groups. Rats in group 1 (n = 10) were fed Purina chow diet, whereas those in group 2 (n = 10) were fed the same diet supplemented with 0.5% NS. After a further 24 weeks, the rats were killed and tumors were excised and processed. RESULTS: NS reduced the incidence of MNU-induced mammary tumors and the number of tumors by 68.4%, and the tumor burden by 60.5%. The inhibitory effect of NS was also reflected by decreased tumor weight; the tumor weights per rat and per group were decreased by 41% and 78%, respectively. In addition, 30% of the control rats developed ulcerated tumors, in contrast to 10% in the nutrient supplemented rats. CONCLUSION: These findings suggest that the specific formulation of lysine, proline, arginine, ascorbic acid, and green tea extract tested significantly reduces the incidence and growth of MNU-induced mammary tumors, and therefore has strong potential as a useful therapeutic regimen for inhibiting breast cancer development

Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan

Several in vitro studies have demonstrated that genetic polymorphisms result in functionally significant changes in cytochrome p4501A1 (either CYP1A1 MspI or exon 7) but the few epidemiologic studies of these polymorphisms in oesophageal squamous-cell carcinoma have been inconclusive. These inconclusive results motivated us to further examine the relationship between CYP1A1 MspI and exon 7 polymorphisms and risk of oesophageal cancer. In total, 146 cases of oesophageal squamous-cell-carcinoma and 324 control cases (a total of 470 cases) were genotyped from records at three Taiwan hospitals. No significant association was noted for the CYP1A1 MspI polymorphism variable between carcinoma and control cases. In contrast, the frequency of Ile/Ile, Ile/Val, and Val/Val in exon 7 was 68 (46.6%), 62 (42.5%), and 16 (11.0%) in carcinoma cases and 179 (55.3%), 127 (39.2%), and 18 (5.6%) in control cases, respectively. After factoring out other potential contributing factors, patients with Val/Val showed a 2.48 (95% CT=1.15–5.34) greater risk of developing oesophageal cancer than those with Ile/Ile. A slightly (albeit not significantly) greater risk was identified in subjects with Ile/Val (OR=1.34; 95% CI=0.86–2.07). These findings suggest that an exon 7 polymorphism, not a MspI polymorphism, in CYP1A1 may be pivotal in the development of oesophageal cancer

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Protestant women in the late Soviet era: gender, authority, and dissent

At the peak of the anti-religious campaigns under Nikita Khrushchev, communist propaganda depicted women believers as either naïve dupes, tricked by the clergy, or as depraved fanatics; the Protestant “sektantka” (female sectarian) was a particularly prominent folk-devil. In fact, as this article shows, women’s position within Protestant communities was far more complex than either of these mythical figures would have one believe. The authors explore four important, but contested, female roles: women as leaders of worship, particularly in remote congregations where female believers vastly outnumbered their male counterparts; women as unofficial prophetesses, primarily within Pentecostal groups; women as mothers, replenishing congregations through high birth rates and commitment to their children’s religious upbringing; and women as political actors in the defence of religious rights. Using a wide range of sources, which include reports written by state officials, articles in the church journal, letters from church members to their ecclesiastical leaders in Moscow, samizdat texts, and oral history accounts, the authors probe women’s relationship with authority, in terms of both the authority of the (male) ministry within the church, and the authority of the Soviet state

EGCG Enhances the Therapeutic Potential of Gemcitabine and CP690550 by Inhibiting STAT3 Signaling Pathway in Human Pancreatic Cancer

Background: Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogene, which promotes cell survival, proliferation, motility and progression in cancer cells. Targeting STAT3 signaling may lead to the development of novel therapeutic approaches for human cancers. Here, we examined the effects of epigallocathechin gallate (EGCG) on STAT3 signaling in pancreatic cancer cells, and assessed the therapeutic potential of EGCG with gemcitabine or JAK3 inhibitor CP690550 (Tasocitinib) for the treatment and/or prevention of pancreatic cancer. Methodology/Principal Findings: Cell viability and apoptosis were measured by XTT assay and TUNEL staining, respectively. Gene and protein expressions were measured by qRT-PCR and Western blot analysis, respectively. The results revealed that EGCG inhibited the expression of phospho and total JAK3 and STAT3, STAT3 transcription and activation, and the expression of STAT3-regulated genes, resulting in the inhibition of cell motility, migration and invasion, and the induction of caspase-3 and PARP cleavage. The inhibition of STAT3 enhanced the inhibitory effects of EGCG on cell motility and viability. Additionally, gemcitabine and CP690550 alone inhibited STAT3 target genes and synergized with EGCG to inhibit cell viability and induce apoptosis in pancreatic cancer cells. Conclusions/Significance: Overall, these results suggest that EGCG suppresses the growth, invasion and migration of pancreatic cancer cells, and induces apoptosis by interfering with the STAT3 signaling pathway. Moreover, EGCG furthe

A comparison of risk factors for mortality from heart failure in Asian and non-Asian populations: An overview of individual participant data from 32 prospective cohorts from the Asia-Pacific Region

Background: Most of what is known regarding the epidemiology of mortality from heart failure (HF) comes from studies within Western populations with few data available from the Asia-Pacific region where the burden of heart failure is increasing.Methods: Individual level data from 543694 (85% Asian; 36% female) participants from 32 cohorts in the Asia Pacific Cohort Studies Collaboration were included in the analysis. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality from HF were estimated separately for Asians and non-Asians for a quintet of cardiovascular risk factors: systolic blood pressure, diabetes, body mass index, cigarette smoking and total cholesterol. All analyses were stratified by sex and study.Results: During 3,793,229 person years of follow-up there were 614 HF deaths (80% Asian). The positive associations between elevated blood pressure, obesity, and cigarette smoking were consistent for Asians and non-Asians. There was evidence to indicate that diabetes was a weaker risk factor for death from HF for Asians compared with non-Asians: HR 1.26 (95% CI: 0.74-2.13) versus 3.04 (95% CI 1.76-5.25) respectively; p for interaction = 0.022. Additional adjustment for covariates did not materially change the overall associations. There was no good evidence to indicate that total cholesterol was a risk factor for HF mortality in either population.Conclusions: Most traditional cardiovascular risk factors including elevated blood pressure, obesity and cigarette smoking appear to operate similarly to increase the risk of death from HF in Asians and non-Asians populations alike. © 2014 Huxley et al.; licensee BioMed Central Ltd

Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility

The influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1* A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects ≥ 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19–3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23–0.77), P = 0.03]. © 1999 Cancer Research Campaig