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Background: Studies suggest that nuclear factor kappa-B (NFκB) activation may be a critical event in the production of proinflammatory molecules in Helicobacter pylori-associated gastritis. Materials and Methods: This study examines the expression and activity of NFκB in situ in antral biopsies of 42 consecutive patients with immunohistochemical techniques. Results: NFκB was highly expressed in the gastric epithelial cells. The number of cells showing activated NFκB correlated with the activity of gastritis (P < 0.05), a measure of neutrophil influx, whereas no correlation was found with the chronicity of inflammation, a measure of the presence of mononuclear inflammatory cells. There was also a strong inverse association with the presence and grade of atrophy. Conclusion: This correlation is direct evidence of the importance of NFκB dependent signal transduction for neutrophil influx in gastritis. The role of NFκB appears to be only in the initial stages of gastritis, there is no role for the molecule in the development of chronic inflammation or atrophy.

Byline: Neena. Srivastava, B. Achyut, Jai. Prakash, C. Agarwal, D. Pant, Balraj. Mittal Background: Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause [...]

The expression of growth factors, proteolytic enzymes, fibrogenic factors, and cytokines is altered in the Helicobacter pylori–infected gastric mucosa. Therefore, we aimed to evaluate the association of functional promoter variants of transforming growth factor ( TGF) -B1 and matrix metalloproteinase ( MMP) -7 genes with gastritis and gastric precancerous lesions. After upper gastrointestinal endoscopy, a total of 130 rapid urease test–positive patients with nonulcer dyspepsia were examined for H. pylori infection using modified Giemsa stain and IgG anti-CagA ELISA. All patients and 200 asymptomatic controls were genotyped for TGF-B1 (−509 C>T) and MMP-7 (−181 A>G) substitutions using PCR-RFLP. The genotype and allele frequencies of TGF-B1 and MMP-7 polymorphisms did not differ between patients and controls ( p > 0.05). However, the CagA-positive patients with TGF-B1 −509 T allele had higher risk for gastric atrophy ( p = 0.026, odds ratio [OR] = 2.38) and lymphoid follicle development ( p = 0.028, OR = 2.29). In addition, CagA-positive patients carrying MMP-7 −181 G allele had risk for lymphoid follicle formation ( p = 0.027, OR = 2.30). Thus, the present study revealed significant association of functional MMP-7 and TGF-B1 gene variants toward susceptibility to H. pylori–induced precancerous gastric lesions. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) causes gastritis, development of lymphoid follicles and later monoclonal mucosa-associated lymphoid tissue (MALT) lymphoma. We evaluated the association of tumor necrosis factor (TNF)-alpha (-308 G/A) and IL-10 (-819 C/T) gene polymorphisms with gastritis and lymphoid follicle formation. H. pylori infection was detected using modified Giemsa staining and IgG anti-CagA enzyme-linked immunosorbent assay (ELISA). One hundred and thirty patients with non-ulcer dyspepsia (NUD) and 200 healthy age-matched controls were genotyped for TNF-alpha and IL-10 polymorphisms using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). Subjects with IL-10 -819 T allele [patients (46.5%) versus controls (35.7%), p = 0.006, OR = 1.56, 95% CI = 1.14-2.15] were at risk of gastritis. Infection with H. pylori was more often associated with lymphoid follicles formation than its absence (46% versus 22%, p = 0.009). TNF-alpha polymorphism did not influence gastritis but patients with TNF-alpha -308 A allele carriers showed >2 fold risk of lymphoid follicle formation [presence (26%) versus absence (11.25%), p = 0.029, OR = 2.8; 95% CI = 1.09-7.08]. There was a trend towards association of lymphoid follicles and TNF-alpha -308 A allele carriers with H. pylori infection than without (58.5% versus 22.2%; p = 0.064). IL-10 -819 T and TNF-alpha -308 A alleles may increase risk of gastritis and lymphoid follicle formation. [ABSTRACT FROM AUTHOR]

Tumor cell survival in the hostile distant organ is a ratelimiting step in cancer metastasis. Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor promoting microenvironment. However, it is unclear whether these myeloid cells in the premetastatic site have any direct effect on tumor cell survival. Here, we report that chemokine CCL9 was highly induced in Gr-1+CD11b+ immature myeloid cells and in premetastatic lung in tumor-bearing mice. Knockdown of CCL9 in myeloid cells decreased tumor cell survival and metastasis. Importantly, CCL9 overexpression in myeloid cells lacking TGFb signaling rescued the tumor metastasis defect observed in mice with myeloid-specific Tgfbr2 deletion. The expression level of CCL23, the human orthologue for CCL9, in peripheral blood mononuclear cells correlated with progression and survival of cancer patients. Our study demonstrates that CCL9 could serve as a good candidate for antimetastasis treatment by targeting the rate-limiting step of cancer cell survival. In addition, targeting CCL9 may avoid the adverse effects of TGFβ-targeted therapy. [ABSTRACT FROM AUTHOR]

Antiangiogenic agents caused paradoxical increase in pro-growth and pro-angiogenic factors and caused tumor growth in glioblastoma (GBM). It is hypothesized that paradoxical increase in pro-angiogenic factors would mobilize Bone Marrow Derived Cells (BMDCs) to the treated tumor and cause refractory tumor growth. The purposes of the studies were to determine whether whole body irradiation (WBIR) or a CXCR4 antagonist (AMD3100) will potentiate the effect of vatalanib (a VEGFR2 tyrosine kinase inhibitor) and prevent the refractory growth of GBM. Human GBM were grown orthotopically in three groups of rats (control, pretreated with WBIR and AMD3100) and randomly selected for vehicle or vatalanib treatments for 2 weeks. Then all animals underwent Magnetic Resonance Imaging (MRI) followed by euthanasia and histochemical analysis. Tumor volume and different vascular parameters (plasma volume (v p ), forward transfer constant (K trans ), back flow constant (k ep ), extravascular extracellular space volume (v e ) were determined from MRI. In control group, vatalanib treatment increased the tumor growth significantly compared to that of vehicle treatment but by preventing the mobilization of BMDCs and interaction of CXCR4-SDF-1 using WBIR and ADM3100, respectively, paradoxical growth of tumor was controlled. Pretreatment with WBIR or AMD3100 also decreased tumor cell migration, despite the fact that ADM3100 increased the accumulation of M1 and M2 macrophages in the tumors. Vatalanib also increased K trans and v e in control animals but both of the vascular parameters were decreased when the animals were pretreated with WBIR and AMD3100. In conclusion, depleting bone marrow cells or CXCR4 interaction can potentiate the effect of vatalanib.

Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 10(6) GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Low oxygen tension, hypoxia, is a characteristic of many tumors and associated with the poor prognosis. Hypoxia invites bone marrow derived cells (BMDCs) from bone marrow to the site of tumor. These recruited CXCR4+ BMDCs provide favorable environment for the tumor growth by acquiring pro-angiogenic phenotype such as CD45+VEGFR2+ Endothelial Progenitor Cells (EPC), or CD45+Tie2+ myeloid cells. CD11b+CD13+ myeloid population of the BMDCs modulate tumor progression. These myeloid populations retain immunosuppressive characteristics, for example, myeloid derived suppressor cells (MDSCs), and regulates immune- suppression by inhibiting cytotoxic T cell function. In addition, MDSCs were observed at the premetastatic niche of the distant organs in other tumors. Protumorigenic and prometastatic role of the myeloid cells provides a basis for therapeutic targeting of immunosuppression and thus inhibiting tumor development and metastasis.

Background: Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause of obesity. Therefore, we aimed to evaluate association of genetic polymorphisms of beta(2)-adrenergic receptor (beta(2)-AR) and insulin receptor substrate-1 (IRS-1) with hormonal levels in northern Indian obese., Methods: A total of 111 obese and 89 age matched non-obese subjects were studied after taking detailed clinical profile. Hormonal assays in serum/plasma for different hormones were done using IRMA and RIA kits. Genetic analysis of beta(2)-AR (-47 and -20, T to C) and IRS-1 (Arg972Gly) was done using PCR-RFLP., Statistical Analysis: Statistical analysis was performed by SPSS (version 11.5) software. All continuous variables were expressed as mean +/- SD and tested by ANOVA test. Comparisons of categorical variables were assessed using X(2) tests or Fisher's exact test. P-value <0.05 was considered as significant., Results: Analysis showed that obese subjects had significantly higher value of blood pressure (systolic), WHR, leptin insulin and glucagon and lower value of GH. In beta(2)-AR (-47) T/C and IRS-1 Gly972Arg gene polymorphisms we did not found significant differences in genotype or allele frequencies. Moreover, none of the studied hormonal or metabolic parameters showed any association with the gene polymorphisms., Conclusions: Study reveals no significant association of beta(2)-AR (-47 and -20, T to C) and IRS-1 Gly 972 Arg polymorphisms with obesity in northern Indians.