Mahboobeh Mahdavinia

Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention.

Colorectal cancer (CRC) is one of the leading causes of cancer and cancer-related mortality worldwide. The disease has been traditionally a major health problem in industrial countries, however the CRC rates are increasing in the developing countries that are undergoing economic growth. Several environmental risk factors, mainly changes in diet and life style, have been suggested to underlie the rise of CRC in these populations. Diet and lifestyle impinge on nuclear receptors, on the intestinal microbiota and on crucial molecular pathways that are implicated in intestinal carcinogenesis. In this respect, the epidemiological transition in several regions of the world offers a unique opportunity to better understand CRC carcinogenesis by studying the disease phenotypes and their environmental and molecular associations in different populations. The data from these studies may have important implications for the global prevention and treatment of CRC.

Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease

RATIONALE The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. OBJECTIVES To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. METHODS Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. MEASUREMENTS AND MAIN RESULTS CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. CONCLUSIONS CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression

BACKGROUND Despite the high prevalence and morbidity of chronic rhinosinusitis (CRS), little is known about the mechanisms that underlie its pathogenesis. Recent studies have suggested that B cells might play an important role in CRS. OBJECTIVE We sought to thoroughly characterize B lineage cells within sinus tissues of patients with CRS and healthy control subjects and to determine whether levels of EBV-induced protein 2, which is known to play an important role in the development of B-cell responses, were increased in patients with CRS. METHODS Cells isolated from sinus tissues of patients with CRS and healthy control subjects were characterized by means of flow cytometry and immunohistochemistry. Local production of antibodies was measured in tissue extracts, nasal lavage fluid, and sera by using multiplex bead arrays and ELISA. Quantitative RT-PCR, ELISA, and Western blotting were used to assess gene and protein expression from tissue extracts. RESULTS Nasal polyps (NPs) from patients with CRS had increased levels of both B cells and plasma cells compared with uncinate tissue from healthy control subjects (P<.05). NPs also contained significantly increased levels of several antibody isotypes compared with normal uncinate tissue (P<.05), but no differences in circulating antibody levels were found. Interestingly, levels of EBV-induced protein 2 were also increased in NPs (P<.05) and were positively correlated with expression of plasma cell markers (CD138 and B lymphocyte-induced maturation protein) in sinus tissue. CONCLUSION B cells and plasma cells are enriched in NPs, actively produce antibodies locally, and might contribute to chronic inflammation in patients with CRS. Elucidating the mechanisms that underlie this excessive local B-cell response might provide novel insights for the development of improved therapeutic strategies.

Family history of colorectal cancer in Iran

BackgroundPrevious reports show a high proportion of young CRC patients in Iran. In this study we aim to look for the clustering of colorectal cancer in families of a series of CRC patients from Iran.MethodsThe family history of cancer is traced in 449 CRC patients of which 112 were 45 yrs or younger and 337 were older than 45 yrs at time of diagnosis. The patients were admitted in two hospitals in Tehran, during a 4-year period.ResultsClinical diagnosis of HNPCC was established in 21 (4.7%) probands. Family history of CRC was more frequently reported by early-onset than by late-onset patients (29.5% vs. 12.8%, p < 0.001).Distribution of tumor site differed significantly between those with and without family history of CRC. Right colon cancer was the most frequent site (23/45, 35.4%) observed in patients with positive family history of colorectal cancer.ConclusionThe relatively high frequency of CRC clustering along with HNPCC in our patients should be further confirmed with larger sample size population-based and genetic studies to establish a cost effective molecular screening for the future.

Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity

To the Editor: Chronic rhinosinusitis (CRS) is a common chronic diseasewith significant burden and effect on the quality of life of affected individuals, characterized by inflammation of the nasal mucosa and paranasal sinuses. Patients can be subdivided into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). In addition, aspirin exacerbated respiratory disease (AERD) is a subgroup of CRSwNP characterized by the triad of CRSwNP, asthma, and hypersensitivity to aspirin or nonsteroidal antiinflammatory drugs. Eosinophilia is evident in the nasal mucosa and submucosa of nasal polyps (NPs) from patients in Europe and the United States, but less so in Asian countries such as China or Japan. In this study we attempted, for the first time, to evaluate the role of another important inflammatory leukocyte, the basophil, in CRS. Basophils are granulocytes found mainly in the circulation and are known to have a role in allergic diseases, parasite expulsion, and immunity against ectoparasites. Basophil numbers are elevated in the bronchial mucosa and submucosa of asthmatic patients, the nasal submucosa in patients with allergic rhinitis, and in the skin of those with multiple inflammatory dermatologic conditions, including eczema and urticaria. AlthoughCRSwNP is a highlyTH2-biaseddisease,making basophil involvement likely, there are no reports of basophils in CRS. In the current study we used 2D7, a mouse mAb against a basophilspecific intermediate form of major basic protein, to detect basophils in uncinate tissue (UT)or polyp tissue obtained during surgery from patients with CRS and control subjects as described previously. This antibody is shown to be a specific marker for basophils and does not recognize any other cell type. We used the immunohistochemistry protocol detailed in previous studies using 2D7. Mucosa and submucosa in the tissue biopsies were delineated, and the total number of positively stained cells in each field was counted in 50 random hpf with 1003magnification. Results are reported as the number of positive cells per square millimeter. A tissue section was stained with hematoxylin and eosin. Eosinophils were identified on the basis of their cellular features and distinct cytoplasmic eosinophilic granules. For all polyp samples, a serial section was stained with a tryptase mAB, a specificmarker for mast cells as described previously. Cells were counted and data expressed as described above for basophils. Data are presented as mean 6 SEM. Comparisons between groups were assessed by using ANOVA and Newman-Keuls multiple comparison tests. Correlations were measured using a Spearman rank correlation test. All statistical analyses were performed using GraphPad Prism version 6.00 for Windows (GraphPad Software, La Jolla, Calif; www.graphpad.com). A P value of less than .05 was considered statistically significant. A total of 73 sections were labeled with 2D7, including polyps from 27 patients with and without AERD (10 with AERD and 17 without AERD) and UT from 16 patients with CRSwNP, 15 patients with CRSsNP, and 15 control cases with no evidence of CRS. Cells were identified as basophils on the basis of a brown cytoplasmic granular staining pattern (Fig 1, A). Negative control slides were labeled with an isotype-matched nonimmune antibody and showed no staining. As detailed in Table I, there were no 2D7 basophils detected within the uncinate mucosa and submucosa of control subjects. A small number of these cells were detected in the UTof patients with CRSsNP, and a greater number was detected in the UTof patients with CRSwNP, though the quantities detected were not significantly greater than in control UT. The 2D7-positive cells per square millimeter of tissue were significantly higher in the NP tissue of patients with CRSwNP than in the UT of control subjects or patients with CRSsNP and CRSwNP (Fig 1, B). This count was also significantly higher when compared with the corresponding UT of the same patients with CRSwNP, paired sets of the polyp tissue and the UT having been evaluated from 12 patients with CRSwNP. Interestingly, the number of basophils detected in NPs from subjects with AERD was not higher than in normal or CRS UT and was significantly lower than in NPs from patients without AERD. Eosinophil counts in the UT of control patients with no evidence of sinusitis were significantly lower than in the UT of patients with CRSwNP (Table I). Polyp tissue had a significantly higher number of eosinophils than did the UT of all groups, including controls and patients with CRSsNP and CRSwNP. Polyps from subjects with AERD had a significantly higher eosinophil count than did the UT of all groups, with a trend toward higher levels than in non-AERD polyps. Basophil and eosinophil counts in all tissues (excluding AERD polyps) significantly correlated with one another (P < .001; Spearman r 5 0.67) (Fig 1, D). But the basophil and mast cell counts did not correlate. Basophils and eosinophils utilize similar pathways for recruitment and might be expected to be recruited to an inflammatory site in parallel.We therefore calculated the ratio of eosinophils to basophils by dividing the total number of eosinophils per hpf by the number of basophils per hpf in a fixed area in serially cut slides. The eosinophil to basophil ratio in normal UT had a mean value of 3.0; this value was 13.1 in CRSsNP UT and 49.0 in CRSwNPUT. Furthermore, the magnitude of the ratio of eosinophils to basophils was highest in NPs, with a mean of 89.2 in non-AERD polyps and 287.3 in AERD polyps. Values of this ratio were significantly higher in polyps than in the UT of CRSwNP, CRSsNP, and control cases. The blood basophil counts within 6 months of the time of surgery were available for 40 cases: 13 with analysis of polyp tissue and 27 with analysis of the UT. There was no correlation between the blood basophil count and the number of basophils in either the polyp tissue or the UT. This appears to exclude systemic basophilia as a likely cause of the observed increase in the number of basophils in the polyp tissue. We also correlated the basophil numbers in polyps with total serum IgE (available in 13 cases) and the presence of anosmia or hyposmia as a marker for disease severity and positive skin test result. None of these comparisons was significant (both including and excluding AERD polyps). Potentially other patient-related factors, such as treatment, might have affected the number of basophils. We compared the number of basophils in the UT and the polyp tissue of patients who were on oral steroids at the time of surgery compared with those who

Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia

In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from second-generation Asian patients, similar to studies of native-born patients in Asian countries, suggesting the hypothesis that there may be genetic regulation of eosinophilia.

A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS)

Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS.

P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K-ras mutations†

CRC‐associated P53 mutations have not been studied extensively in non‐Western countries at relatively low CRC risk. We examined, for the first time, 196 paraffin‐embedded CRC cases from Northern Iran for mutations in P53 exons 5–8 using PCR‐direct sequencing. P53 status and mutation site/type were correlated with nuclear protein accumulation, clinicopathologic variables and data on K‐ras mutations and high‐level microsatellite instability (MSI‐H). We detected 96 P53 mutations in 87 (44.4%) cases and protein accumulation in 84 cases (42.8%). P53 mutations correlated directly with stage and inversely with MSI‐H. Distal CRCs were more frequently mutated at major CpG hotspot codons [248 (8/66, 12.1%), 175 (7/66, 10.6%), and 245 (7/66, 10.6%)], while in proximal tumors codon 213, emerged as most frequently mutated (5/28, 17.9% vs. 3/66, 4.5%, P = 0.048). Transitions at CpGs, the most common mutation type, were more frequent in non‐mucinous (25% vs. 10.4% in mucinous, P = 0.032), and distal CRC (27% vs. 12.5% in proximal, P = 0.02), and correlated with K‐ras transversions. Transitions at non‐CpGs, second most common P53 mutation, were more frequent in proximal tumors (15.6% vs. 4.7% in distal, P = 0.01), and correlated with K‐ras transitions and MSI‐H. Overall frequency and types of mutations and correlations with P53 accumulation, stage and MSI‐H were as reported for non‐Iranian patients. However P53 mutation site/type and correlations between P53 and K‐ras mutation types differed between proximal and distal CRC. The codon 213 P53 mutation that recurred in proximal CRC was previously reported as frequent in esophageal cancer from Northern Iran. J. Cell. Physiol. 216: 543–550, 2008.

Injection of botulinum toxin before pneumatic dilatation in achalasia treatment: a randomized-controlled trial.

Pneumatic dilatation is the first line therapy in achalasia, but half of patients relapse within 5 years of therapy and require further dilatations.

Management of allergic bronchopulmonary aspergillosis: a review and update

Since the first description of allergic bronchopulmonary aspergillosis (ABPA) in the 1950s there have been numerous studies that have shed light on the characteristics and immunopathogenesis of this disease. The increased knowledge and awareness have resulted in earlier diagnosis and treatment of patients with this condition. This article aims to provide a summary and updates on ABPA by reviewing the results of recent studies on this disease with a focus on articles published within the last 5 years. A systematic search of PubMed/Medline with keywords of ABPA or allergic bronchopulmonary aspergillosis was performed. All selected articles were reviewed with a focus on findings of articles published from December 2006 to December 2011. The relevant findings are summarized in this paper.