Cytokine gene polymorphism and graft-versus-host disease: a survey in Iranian bone marrow transplanted patients

Graft versus host disease (GVHD) is a major complication of bone marrow transplantation (BMT). Numerous studies have shown the potential role of cytokine genotypes in the occurrence of GVHD. In this retrospective, case–control study we aimed to investigate the association between 13 cytokine genes and acute GVHD (aGVHD) after HLA-identical sibling BMT in 91 Iranian subjects. Negative association was found between aGVHD and donor IL-10/GCC haplotype or donor IL-4Ra-A allele in the population study. When compared within the leukemia subgroup, we observed positive association between recipient IL-1α ?889/C allele and aGVHD. Also there were negative association between recipient IL-10/CAA haplotype and donor IL-4Ra/A allele and development of aGVHD. Among the different genotypes only donor IL-4Ra and donor IL-12 showed significant association. We conclude that several cytokine polymorphisms are positively and negatively associated with aGVHD in Iranian HLA matched siblings, of which IL-4Ra and IL-12 may play important roles.     

Découverte fortuite de fixations colorectales focales du FDG en TEP/TDM : corrélation aux données de la coloscopie

PurposeFDG-PET is an established tool for the diagnosis of recurrent or metastatic colorectal carcinoma. Several case series suggest that FDG-PET often detects incidental adenomatous polyps or colorectal adenocarcinomas. The aim of this study was to correlate unexpected colorectal foci of FDG uptake to pathology findings after systematic colonoscopy.Patients and methodsWe reviewed the records of 3541 patients who underwent FDG PET/CT in our institution over a 30-month period for the assessment of a known or suspected malignancy. In 85 of them, incidental, nodular shaped and well-circumscribed foci of abnormal uptake were identified in the area of the colon or rectum. Patients with segmental or diffuse abnormal colorectal uptake were excluded, as well as patients with known benign or malignant colorectal disease. Colonoscopy and complete pathology report was available in 29 patients. Maximal standardized uptake value (SUV_max) was measured in all lesions.ResultsUnexpected colorectal foci of FDG uptake were associated with colonoscopic abnormalities in 23 patients (true positive rate: 79 %). Adenocarcinomas were found in six patients (SUV_max = 7.3 ± 2.6), tubulous adenomas in four patients (SUV_max = 7.3 ± 4.9) and tubulovillous adenomas in 12 patients (SUV_max = 4.2 ± 1.1). Hyperplasic polyps with no sign of dysplasia were found in the last patient (SUV_max = 3.3). Concomitant CT abnormalities were found on PET/CT fusion in eight patients and consisted of wall thickening (n = 5) or nodular mass (n = 3). Conversely, PET was falsely positive in six patients (21 %), with no concomitant CT abnormalities and no abnormal findings at endoscopy (SUV_max = 6.2 ± 2.8, no significant difference with true positive lesions).ConclusionOur findings emphasize the need to perform a colonoscopy in front of incidental nodular colorectal foci of FDG uptake because malignant or pre-malignant neoplasms, which are not clinically apparent, are found in more than three-quarter of cases.     

Similarities and differences in the transcriptional regulation of the leptin gene promoter in gastric and adipose cells

The stomach was reported to synthesize and secrete leptin mainly in the gastric lumen. Gastric leptin release is markedly increased after food intake, by vagal cholinergic stimulation and by cholecystokinin and secretin. Here we show that human gastric MKN-74 cells produce leptin that increases upon challenge with cholecystokinin, insulin, glucocorticoids and all-trans retinoic acid through activation of the leptin gene promoter. In addition, we demonstrate that forskolin and BRL37344 which increased cAMP levels, fail to affect the activity of leptin gene promoter in MKN74 expressing beta(3)-adrenoceptor cells but, induce a 2-fold decrease in this activity in adipose 3T3-L1 cells. These data described for the first time, similarities and more interestingly, differences in the regulation of the leptin gene promoter in gastric cells as compared to adipocytes.     

Cytologic findings of a pleomorphic adenoma of the breast: a case report

BACKGROUND: Pleomorphic adenoma of the breast is a rare benign tumor. Only a few cases have been reported. The histologic features have been described well. However, the cytologic findings have been described in only a few papers. CASE: A 47-year-old female presented with a left breast mass of several months' duration. The clinical and mammographic findings were highly suspicious for malignancy. Following an aspiration biopsy diagnosis of "positive for malignancy," the mass was excised. The histologic diagnosis was pleomorphic adenoma (mixed tumor of salivary gland type) rather than carcinoma. CONCLUSION: The cytologic presentation of pleomorphic adenoma of the breast can masquerade as that of a malignant tumor, in this case colloid carcinoma. This case delineates the cytomorphologicfeatures of pleomorphic adenoma, which may mimic carcinoma.     

Design of a specific colonic mucus marker using a human commensal bacterium cell surface domain

Imaging living cells and organs requires innovative, specific, efficient, and well tolerated fluorescent markers targeting cellular components. Such tools will allow proceeding to the dynamic analysis of cells and the adaptation of tissues to environmental cues. In this study, we have identified and synthesized a novel non-toxic fluorescent marker allowing a specific fluorescent staining of the human colonic mucus. Our strategy to identify a molecule able to specifically bind to the human colonic mucus was on the basis of the mucus adhesion properties of commensal bacteria. We identified and characterized the mucus-binding property of a 70-amino acid domain (MUB(70)) expressed on the surface of Lactobacillus strains. The chemical synthesis of MUB(70) was achieved using the human commensal bacterium Lactobacillus reuteri AF120104 protein as a template. The synthesized Cy5-conjugated MUB(70) marker specifically stained the colonic mucus on fixed human, rabbit, and guinea pig tissues. Interestingly, murine tissue was not stained, suggesting significant differences in the composition of the murine colonic mucus. In addition, this marker stained the mucus of living cultured human colonic cells (HT29-MTX) and human colonic tissue explants. Using a biotinylated derivative of MUB(70), we demonstrated that this peptide binds specifically to Muc2, the most abundant secreted mucin, through its glycosylated moieties. Hence, Cy5-MUB(70) is a novel and specific fluorescent marker for mammalian colonic mucus. It may be used for live imaging analysis but also, as demonstrated in this study, as a marker for the diagnosis and the prognosis of colonic mucinous carcinomas.     

Nonsense-mediated mRNA decay impacts MSI-driven carcinogenesis and anti-tumor immunity in colorectal cancers

Nonsense-mediated mRNA Decay (NMD) degrades mutant mRNAs containing premature termination codon (PTC-mRNAs). Here we evaluate the consequence of NMD activity in colorectal cancers (CRCs) showing microsatellite instability (MSI) whose progression is associated with the accumulation of PTC-mRNAs encoding immunogenic proteins due to frameshift mutations in coding repeat sequences. Inhibition of UPF1, one of the major NMD factors, was achieved by siRNA in the HCT116 MSI CRC cell line and the resulting changes in gene expression were studied using expression microarrays. The impact of NMD activity was also investigated in primary MSI CRCs by quantifying the expression of several mRNAs relative to their mutational status and to endogenous UPF1 and UPF2 expression. Host immunity developed against MSI cancer cells was appreciated by quantifying the number of CD3epsilon-positive tumor-infiltrating lymphocytes (TILs). UPF1 silencing led to the up-regulation of 1251 genes in HCT116, among which a proportion of them (i.e. 38%) significantly higher than expected by chance contained a coding microsatellite (P<2x10(-16)). In MSI primary CRCs, UPF1 was significantly over-expressed compared to normal adjacent mucosa (P<0.002). Our data provided evidence for differential decay of PTC-mRNAs compared to wild-type that was positively correlated to UPF1 endogenous expression level (P = 0.02). A negative effect of UPF1 and UPF2 expression on the host's anti-tumor response was observed (P<0.01). Overall, our results show that NMD deeply influences MSI-driven tumorigenesis at the molecular level and indicate a functional negative impact of this system on anti-tumor immunity whose intensity has been recurrently shown to be an independent factor of favorable outcome in CRCs.     

Potential of fecal microbiota for early-stage detection of colorectal cancer

Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.     

Hypo-Vascular Liver Metastases Treated with Transarterial chemoembolization: Assessment of Early Response by Volumetric Contrast-Enhanced and Diffusion-Weighted Magnetic Resonance Imaging

OBJECTIVE: To evaluate the value of anatomic and volumetric functional magnetic resonance imaging (MRI) in early assessment of response to trans-arterial chemoembolization (TACE) in hypovascular liver metastases. METHODS: This retrospective study included 52 metastatic lesions (42 targeted and 10 non-targeted) in 17 patients who underwent MRI before and early after TACE. Two reviewers reported response by anatomic criteria (Response Evaluation Criteria in Solid Tumor [RECIST], modified RECIST [mRECIST], and European Association for the Study of Liver Disease [EASL]) and functional criteria (volumetric apparent diffusion coefficient and contrast enhancement). Treatment endpoint was RECIST at 6 months. A 2-sample paired t test was used to compare the mean changes after intra-arterial therapy. P < .05 was considered statistically significant. RESULTS: Reduction in mRECIST and EASL at 1 month was significant in the whole cohort as well as in responders by RECIST at 6 months, and the changes fulfilled partial response criteria for both metrics in responders. Responders also had significant changes in volumetric apparent diffusion coefficient (P = .01 and P = .03) and contrast enhancement (P < .0001 and P < .0001) at 1 month for both readers, respectively. CONCLUSION: At 1 month post treatment, responders did not fulfill RECIST criteria but fulfilled mRECIST and EASL criteria. In addition, volumetric contrast-enhanced and diffusion-weighted MRI may be helpful in evaluating early treatment response after TACE in hypovascular liver metastases in patients who have failed to respond to initial chemotherapy.