Haidy El-Azzamy, Andrea Balogh, Roberto Romero, Yi Xu, Christopher LaJeunesse, Olesya Plazyo, Zhonghui Xu, Theodore G. Price, Zhong Dong, Adi L. Tarca, Zoltan Papp, Sonia S. Hassan, Tinnakorn Chaiworapongsa, Chong Jai Kim, Nardhy Gomez-Lopez, Nandor Gabor Than
J Pathol Transl Med. 2017;51(3):264-283. Published online February 22, 2017
Background The decidua has been implicated in the “terminal pathway” of human term parturition, which is characterized by the activation of pro-inflammatory pathways in gestational tissues. However, the transcriptomic changes in the decidua leading to terminal pathway activation have not been systematically explored. This study aimed to compare the decidual expression of developmental signaling and inflammation-related genes before and after spontaneous term labor in order to reveal their involvement in this process.
Methods Chorioamniotic membranes were obtained from normal pregnant women who delivered at term with spontaneous labor (TIL, n = 14) or without labor (TNL, n = 15). Decidual cells were isolated from snap-frozen chorioamniotic membranes with laser microdissection. The expression of 46 genes involved in decidual development, sex steroid and prostaglandin signaling, as well as pro- and anti-inflammatory pathways, was analyzed using high-throughput quantitative real-time polymerase chain reaction (qRT-PCR). Chorioamniotic membrane sections were immunostained and then semi-quantified for five proteins, and immunoassays for three chemokines were performed on maternal plasma samples.
Results The genes with the highest expression in the decidua at term gestation included insulin-like growth factor-binding protein 1 (IGFBP1), galectin-1 (LGALS1), and progestogen-associated endometrial protein (PAEP); the expression of estrogen receptor 1 (ESR1), homeobox A11 (HOXA11), interleukin 1β (IL1B), IL8, progesterone receptor membrane component 2 (PGRMC2), and prostaglandin E synthase (PTGES) was higher in TIL than in TNL cases; the expression of chemokine C-C motif ligand 2 (CCL2), CCL5, LGALS1, LGALS3, and PAEP was lower in TIL than in TNL cases; immunostaining confirmed qRT-PCR data for IL-8, CCL2, galectin-1, galectin-3, and PAEP; and no correlations between the decidual gene expression and the maternal plasma protein concentrations of CCL2, CCL5, and IL-8 were found.
Conclusions Our data suggests that with the initiation of parturition, the decidual expression of anti-inflammatory mediators decreases, while the expression of pro-inflammatory mediators and steroid receptors increases. This shift may affect downstream signaling pathways that can lead to parturition.
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Background Papillary thyroid carcinoma (PTC) is frequently accompanied by lymphocytic thyroiditis (LT). Some reports claim that Hashimoto’s thyroiditis (the clinical form of LT) enhances the likelihood of PTC; however, others suggest that LT has antitumor activity. This study was aimed to find out the relationship between the patterns of helper T cell (Th) cytokines in thyroid tissue of PTC with or without LT and the clinicopathological manifestation of PTC.
Methods Fresh surgical samples of PTC with (13 cases) or without (10 cases) LT were used. The prognostic parameters (tumor size, extra-thyroidal extension of PTC, and lymph node metastasis) were analyzed. The mRNA levels of two subtypes of Th cytokines, Th1 (tumor necrosis factor α [TNF-α], interferon γ [IFN-γ ], and interleukin [IL] 2) and Th2 (IL-4 and IL-10), were analyzed. Because most PTC cases were microcarcinomas and recent cases without clinical follow-up, negative or faint p27 immunoreactivity was used as a surrogate marker for lymph node metastasis.
Results PTC with LT cases showed significantly higher expression of TNF-α (p = .043), IFN-γ (p < .010), IL-4 (p = .015) than those without LT cases. Although the data were not statistically significant, all analyzed cytokines (except for IL-4) were highly expressed in the cases with higher expression of p27 surrogate marker.
Conclusions These results indicate that mixed Th1 (TNF-α, IFN-γ , and IL-2) and Th2 (IL-10) immunity might play a role in the antitumor effect in terms of lymph node metastasis.
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There is considerable experimental evidence to indicate that tumor growth is dependent on angiogenesis. However, we do not understand how the angiogenic activity is initiated by a given tumor. There is a clear distinction between a stage without neovascularization, which correlates with a paucity of metastases, and a stage in which increasing neovascularization correlates with a rising rate of metastasis. The authors therefore asked whether the extent of angiogenesis in human prostatic carcinoma is correlated with the tumor grades or some growth factors. To investigate how tumor angiogenesis correlates with tumor aggressiveness, the authors counted microvessels within the various grades of invasive prostatic carcinomas of 44 patients and the nodular hyperplasias of 10 patients. Highlighting of the vessels by immunohistochemical staining for factor VIII-related antigen and assessment of the tumor aggressiveness by the degree of expression of some growth factors(transforming growth factor-alpha, and beta, epidermal growth factor), tumor necrosis factor-alpha and tumor grading(Gleason's score) were done. As a result, both microvessel counts and the expression of growth factors and tumor necrosis factor correlated with tumor grades. In conclusion, the number of microvessels per 200 X fields in the areas of most intense neovascularization in a prostatic carcinoma may be a predictor of the patient's prognosis.
Therefore, assessment of tumor angiogenesis may prove valuable in selecting patients with prostatic carcinoma, especially small needle biopsy, for aggressive therapy.
This study was carried out to elucidate the cytokine mRNAs expression and morphological features according to a microglial proliferation and apoptosis in a rat lumbar spinal cord, after a right sciatic nerve transection. The control group was composed of 5 rats (Spraque-Dawley) and the experimental group was composed of 70 rats. On post operation day (pod) 1, 2, 3, 5, and 7 eight rats were sacrificed on those days. On pod 10 five rats were sacrificed as well as five rats sacrificed on post operation weeks 2, 3, 4, 5, and 6. On light microscopy, activated microglia were often found in a perineuronal position around motoneurons in the ventral gray matter and more randomly distributed throughout the neuropil in the dorsal gray matter of lumbar spinal cord. GSA I-B4-positive microglia began to increase from 1 day after transection, and reached peak at 2~3 days and it persisted at 5~7 days and decreased thereafter. TUNEL-positive microglia was not observed in control group and began to increase from 5 days after transection and increased gradually until 3 weeks and decreased thereafter. On in situ RT-PCR, the positive signal for IL-1alpha and IL-6 mRNA was found mainly in the cytoplasm of the activated microglia and astrocytes at 1 day after transection and showed stronger signal at 3 days and decreased gradually until 10 days. TNF-alpha mRNA was detected 1 day after transection and remained for 7 days and localized to activated microglia as well as probably some astrocytes. The signal intensity of IL-1alpha and IL-6 mRNA was generally stronger than TNF-alpha mRNA. On transmission electron microscopy, there were chromatin condensation with margination toward nuclear membrane and condensation of cytoplasm at 3 days after transection. Apoptotic bodies were found after 5 days and increased gradually until 3 weeks.
According to the above findings, it is concluded that apoptosis appears to be one mechanism by which activated microglia are gradually eliminated and cytokine expression seems to played an active role in the microglial turnover.
Endomyocardial biopsy (EMB) is a valuable diagnostic procedure for the surveillance of cardiac allograft rejection. Interpretation of individual cases is still problematic due to variations of findings for grading of rejection and other associated lesions. We reevaluated an experience on endomyocardial biopsies to develop better diagnostic criteria for rejection and other complications.
Immunohistochemical studies against cytokines were performed to assess the usefulness of the method for the diagnosis or researches. A total of 249 EMBs taken from 33 cardiac allograft recipients were reviewed. There were 25 males and 8 females. Dilated cardiomyopathy was present (24 cases) and valvular heart disease (4 cases), restrictive cardiomyopathy (3 cases) were also common conditions. We applied the grading system of the International Society for Heart Transplantation (ISHT) for the assessment of acute cellular rejection. Grades of 0, 1A, 1B, 2, 3A and 3B were 39.0%, 28.1%, 11.2%, 11.5%, 12.4% and 1.6% respectively, but 3.2% were inadequate. Thirty five episodes of grade 3A or 3B were present in 17 patients. The response to therapy was assessed using a next follow up biopsy, which revealed resolving or resolved rejection in 85% of patients. The intensity of immunohistochemical stains for IL-6 and TNF-alpha was increased in proportion to the histologic grade but Quilty lesion and cardiomyopathy also showed a positive reaction.
The other pathologic findings were ischemic change, previous biopsy site, interstitial edema and fibrosis, and Quilty lesion. These findings showed usefulness of endomyocardial biopsy not only for the evaluation of cardiac allograft rejection but also for the diagnosis of associated cardiac lesions. Immunohistochemical study of the cytokines was related to the degree of inflammation rather than degree of rejection.
The pathogenetic role of intrauterine infection to the neonatal pulmonary injury and bronchopulmonary dysplasia was assessed by studying the interleukin-6 (IL-6) level in the umbilical cord blood and the early morphologic changes of the neonatal lung.
Patients were grouped into bronchopulmonary dysplasia (4 cases), chorioamnionitis without chronic lung injury (4 cases), and 6 cases without morphologic evidence of chronic lung injury or placental inflammation. IL-6 level of umbilical cord blood was higher in babies with bronchopulmonary dysplasia (17.7 pg/ml) compared to those with chorioamnionitis (4.7 pg/ml) or those with morphologically normal lung and placenta (6.2 pg/ml). Morphologic parameters of neonatal pulmonary injury were hyaline membrane, terminal bronchiole inflammation, terminal bronchiole regeneration, alveolar collapse and fibroblastic proliferation. Bronchiolar regeneration was the most peculiar feature seen in the lung with bronchopulmonary dysplasia. Alveolar collapse and interstitial fibroblastic reaction were commonly seen in bronchopulmonary dysplasia.
The postnatal age at death was higher in those with bronchopulmonary dysplasia, although the occurrence of the morphologic changes was related with the chronicity of those lesions. These findings suggest that intrauterine infection is an aggravating factor for the neonatal pulmonary injury and bronchopulmonary dysplasia, although the early stage of the lung injury is not a definitive indicator for the progressive pulmonary damage leading to the bronchopulmonary dysplasia.