Summary C4d is a marker of the activated complement cascade used to assess the humoral component of rejection, mostly in kidney allograft transplants. The role of C4d deposition has recently been ...addressed in hepatic allograft but has never been tested in a series of inflammatory liver diseases without previous liver transplantation. The aim of this study was to compare the immunohistochemistry profile of C4d deposition in a pediatric population, between a cohort of patients with autoimmune hepatitis (AIH) and a series of patients with chronic viral hepatitis B or C. Immunohistochemical analysis was performed on 64 liver biopsies. C4d deposition was observed in 25 (83%) of 30 AIH biopsies examined, in 6 (40%) of 15 hepatitis C biopsies, and in 17 (89%) of 19 hepatitis B biopsies. No expression of C4d was observed in 4 noninflammatory liver specimens used as negative controls. In the AIH group, a staining of the periportal sinusoids was often observed, as well as focal periductal reinforcement. Centrolobular vein staining was observed in the 3 hepatitis groups with a higher frequency in viral hepatitis B biopsies. Regardless of the etiology, lymphoid aggregates demonstrated an accentuation of the staining. These results confirm a role for a humoral immune response in pediatric autoimmune as well as in viral hepatitis. The relative ratios of positive cases imply that this immunostaining does not represent a strong diagnostic criterion in the differentiation between viral hepatitis and AIH. However, differences in the pattern of the staining were observed, depending on the etiology of the disease. The high prevalence of C4d reactivity in viral hepatitis strongly suggests that C4d does not represent a useful marker in the differentiation between acute rejection and viral hepatitis relapse in liver transplants.
Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such ...differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females.
We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet–induced NAFLD model in IL22RA knock out mice and their wild-type littermates.
Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD.
Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.
Display omitted
Background Regression of breast tumors in response to neoadjuvant chemotherapy is variable. The goal of breast-conservation operation after neoadjuvant chemotherapy is generally to resect any ...residual tumor with negative margins. There are limited data about the success of achieving negative resection margins in these patients. The purpose of this study was to compare surgical margin involvement of breast-conservation resection specimens from patients treated initially with operation with those from patients receiving neoadjuvant chemotherapy. Methods Between January 2003 and June 2006, 478 breast-conservation operations were performed for invasive breast cancer at our institution. Seventy-six patients received neoadjuvant chemotherapy. Data collected included age, tumor size, nodal status, hormonal receptors and Her-2-neu status, lymphovascular invasion, histologic grade and type, use of guidewire, preoperative chemotherapy regimens, and microscopic evaluation of surgical margins. Univariate analyses and a regression model were used to identify factors associated with margin involvement. Results No statistical difference was observed for margin involvement between patients treated with neoadjuvant chemotherapy and those treated initially with operation (21% versus 18%; p = 0.52). Variables associated with positive margins in a logistic regression model were carcinoma type (43% of all lobular carcinomas had positive margins versus 16% in ductal carcinomas; p = 0.002) and hormonal receptor status (margin involvement was present in 20% of tumors that exhibited hormonal receptors versus 10% in negative receptors tumors; p = 0.014). Conclusions Breast conservation after neoadjuvant systemic therapy yields no higher incidence of positive margins than primary surgical treatment. Special consideration should be accorded to lobular carcinoma, because our findings, consistent with previous studies, demonstrate an association with margin involvement.
Introduction
Malignant rhabdoid tumor (MRT) is defined as a high-grade sarcoma derived from an uncertain cell of origin. Its diagnosis is associated with poor prognosis and patient’s life expectancy ...is greatly reduced.
Material and method
Here, we describe a unique case of 9-month-old boy who presented with a large MRT arising from the soft tissue of the neck. Following intensive multimodal treatment, the patient benefited from a 25 years’ remission until the discovery of multiple liver metastases.
Conclusion
MRT of soft tissue needs to be distinguished from other soft tissue neoplasms, as MRT is highly aggressive and is usually associated with a poor outcome. In addition, this is the longest remission time reported in a patient with soft tissue MRT and this might be related to the use of early intensive multimodal treatments.
Adenocarcinoma at the gastroesophageal junction Al-Haddad, Sahar; Chang, Andrew C.; De Hertogh, Gert ...
Annals of the New York Academy of Sciences,
September 2014, Letnik:
1325, Številka:
1
Conference Proceeding, Journal Article
Recenzirano
Odprti dostop
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the clinical differences between carcinomas arising slightly above, slightly below, and within ...the gastroesophageal junction (GEJ); information provided by biopsies; information provided by resection specimens following neoadjuvant therapy; histologic differences existing between carcinomas arising slightly above, slightly below, and within the GEJ; differences provided by immunohistochemistry in these tumors; information given by endoscopic mucosal resection specimens; the role of esophageal pyloric gland adenomas as precursors of adenocarcinomas in the region of the cardia; the role of pancreatic metaplasia; Her2 immunoreactivity to make distinctions in the site of origin; and intestinal metaplasia limited to the cardia as a precursor of adenocarcinoma.
Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. ...We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention.
Display omitted
•CCL2 is elevated in human dysplastic colon lesions, adenoma, and adenocarcinoma•CCL2 affects MDSC accumulation and function in colonic carcinogenesis•CCL2 modulates T cell suppression of PMN-MDSCs in a STAT3-mediated fashion•CCL2 neutralization re-shapes the tumor microenvironment, halting colon cancer
Chun et al. have found that CCL2 promotes colorectal carcinogenesis by influencing MDSC accumulation and function and shaping a tumor-permissive tissue microenvironment. This works suggests that CCL2 and MDSCs represent effective therapeutic targets for colon cancer prevention and interception.
Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal ...inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission. However, loss of Nfasc155 was sufficient to cause a robust delay in postnatal synapse elimination at the NMJ across all muscle groups examined. Nfasc155 regulated neuronal remodeling independently of its canonical role in forming paranodal axo-glial junctions, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Rather, high-resolution proteomic screens revealed that loss of Nfasc155 from glial cells was sufficient to disrupt neuronal cytoskeletal organization and trafficking pathways, resulting in reduced levels of neurofilament light (NF-L) protein in distal axons and motor nerve terminals. Mice lacking NF-L recapitulated the delayed synapse elimination phenotype observed in mice lacking Nfasc155, suggesting that glial cells regulate synapse elimination, at least in part, through modulation of the axonal cytoskeleton. Together, our study reveals a glial cell-dependent pathway regulating the sculpting of neuronal connectivity and synaptic circuitry in the peripheral nervous system.
PDF
