Stage I-III colon cancer patients with tumor deposits behave similarly to stage IV patients. Cross-section analysis of 392 patients.

BACKGROUND AND OBJECTIVES: Tumor deposits (TDs) are associated with adverse prognostic factors and decreased survival in colorectal cancer. However, controversy exists regarding their definition, evaluation, and staging categories. This study aimed to determine the survival and recurrence impact of the TD in colon adenocarcinomas; and to determine if TD patients behave similarly to stage IV patients. METHODS: Cross-section study from 392 patients with colon adenocarcinoma from 2005 to 2012. We performed survival analysis and further stratified patients considering TD patients as a "stage IV-TD" to demonstrate if they behave similarly than stage IV patients. RESULTS: From 392 patients, 204 (52%) were men, the mean age was 57.4 ± 13.9 years and 11.5% of cases had TD. In a multivariate analysis, TD failed to predict mortality and recurrence. Considering cases with TD as stage IV-TD, their mean survival was similar to stage IV patients (69.3 and 64.6 months, respectively) and different to those in stage III (110.5 months), II (135.7 months), and I (114.9 months) (P < 0.001). CONCLUSIONS: TD failed to predict mortality and recurrence. Patients with TD in stage I-III shows similar mortality than stage IV patients; then, we suggest putting them into a substage IV category instead of the N1c category.

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.

BACKGROUND: Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases. METHODS: In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury. RESULTS: During the acute post-injury period (24 h-15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1(-/-) mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1(-/-) mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1(-/-) mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFß. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI. CONCLUSION: Collectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.

Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation.

Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1(-/-) mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115(+)Ly6C(-)CD11c(+) dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-γ and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-γ- and IL-17-producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35-55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.

Increased accumulation of regulatory granulocytic myeloid cells in mannose receptor C type 1-deficient mice correlates with protection in a mouse model of neurocysticercosis.

Neurocysticercosis (NCC) is a central nervous system (CNS) infection caused by the metacestode stage of the parasite Taenia solium. During NCC, the parasites release immunodominant glycan antigens in the CNS environment, invoking immune responses. The majority of the associated pathogenesis is attributed to the immune response against the parasites. Glycans from a number of pathogens, including helminths, act as pathogen-associated molecular pattern molecules (PAMPs), which are recognized by pattern recognition receptors (PRRs) known as C-type lectin receptors (CLRs). Using a mouse model of NCC by infection with the related parasite Mesocestoides corti, we have investigated the role of mannose receptor C type 1 (MRC1), a CLR which recognizes high-mannose-containing glycan antigens. Here we show that MRC1(-/-) mice exhibit increased survival times after infection compared with their wild-type (WT) counterparts. The decreased disease severity correlates with reduced levels of expression of markers implicated in NCC pathology, such as interleukin-1ß (IL-1ß), IL-6, CCL5, and matrix metalloproteinase 9 (MMP9), in addition to induction of an important repair marker, fibroblast growth factor 2 (FGF2). Furthermore, the immune cell subsets that infiltrate the brain of MRC1(-/-) mice are dramatically altered and characterized by reduced numbers of T cells and the accumulation of granulocytic cells with an immune phenotype resembling granulocytic myeloid-dependent suppressor cells (gMDSCs). The results suggest that MRC1 plays a critical role in myeloid plasticity, which in turn affects the adaptive immune response and immunopathogenesis during murine NCC.

Interobserver Variability in Assessing Pathologic Response to Preoperative Treatment in Rectal Cancer: Standardization of an Evaluation Method and Comparisons Between Published Scales.

BACKGROUND: Evaluating tumor response of rectal cancer to preoperative chemoradiotherapy (NCRT) has a prognostic value on overall survival; however, grading tumor response is a controversial issue due to lack of reproducibility and the lack of information about the standardization of the evaluation. METHODS: We performed this study to examine the variability between observers' assessment of the pathological responses to NCRT using a systematic quantitative grading system based on a percentage of tumor response against the proportion of residual tumor burden. As a secondary aim, we classified the tumor response according to six published systems to determine the correlation between the observers into each grading system. RESULTS: From 70 cases, the mean age was 60.6 ± 11.78 years, 36 (51.47%) patients were female, the pathological T stage was pT3 in 48.6% of cases, pT2 in 32.9%, pT1 in 11.4% and 7.1% in pT4, whereas 40% had lymph node metastasis. The median lymph node count was ten lymph nodes (range 6-43). Our method of tumor regression evaluation has a good intraclass correlation (ICC) value. From the scales compared regarding interobserver agreement, the Ryan's and Royal College of Pathologists showed fair agreement (but good ICC); the scales from Dworak, Becker, and Rizk showed substantial agreement (and good to excellent ICC values); and the scale from Rödel showed almost-perfect agreement. RESULTS: All the evaluated systems showed good interobserver agreement, but the best interobserver agreement was reached with the Rödel's scale.

Invarianza factorial según sexo del Cuestionario de Agresión Proactiva y Reactiva en adolescentes peruanos / Reactive Proactive Aggression Questionnaire and its factorial invariance according to sex in Peruvian adolescents

Introducción: en esta investigación se analiza la validez, confiabilidad e invarianza del Cuestionario de Agresión Reactiva/Proactiva. Método: el estudio fue de tipo instrumental. Se evaluó a 2803 adolescentes, de los cuales 48.9% fueron mujeres 51.1% varones de la ciudad de Arequipa. Se aplicó el Cuestionario de Agresión Reactiva Proactiva (RPQ). Resultados: la prueba obtuvo índices de bondad de ajuste adecuados y se confirmó la estructura bifactorial mediante el análisis factorial confirmatorio. La prueba presentó invarianza escalar y estricta en función al sexo de los estudiantes evaluados, de modo que los varones muestran una mayor agresividad reactiva y proactiva que las mujeres. Las medidas de confiabilidadfueron satisfactorias. Conclusión: el RPQ es válido con una estructura de dos factores, además es invariante en función al sexo de los evaluados.

Introduction: in this research, we analyze the validity, reliability and invariance of the Reactive/Proactive Aggression Questionnaire. Method: the study was an instrumental sort of. We assessed 2803 adolescents, 48.9% female and 51.1% male from Arequipa City. The Reactive/Proactive Aggression Questionnaire (RPQ) was applied. Results: the test obtained adequate levels of goodness of fit and the bifactorial structure was confirmed by a confirmatory factor analysis. The test presented scalar and strict invariance based on the sex of the evaluated students, so men showed greater reactive and proactive aggressiveness than women. Reliability measures were satisfactory. Conclusion: the RPQ is valid with a two-factor structure; it is also invariant depending on the sex of those evaluated.

Isolation and analysis of mouse microglial cells.

Microglia are mononuclear phagocytes that make up about 10% of the central nervous system (CNS). They are known for their surveillant behavior, which involves continuous monitoring of neural tissue by extending and retracting their processes. Microglial cells are derived from myeloid progenitor cells and play important roles in homeostasis as well as inflammatory and immune responses in the brain. This unit describes several microglial cell isolation protocols that can be easily adapted for projects requiring a rapid and efficient analysis of mouse microglial cells by flow cytometry. Methods for visualizing microglial cells using in situ immunohistochemistry and immunochemistry in free-floating sections are also included.

The fine balance of chemokines during disease: trafficking, inflammation, and homeostasis.

The action of chemokines (or "chemotactic cytokines") is recognized as an integral part of inflammatory and regulatory processes. Leukocyte mobilization during physiological conditions, trafficking of various cell types during pathological conditions, cell activation, and angiogenesis are among the target functions exerted by chemokines upon signaling via their specific receptors. Current research is focused in analyzing changes in chemokine/chemokine receptor patterns during various diseases with the aim to modulate pathological trafficking of cells, or to attract particular cell types to specific tissues. This review focuses on defining the role(s) of certain chemokine ligands and receptors in inflammatory neurological conditions such as multiple sclerosis. In addition, the role(s) of chemokines in neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease is also described, as well as the contribution of chemokines to the pathogenesis of cancer, diabetes, and cardiovascular disease.

Analyses of microglia effector function using CX3CR1-GFP knock-in mice.

The generation of bone marrow radiation chimeric mice is a beneficial tool to utilize when studying inflammation of the central nervous system (CNS). It is widely accepted that blood-derived progenitors are capable of populating the CNS during chronic diseases and severe injuries; however, they are neither consistent nor efficient in doing so. The lack of the appropriate recruitment could explain delays in recovery and repair after an increase of toxic proteins in chronic neurodegenerative diseases. With the ingenious development of bone marrow chimeric mice, some of these concerns can be addressed and allow us to hypothesize about further implications and possible mechanisms that may lead to medicinal applications. Bone marrow chimeric mice are often used to distinguish the intrinsic versus extrinsic effects of specific mutations. In our case, chimeras help us to better understand the role of CX3CR1 in microglia and peripheral myeloid cells. To detect cell autonomous effects on myeloid cell differentiation, CX3CR1-deficient mice are used as donors and wild-type mice are used as recipients. In order to detect effects on the "immune cell environment," wild-type donors are used for the transfer into Cx 3 cr1 (-/-) recipients. The resulting chimeric mice can then be used for the analysis of microglial motility, regulation of neuroinflammation, and persistence. This technique can be applied to a broad spectrum of research ranging from neurodegenerative diseases to viral and parasitic pathogenicity and everything in between. This protocol describes the approach to generate chimeric mice and analyze the role of CX3CR1 in CNS inflammation in bone marrow radiation chimeras.