Caffeine-Supplemented Diet Prevents Fatigue-Like Behavior in Tumor-Bearing Mice.

Caffeine is a widely consumed stimulant, known for its positive effects on physical and mental performance. These effects are potentially beneficial for ameliorating cancer-related fatigue, which affects the quality of life of patients with cancer. This study aimed to determine the anti-fatigue and antitumor effects of caffeine in tumor-bearing mice. BALB/c mice were intravenously injected with C26 colon carcinoma cells and fed with normal or 0.05% caffeine-supplemented diet. Fatigue-like behavior was assessed by running performance using a treadmill test. Lung, blood, liver, muscle, and epididymal adipose tissue samples were collected on day 13 and examined. The antitumor effect of caffeine was assessed using subcutaneous tumor-bearing mice fed with 0.05% caffeine-supplemented diet, and the tumor volume was measured. C26 tumor-bearing mice showed fatigue-like behavior associated with hypoglycemia, depleted liver glycogen and non-esterified fatty acid (NEFA) levels. C26 tumor-bearing mice fed with 0.05% caffeine-supplemented diet showed improved running performance associated with restored NEFA levels. However, exacerbated hypoglycemia and liver glycogen levels after caffeine consumption may be due to tumor-induced catabolic signals, as the tumor volume was not affected. Collectively, caffeine may exert anti-fatigue effects through enhanced lipolysis leading to restored NEFA levels, which can be used as an alternative energy source.

Palliative procedures in lung cancer.

Palliative care aims to optimize comfort and function when cure is not possible. Image-guided interventions for palliative treatment of lung cancer is aimed at local control of advanced disease in the affected lung, adjacent mediastinal structures, or distant metastatic sites. These procedures include endovascular therapy for superior vena cava syndrome, bronchial artery embolization for hemoptysis associated with lung cancer, and ablation of osseous metastasis. Pathophysiology, clinical presentation, indications of these palliative treatments, procedural techniques, complications, and possible future interventions are discussed in this article.

Survivin-induced Aurora-B kinase activation: A mechanism by which APC mutations contribute to increased mitoses during colon cancer development.

APC mutations initiate most colorectal cancers (CRCs), but cellular mechanisms linking this to CRC pathology are unclear. We reported that wild-type APC in the colon down-regulates the anti-apoptotic protein survivin, and APC mutation up-regulates it, explaining why most CRCs display survivin overexpression and apoptosis inhibition. However, it does not explain another hallmark of CRC pathology--increased mitotic figures and cell proliferation. Because survivin activates aurora-B kinase (ABK) in vitro, catalyzing mitosis, we hypothesized that in normal colonic crypts, APC controls ABK activity, while in neoplastic APC-mutant crypts, ABK activity is up-regulated, increasing mitosis. We quantitatively mapped intracryptal distributions of survivin, ABK, and markers of activated downstream signaling and mitosis (INCENP, phospho-histone-H3, phospho-centromere-protein-A). In normal crypts, gradients for these markers, ABK:survivin:INCENP complexes, and ABK activity were highest in the lower crypt (inverse to the APC gradient). In neoplastic crypts that harbor APC mutations, proliferating (Ki-67+) cells and cells expressing survivin, ABK, and phospho-histone-H3 were distributed farther up the crypt. Hence, as cells migrate up neoplastic crypts, transitions between cell phenotypes (eg, from stem to proliferating) appear delayed. In CRC cell lines, increasing wild-type APC, inhibiting TCF-4, or decreasing survivin expression down-regulated ABK activity. Thus, APC mutation-induced up-regulation of the survivin/ABK cascade can explain delayed crypt cell maturation, expansion of proliferative cell populations (including mitotic figures), and promotion of colon tumorigenesis.

Pulmonary interstitial glycogenosis in the setting of lung growth abnormality: radiographic and pathologic correlation.

Pulmonary interstitial glycogenosis (PIG) is a rare pediatric interstitial lung disease. We report a case of a term boy presenting with tachypnea at birth requiring supplemental oxygen. Chest radiographs followed by high-resolution CT (HRCT) demonstrated hyperinflation and diffuse interstitial markings interspersed with multiple cystic spaces. An open lung biopsy demonstrated a minor component of PIG superimposed upon poor alveolarization. PIG in the setting of lung growth abnormality might be more common than previously described. Additionally, radiographic findings associated with most pediatric interstitial lung diseases are nonspecific, and histopathologic correlation is essential for diagnosis.

Adnexal torsion: new clinical and imaging observations by sonography, computed tomography, and magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to review the clinical, imaging, and pathologic findings associated with adnexal torsion. METHODS: A review of surgically proven cases of torsion between 1990 and 2006 included clinical, surgical, and pathologic data and preoperative sonographic, computed tomographic (CT), and magnetic resonance imaging (MRI) studies. Imaging reports were assessed to determine whether a correct preoperative diagnosis was made. Factors related to failure to make a correct diagnosis were evaluated. RESULTS: Fifty-eight cases of torsion were evaluated (patient ages, 12-85 years; 14 postmenopausal). There was a slight right-sided predominance (55%); in most cases (72%), both the ovary and fallopian tube were involved. Common symptoms/signs were pain (91%), leukocytosis (64%), nausea/vomiting (62%), and a palpable mass (41%). Twenty-eight patients (48%) had previous abdominal surgery; in 12 (46%) of these 28, pelvic adhesions were noted. At pathologic examination, underlying adnexal masses were found in 30 cases (52%); they were benign in 26 (87%) of 30 cases. Common imaging findings were an adnexal mass (65% on sonography, 87% on CT, and 75% on MRI), a displaced adnexal mass/enlarged ovary (53% on sonography, 87% on CT, and 75% on MRI), and ascites (53% on sonography, 73% on CT, and 50% on MRI). A correct preoperative diagnosis was made by initial sonography in 15 (71%) of 21 cases versus initial CT in 5 (38%) of 13. A correct imaging diagnosis was made more frequently in premenopausal than in menopausal patients (P = .02) and in patients without an underlying adnexal mass compared with those with a mass (P = .05). CONCLUSIONS: Although CT shows features suggestive of torsion, in our study, the diagnostic value of initial CT was less than that of initial sonography. A correct preoperative diagnosis was made less often with an underlying adnexal mass and in postmenopausal women. Previous surgery and adhesions may be predisposing factors for adnexal torsion.

The role of activating protein 1 in the transcriptional regulation of the human FCGR2B promoter mediated by the -343 G -> C polymorphism associated with systemic lupus erythematosus.

The inhibitory receptor FcgammaRIIb is a negative regulator of antibody production and inflammatory responses. The -343 G --> C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The -343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The -343 G --> C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of FcgammaRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the -343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.

Regulated expression of FcgammaR in human dendritic cells controls cross-presentation of antigen-antibody complexes.

Receptors for IgG (FcgammaR) expressed in dendritic cells (DCs) influence the initiation of Ab-mediated immunity. Dynamic variations in FcgammaR expression allow DCs to adjust their capacity to capture Ab-opsonized Ag. The current paradigm predicts a progressive decline in FcgammaR-mediated phagocytic function upon DC maturation. Surprisingly, we find that expression of the phagocytic receptor FcgammaRIIa is preserved in immature and mature DCs at comparable levels with macrophages. Moreover, phagocytosis of antigenic peptides directed to FcgammaRIIa on DCs leads to dramatic increases in Ag cross-presentation and T cell activation. In immature DCs, high expression of inhibitory FcgammaRIIb correlates with decreased uptake and cross-presentation of Ab-Ag complexes. In contrast, engagement of FcgammaRIIb is not associated with changes in cross-presentation in mature DCs. We provide evidence that FcgammaRIIb expression is patently reduced in mature DCs, an effect that is modulated by treatment with cytokines. The regulated expression of activating and inhibitory FcgammaRs in DCs emerges as a critical checkpoint in the process of Ag uptake and cross-presentation.

FcgammaRIIa is a target for modulation by TNFalpha in human neutrophils.

Activation of neutrophils by the interaction of immune complexes with Fc gamma receptors (FcgammaR) is amplified in tumor necrosis factor-alpha (TNFalpha)-primed cells, whereas interleukin-10 (IL-10) has been reported to suppress cytokine-mediated neutrophil activation. We examined whether the expression and function of FcgammaR in human neutrophils is modulated by TNFalpha and IL-10 in vitro, and whether FcgammaRIIa expression is altered following treatment with the TNFalpha inhibitor infliximab in rheumatoid arthritis (RA) patients in vivo. TNFalpha treatment induced upregulation of expression and function of the major activating Fc receptor, FcgammaRIIa, in neutrophils from healthy donors. Unexpectedly, treatment with IL-10 led to gain of FcgammaRIIa function in TNFalpha-primed neutrophils. In neutrophils from RA patients initiating infliximab therapy and followed longitudinally through consecutive treatments, FcgammaRIIa protein decreased during the course of TNFalpha blockade, indicating that FcgammaRIIa is a target of TNFalpha modulation in human neutrophils in vivo.

Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus.

The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G-C substitution at position -343 relative to the start of transcription) with altered FcgammaRIIb expression and function. The G-C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcgammaRIIb receptors was significantly reduced in activated B cells from (-343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in -343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.

Cytokine-mediated regulation of activating and inhibitory Fc gamma receptors in human monocytes.

Fc gamma receptors (Fc gammaR) trigger inflammatory reactions in response to immunoglobulin-opsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory Fc gammaR ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating Fc gammaRIIa and inhibitory Fc gammaRIIb receptors to investigate the expression and regulation of Fc gammaRII isoforms in human monocytes. Cross-linking of Fc gammaRIIa triggered phagocytosis and cytokine production. Cross-linking of Fc gammaRIIb was associated with phosphorylation of the immunoreceptor tyrosine-based inhibitory motif and with a marked reduction in monocyte effector functions. Our study revealed that tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-10, and IL-13 altered the transcriptional activity of the Fc gammaRIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory Fc gammaR in human monocytes. TNF-alpha decreased the expression of inhibitory Fc gammaRIIb. IL-10 up-regulated all classes of Fc gammaR and induced alternative activation in monocytes, an effect that was synergistic with that of TNF-alpha. In contrast, IL-4 and IL-13, in combination with TNF-alpha, decreased the expression of activating Fc gammaR and markedly down-regulated Fc gammaR-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of Fc gammaR with opposing function and thus, may regulate the amplitude of Fc gammaR-mediated uptake and inflammation.

Multiple mechanisms in indomethacin-induced impairment of hepatic cytochrome P450 enzymes in rats.

BACKGROUND & AIMS: Indomethacin impairs liver microsomal monooxygenase activities mediated by cytochrome P450 (CYP). We investigated the inhibition mechanism and the isoform selectivity in vitro and in vivo. METHODS: In an in vitro study, liver microsomes from male Wistar rats were preincubated with indomethacin and a reduced nicotinamide adenine dinucleotide phosphate-generating system, followed by assay of monooxygenase activities indicative of several CYP isoforms. In an in vivo study, rats were intraperitoneally treated with indomethacin, followed by preparation of microsomes and the enzyme assays. RESULTS: The preincubation of microsomes with indomethacin and reduced nicotinamide adenine dinucleotide phosphate decreased CYP3A2 activity but not any other isoforms. Kinetic analysis showed the mechanism-based inactivation of CYP3A2. The metabolism of [14C]indomethacin resulted in covalent binding to microsomal protein, which was diminished by inhibiting CYP3A enzyme. Administration of indomethacin caused impairment of not only CYP3A2 but also other CYP isoforms. Rats were protected from the impairment of the CYP enzymes except CYP3A2 by depleting macrophages and inhibiting inducible nitric oxide synthase. CONCLUSIONS: Metabolism of indomethacin causes inactivation of CYP3A2, which is the result of the covalent binding of its metabolite, whereas partially selective in vivo impairment of CYP isoforms is suggested to be indirect inhibition by inflammatory mediators probably released from Kupffer cells.