Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. ...To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We previously observed degranulated mast cells (MC) in association with perivascular brain edema formation during focal cerebral ischemia. Brain MC are typically located perivascularly and contain ...potent fast-acting vasoactive and proteolytic substances. We examined in a rat model of transient middle cerebral artery occlusion (MCAO) whether, in the early phase of ischemia, MC regulate microcirculation, the blood–brain barrier (BBB) permeability, and edema formation. First, animals received MC inhibitor (cromoglycate), MC-degranulating drug (compound 48/80), or saline. Thereafter, we performed transient MCAO in gene-manipulated MC-deficient rats and their wild-type (WT) littermates, calculating brain swelling, visualizing BBB leakage by intravenously administered Evans blue albumin, and determining neutrophil infiltration with light microscopy. Cerebral blood flow, monitored by laser-Doppler flowmetry in separate experiments, was similar among pharmacological treatments. Ischemic swelling resulted in increased hemispheric volume of 13.4% ± 1.0% in controls, 8.1% ± 0.4% (39% reduction) after cromoglycate, and 25.2% ± 2.0% (89% increase) after compound 48/80 (P < 0.05). Early ischemic BBB leakage was reduced by 51% after cromoglycate, and 50% enhanced by compound 48/80 (P < 0.05). The cromoglycate group showed 37% less postischemic neutrophil infiltration than did controls (P < 0.05). Furthermore, MC-deficient rats responded to focal ischemia with 58% less brain swelling (6.7% ± 1.2%) than did their WT littermates (15.8% ± 1.4%, P < 0.05). Blood-brain barrier damage was 47% lower in MC-deficient rats than in the WT (P < 0.05). Neutrophil infiltration after MCAO was decreased 47% in MC-deficient rats in comparison to WT (P < 0.05). Pharmacological MC inhibition thus appears to deserve further investigation regarding reduction of brain swelling and inflammation early after stroke.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Thrombolysis with tissue plasminogen activator (tPA) improves stroke outcome, but hemorrhagic complications and reperfusion injury occasionally impede favorable prognosis after vessel recanalization. ...Perivascularly located cerebral mast cells (MCs) release on degranulation potent vasoactive, proteolytic, and fibrinolytic substances. We previously found MCs to increase ischemic and hemorrhagic brain edema and neutrophil accumulation. This study examined the role of MCs in tPA-mediated hemorrhage formation (HF) and reperfusion injury.
Exposure to tPA in vitro induced strong MC degranulation. In vivo experiments in a focal cerebral ischemia/reperfusion model in rats showed 70- to 100-fold increase in HF after postischemic tPA administration (P<0.001). Pharmacological MC stabilization with cromoglycate led to significant reduction in tPA-mediated HF at 3 (97%), 6 (76%), and 24 hours (96%) compared with controls (P<0.01, P<0.001, and P<0.01, respectively). Furthermore, genetically modified MC-deficient rats showed similarly robust reduction of tPA-mediated HF at 6 (92%) and 24 (89%) hours compared with wild-type littermates (P<0.01 and P<0.001, respectively). MC stabilization and MC deficiency also significantly reduced other hallmarks of reperfusion injury, such as brain swelling and neutrophil infiltration. These effects of cromoglycate and MC deficiency translated into significantly better neurological outcome (P<0.01 and P<0.05, respectively) and lower mortality (P<0.05 and P<0.05, respectively) after 24 hours.
MCs appear to play an important role in HF and reperfusion injury after tPA administration. Pharmacological stabilization of MCs could offer a novel type of therapy to improve the safety of administration of thrombolytics.
Apoptotic cell death contributes to neuronal loss in the penumbral region of brain infarction. Activated caspase-3 (ACA-3) cleaves proteins including poly(ADP-ribose) polymerase-1 (PARP-1) important ...in DNA repair, thus promoting apoptosis. Overactivation of PARP-1 depletes NAD
+
and ATP, resulting in necrosis. These cell death phenomena have been investigated mostly in experimental animals. We studied an autopsy cohort of 13 fatal ischemic stroke cases (symptoms 15 h to 18 days) and 2 controls by immunohistochemical techniques. The number of PARP-1 immunoreactive neurons was highest in the periinfarct area. Nuclear PARP-1 correlated with increasing neuronal necrosis (
P
= 0.013). Cytoplasmic PARP-1 correlated with TUNEL in periinfarct and core areas (
P
= 0.01). Cytoplasmic cleaved PARP-1 was inversely correlated with increasing necrotic damage (
P
= 0.001). PAR-polymers were detected in neurons confirming enzymatic activity of PARP-1. Cytoplasmic ACA-3 correlated with death receptor Fas (
r
s
= 0.48;
P
= 0.005). In conclusion, the confirmation of the same pathways of cell death than previously described in experimental animal models encourages neuroprotective treatments acting on these mediators also in human stroke.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Concomitant deregulation of MYC and BCL2 comprises clinically significant, yet poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these ...lymphomas, we analyzed translocations and protein expression of BCL2, BCL6, and MYC; correlated the findings with comprehensive mutational, transcriptomic, and clinical data in 181 patients with primary DLBCL; and validated the key findings in independent data sets. Structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression. Molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, including loss of TP53, and distinctive gene expression profiles. Double protein expression (DPE) arose from heterogeneous molecular backgrounds that exhibited subtype-dependent patterns. In the germinal center B-cell (GCB) DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas among the activated B-cell (ABC) DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of the International Prognostic Index (IPI) and cell of origin, and together with the loss of TP53 had a synergistic dismal impact on survival. In the DPE DLBCL, the loss of TP53 was associated with a chemorefractory disease, whereas among the other DLBCLs, no correlation with survival was seen. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1-like survival independent of IPI and concurrent DPE status. Taken together, our findings define molecular characteristics of the DPE in DLBCL, and recognize clinically feasible predictors of outcome. Given the emerging taxonomical significance of BCL2, BCL6, MYC, and TP53, our findings provide further depth and validation to the genomic classification of DLBCL.
•DPE arises from heterogeneous molecular backgrounds that show GCB- and ABC-dependent patterns.•MYC deregulation with TP53 loss, and BCL6 translocations have taxonomical implications that recognize DPE DLBCLs with differential outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Purpose— Activation of transcription factor nuclear factor-κB (NF-κB) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable ...number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-κB after permanent MCAO (pMCAO) was investigated. Methods— Mice transgenic for a NF-κB–driven β-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-κB and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-κB. Results— pMCAO increased NF-κB transcriptional activity to 260% (36.9±4.5 compared with 14.4±2.6; n=10; P <0.01) in the brain; this NF-κB activation was completely blocked by PDTC (17.2±2.6; n=9; P <0.05). In p50 −/− mice, pMCAO resulted in 41% (18±3.2 mm 3 ; n=12) smaller infarcts compared with wild-type controls (32.9±3.8 mm 3 ; n=9; P <0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6±4.2 mm 3 ; n=8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-κB was activated in neurons in the penumbral areas. Conclusions— NF-κB is induced in neurons during human stroke, and activation of NF-κB in the brain may contribute to infarction in pMCAO.
Gastric cancer is one of the most common malignancies worldwide and the second most common cause of cancer related death. Gene copy number alterations play an important role in the development of ...gastric cancer and a change in gene copy number is one of the main mechanisms for a cancer cell to control the expression of potential oncogenes and tumor suppressor genes.
To highlight genes of potential biological and clinical relevance in gastric cancer, we carried out a systematic array-based survey of gene expression and copy number levels in primary gastric tumors and gastric cancer cell lines and validated the results using an affinity capture based transcript analysis (TRAC assay) and real-time qRT-PCR.
Integrated microarray analysis revealed altogether 256 genes that were located in recurrent regions of gains or losses and had at least a 2-fold copy number- associated change in their gene expression. The expression levels of 13 of these genes, ALPK2, ASAP1, CEACAM5, CYP3A4, ENAH, ERBB2, HHIPL2, LTB4R, MMP9, PERLD1, PNMT, PTPRA, and OSMR, were validated in a total of 118 gastric samples using either the qRT-PCR or TRAC assay. All of these 13 genes were differentially expressed between cancerous samples and nonmalignant tissues (p < 0.05) and the association between copy number and gene expression changes was validated for nine (69.2%) of these genes (p < 0.05).
In conclusion, integrated gene expression and copy number microarray analysis highlighted genes that may be critically important for gastric carcinogenesis. TRAC and qRT-PCR analyses validated the microarray results and therefore the role of these genes as potential biomarkers for gastric cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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