Do incompatible arguments cause extensive processing in the evaluation of arguments? The role of congruence between argument compatibility and argument quality.

Previous studies have demonstrated that arguments incompatible with prior beliefs are subjected to more extensive refutational processing, scrutinized longer, and judged to be weaker than arguments compatible with prior beliefs. However, this study suggests whether extensive processing is implemented when evaluating arguments is not decided by argument compatibility, but by congruence between two evaluating tendencies elicited by both argument compatibility and argument quality. Consistent with this perspective, the results of two experiments show that relative to congruent arguments, participants judged arguments eliciting incongruent evaluating tendencies as less extreme in strength, spent more time, and felt more hesitant generating strength judgments for them. The results also show that it is mainly incongruent arguments, not congruent arguments, whose strength ratings were more closely associated with the perceived personal importance of the issue, which intensified the tendency to evaluate arguments depending on argument compatibility. These results suggest that it is the incongruity between argument compatibility and argument quality, and not simply the argument compatibility, that plays a more important role in activating an extensive processing in the evaluation of arguments.

Sunitinib plus paclitaxel in patients with advanced esophageal cancer: a phase II study from the Hoosier Oncology Group.

The combination of sunitinb (37.5 mg orally daily) + paclitaxel (90 mg/m intravenously on days 1, 8, 15 every 4 weeks) was examined in patients with advanced esophageal or gastroesophageal junction cancer, and progression-free survival (PFS) was compared to that of historical controls. The end points included response rate, overall survival, and toxicities. Twenty-eight patients were enrolled at six centers. Median age was 59.5 years. The 24-week PFS rate was 25% (90% confidence interval [CI], 12-42%). Three (11%) of 23 evaluable patients had a response (1 complete response and 2 partial response) (90% CI, 3-25%). Median overall survival was 228 days (90% CI, 140-283 days). Grade 3/4 toxicities included leukopenia/neutropenia (25%), anemia (18%), fatigue (11%), and hemorrhage (11%). There were four grade 5 toxicities including upper gastrointestinal hemorrhage (n = 2), gastrointestinal/esophageal fistula (n = 1), and unexplained death (n = 1). In our study, we found that sunitinib + paclitaxel in patients with advanced esophageal or gastroesophageal junction cancer had a 24-week PFS no better than the PFS of historical controls. The combination also had a high rate of serious toxicities and will not be pursued.

Spontaneous autologous graft-versus-host disease in plasma cell myeloma autograft recipients: flow cytometric analysis of hematopoietic progenitor cell grafts.

Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution.

Insulin secretory deficiency and glucose intolerance in Rab3A null mice.

Insulin secretory dysfunction of the pancreatic beta-cell in type-2 diabetes is thought to be due to defective nutrient sensing and/or deficiencies in the mechanism of insulin exocytosis. Previous studies have indicated that the GTP-binding protein, Rab3A, plays a mechanistic role in insulin exocytosis. Here, we report that Rab3A(-/-) mice develop fasting hyperglycemia and upon a glucose challenge show significant glucose intolerance coupled to ablated first-phase insulin release and consequential insufficient insulin secretion in vivo, without insulin resistance. The in vivo insulin secretory response to arginine was similar in Rab3A(-/-) mice as Rab3A(+/+) control animals, indicating a phenotype reminiscent of insulin secretory dysfunction found in type-2 diabetes. However, when a second arginine dose was given 10 min after, there was a negligible insulin secretory response in Rab3A(-/-) mice, compared with that in Rab3A(+/+) animals, that was markedly increased above that to the first arginine stimulus. There was no difference in beta-cell mass or insulin production between Rab3A(-/-) and Rab3A(+/+) mice. However, in isolated islets, secretagogue-induced insulin release (by glucose, GLP-1, glyburide, or fatty acid) was approximately 60-70% lower in Rab3A(-/-) islets compared with Rab3A(+/+) controls. Nonetheless, there was a similar rate of glucose oxidation and glucose-induced rise in cytosolic [Ca(2+)](i) flux between Rab3A(-/-) and Rab3A(+/+) islet beta-cells, indicating the mechanistic role of Rab3A lies downstream of generating secondary signals that trigger insulin release, at the level of secretory granule transport and/or exocytosis. Thus, Rab3A plays an important in vivo role facilitating the efficiency of insulin exocytosis, most likely at the level of replenishing the ready releasable pool of beta-granules. Also, this study indicates, for the first time, that the in vivo insulin secretory dysfunction found in type-2 diabetes can lie solely at the level of defective insulin exocytosis.

Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis.

The specific biochemical steps required for glucose-regulated insulin exocytosis from beta-cells are not well defined. Elevation of glucose leads to increases in cytosolic [Ca2+]i and biphasic release of insulin from both a readily releasable and a storage pool of beta-granules. The effect of elevated [Ca2+]i on phosphorylation of isolated beta-granule membrane proteins was evaluated, and the phosphorylation of four proteins was found to be altered by [Ca2+]i. One (a 18/20-kDa doublet) was a Ca2+-dependent increase in phosphorylation, and, surprisingly, three others (138, 42, and 36 kDa) were Ca2+-dependent dephosphorylations. The 138-kDa beta-granule phosphoprotein was found to be kinesin heavy chain (KHC). At low levels of [Ca2+]i KHC was phosphorylated by casein kinase 2, but KHC was rapidly dephosphorylated by protein phosphatase 2B beta (PP2Bbeta) as [Ca2+]i increased. Inhibitors of PP2B specifically reduced the second, microtubule-dependent, phase of insulin secretion, suggesting that dephosphorylation of KHC was required for transport of beta-granules from the storage pool to replenish the readily releasable pool of beta-granules. This is distinct from synaptic vesicle exocytosis, because neurotransmitter release from synaptosomes did not require a Ca2+-dependent KHC dephosphorylation. These results suggest a novel mechanism for regulating KHC function and beta-granule transport in beta-cells that is mediated by casein kinase 2 and PP2B. They also implicate a novel regulatory role for PP2B/calcineurin in the control of insulin secretion downstream of a rise in [Ca2+]i.