Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation

The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl+ myeloid leukemia cells. The hop flavonoid xanthohumol inhibits tumor growth by targeting the nuclear factor-kappaB and Akt pathways and angiogenesis. Here, we show that xanthohumol has in vitro activity against Bcr-Abl+ cells and clinical samples and retained its cytotoxicity when imatinib mesylate-resistant K562 cells were examined. Xanthohumol inhibition of K562 cell viability was associated with induction of apoptosis, increased p21 and p53 expression, and decreased survivin levels. We show that xanthohumol strongly inhibited Bcr-Abl expression at both mRNA and protein levels and show that xanthohumol caused elevation of intracellular reactive oxygen species and that the antioxidant N-acetylcysteine blunted xanthohumol-induced events. Further, we observed that xanthohumol inhibits leukemia cell invasion, metalloprotease production, and adhesion to endothelial cells, potentially preventing in vivo life-threatening complications of leukostasis and tissue infiltration by leukemic cells. As structural mutations and/or gene amplification in Bcr-Abl can circumvent an otherwise potent anticancer drug such as imatinib, targeting Bcr-Abl expression as well as its kinase activity could be a novel additional therapeutic approach for the treatment of Bcr-Abl+ myeloid leukemia.     

Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies

AIM: Autoimmune gastritis is frequently associated with autoimmune thyroiditis and other organ-specific autoimmune diseases, and may lead to atrophic body gastritis (ABG). We studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of ABG in patients with autoimmune gastritis. METHODS: We studied 233 patients with autoimmune gastritis and 211 control subjects. All patients and control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin, pepsinogen I and II, and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy. RESULTS: In PCA/positive patients, mean (+/-sd) serum ghrelin levels were significantly lower (238 +/- 107 pmol/liter), and mean (+/-sd) serum gastrin levels were significantly higher (81.2 +/- 128.3 ng/ml), with respect to PCA/negative patients (282 +/- 104 pmol/liter and 20.7 +/- 13.3 ng/ml, respectively; P < 0.0001). Serum ghrelin and gastrin levels were inversely correlated (P = 0.004). A total of 40 patients had ABG documented by the gastric biopsy (90% in PCA/positive patients and 10% in PCA/negative patients). The receiver operating characteristic curve analysis revealed that a cutoff value for serum ghrelin of 188 pmol/liter was associated with the highest sensitivity and specificity (97.3 and 100%, respectively) in detecting gastric atrophy and was superior to gastrin (P = 0.012), PCA (P = 0.002), and the pepsinogen I/II ratio (P = 0.016) measurements. CONCLUSIONS: Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG.     

Thyroid dysfunction in megalin deficient mice

Megalin mediates transcytosis of thyroglobulin (Tg), the thyroid hormone precursor, resulting in its passage into the bloodstream. The process involves especially hormone-poor Tg, which may favour hormone secretion by preventing competition with hormone-rich Tg for proteolytic degradation. To gain more insight into the role of megalin, here we studied thyroid function and histology in megalin deficient mice compared with WT mice. As expected from the knowledge that megalin mediates Tg transcytosis, serum Tg levels were significantly reduced in homozygous (megalin-/-) mice, which, more importantly, were found to be hypothyroid, as demonstrated by significantly reduced serum free thyroxine and significantly increased serum thyroid stimulating hormone (TSH) levels. In heterozygous (megalin+/-) mice, in which megalin expression was normal, thyroid function was unaffected. Although the serological phenotype in megalin-/- mice was not associated with histological alterations or goiter, our results support a major role of megalin in thyroid hormone secretion.     

Polymerase chain reaction-based detection of minimal residual disease in multiple myeloma patients receiving allogeneic stem cell transplantation

BACKGROUND AND OBJECTIVES: Recent advances in the treatment of multiple myeloma (MM) include use of high-dose chemoradiotherapy followed by allografting. Although allografting with bone marrow (BM) or peripheral blood stem cells (PBSC) seems to improve clinical outcome and lengthen survival, only about 50% of patients reach stringently defined complete remission (CR), and most subsequently relapse. We assessed the clinical relevance of minimal residual disease (MRD) in 14 MM patients in CR after allografting with PBSC (6 patients) or BM (8 patients). DESIGN AND METHODS: Among the 30 out of 72 MM patients in our Institute who achieved CR after allografting, 14 had a molecular marker suitable for allo-specific polymerase chain reaction (PCR) analysis.Stringent molecular monitoring was done using clonal markers based upon rearranged immunoglobulin heavy-chain genes. Molecular remission (MCR) was defined as two consecutive negative PCR results. RESULTS: Seven of 14 (50%) molecularly monitored patients, achieved MCR and did not relapse after a median molecular follow-up of 60 months (range 36-120). Median time to obtain first PCR negativity was 12 (BM group) and 6 months (PBSC group), respectively. Of the seven patients (50%) who never achieved MCR, one relapsed. INTERPRETATION AND CONCLUSIONS: In conclusion, 50% of the MM patients in CR studied by us also achieved stringently-defined MCR. MCR was associated with a very low rate of clinical relapse.     

Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia: a molecular based approach using T-cell receptor G and D gene rearrangements

BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) is important in the measurement of response to treatment in childhood B- and T-cell acute lymphoblastic leukemia (ALL) and in adult B-cell ALL. Little is known about MRD evaluation in adult T-cell ALL. This study aimed to determine the prognostic significance of MRD measurements in adult T-cell ALL. DESIGN AND METHODS: T-cell receptor (TCR) gamma (G) and TCR delta (D) gene analyses were carried out at presentation in 49 patients with de novo T-ALL using a polymerase chain reaction (PCR) approach. In 26 of the patients bone marrow (BM) samples were collected at sequential time points (0-2, 3-5, 6-9, 10-24 months) after diagnosis for MRD investigation. The relationship between MRD status and clinical outcome was investigated and correlated with age, gender and white blood cell count at presentation. RESULTS: TCRG clonal gene rearrangements were found in 40 patients (82%). Eleven patients showed TCRD rearrangements (22%), in one of them as the sole molecular marker. V(gamma)I family rearrangements predominated (45 of 65 alleles) together with V(delta)1-J(delta)1/2 (9 of 13 alleles). Continuous clinical remission (CCR) occurred in 17 patients while nine patients relapsed. MRD analysis showed that negative tests during the first 6 months post-induction, and persisting negative MRD after induction were the best predictors of CCR. A positive test after 5 months was better at predicting relapse. In only four of seven patients was relapse preceded by a positive test the 5 months preceding relapse. INTERPRETATION AND CONCLUSIONS: Overall the ability of positive and negative tests to predict relapse or CCR was weaker in this cohort of adult T-ALL patients than in T- and B-lineage childhood ALL and B-lineage adult ALL. TCRG and TCRD gene analysis provides a clonal marker in the majority of adult T-ALL. These results suggest that caution should be taken in using MRD data based on TCR gene rearrangements to predict prognosis in adult T-ALL. Biological reasons may underlie differences between the performance of MRD tests in B- and T-lineage ALL. Further studies in a larger cohort of patients are needed to determine the exact role that MRD determination has in the management of T-ALL in adults.     

Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain

The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.     

Role of environmental and genetic factor interaction in age-related disease development: the gastric cancer paradigm

The association of Helicobacter pylori (Hp) infection with gastric cancer is well known and might be considered a paradigmatic example of the role that interaction among environmental factors and individual background might play in inducing age-associated disease. To evaluate the role of interaction of Hp infection with genetic background, gastric cancer and chronic gastritis patients as well as random selected controls were typed for five inflammation-related polymorphisms of IL-1 and IL-10 cytokine genes. No association among IL-10 or IL-1 variants with an increased risk of gastric cancer was found, whereas an Hp-independent association of IL-1beta -511T positive genotypes to an increased risk of chronic gastritis was found (Hp-/511T+ OR 1.89, 95% CI: 1.01-3.54; Hp+/-511T+ OR 1.83, 95% CI: 1.05-3.19). Stratification of gastric cancer group according to Hp infection does not allow finding a statistically significant association of Hp+ to the higher histological grading (G3) of gastric cancer (OR 1.54, 95% CI: 0.46-5.11). Our findings seem to confirm that cytokine genetic variants might contribute to determining the background for inflammaging in which H. pylori infection might facilitate cancer development.     

Hospitalization for congestive heart failure: is it still a cardiology business?

BACKGROUND: Hospital management of CHF and predictors of hospital mortality remain unclear. METHODS: To address these issues, we analyzed the hospital admissions for CHF during 1996 in a large university hospital. Patients discharged with the principal diagnosis of CHF were considered eligible for the study. RESULTS: Among the 1511 patients (3% of all discharges) who satisfied the inclusion criteria, 75% were treated in general medicine departments (GMD) and 22% in cardiology units (CU). Patients admitted to GMD were older than those treated in CU (79+/-10 vs. 68+/-15 years, P<0.001), included a higher proportion of females (56% vs. 37%, P<0.001), and presented a higher rate of hospital mortality (13% vs. 4%, P<0.001). The overall mean length of stay was 11+/-9 days. At multivariate analysis, length of stay was not associated with the department (i.e. GMD/CU) (P=0.273). CONCLUSIONS: CHF is a common lethal condition often requiring treatment in GMD. Length of stay appears to depend more on patients' characteristics than on differences in practice between GMD and CU. Patients admitted to GMD present higher rates of comorbidity and hospital mortality. Strategies are urgently needed to improve hospital management of CHF.     

Impact of common polymorphisms in candidate genes for insulin resistance and obesity on weight loss of morbidly obese subjects after laparoscopic adjustable gastric banding and hypocaloric diet

CONTEXT: It is unknown whether genetic factors that play an important role in body weight homeostasis influence the response to laparoscopic adjustable gastric banding (LAGB). OBJECTIVE: We investigated the impact of common polymorphisms in four candidate genes for insulin resistance on weight loss after LAGB. DESIGN: The design was a 6-month follow-up study. Setting: The study setting was hospitalized care. PATIENTS: A total of 167 unrelated morbidly obese subjects were recruited according to the following criteria: age, 18-66 yr inclusive; and body mass index greater than 40 kg/m2 or greater than 35.0 kg/m2 in the presence of comorbidities. Intervention: LAGB was used as an intervention. MAIN OUTCOME MEASURE: Measure of correlation between weight loss and common polymorphisms in candidate genes for insulin resistance and obesity was the main outcome measure. RESULTS: The following single nucleotide polymorphisms were detected by digestion of PCR products with appropriate restriction enzymes: Gly972Arg of the insulin receptor substrate-1 gene, Pro12Ala of the proliferator-activated receptor-gamma gene, C-174G in the promoter of IL-6 gene, and G-866A in the promoter of uncoupling protein 2 gene. Baseline characteristics including body mass index did not differ between the genotypes. At the 6-month follow-up after LAGB, carriers of G-174G IL-6 genotype had lost more weight than G-174C or C-174C genotype (P = 0.037), and carriers of A-866A uncoupling protein 2 genotype had lost more weight as compared with G-866G (P = 0.018) and G-866A (P = 0.035) genotype, respectively. Weight loss was lower in carriers of Gly972Arg insulin receptor substrate-1 genotype than Gly972Gly carriers, but not statistically significant (P = 0.06). No difference between carriers of Pro12Ala and Pro12Pro proliferator-activated receptor-gamma genotype was observed. CONCLUSIONS: These data demonstrate that genetic factors, which play an important role in the regulation of body weight, may account for differences in the therapeutic response to LAGB.