Bovine glycomacropeptide is anti-inflammatory in rats with hapten-induced colitis

Milk kappa-casein-derived glycomacropeptide has immunomodulatory and bacterial toxin binding effects. The intestinal anti-inflammatory activity of glycomacropeptide was assessed in trinitrobenzenesulfonic acid-induced colitis in rats. Rats were administered glycomacropeptide daily starting either 2 d before (pretreatment) or 3 h after (post-treatment) colitis induction. Pretreatment with glycomacropeptide had a dose-dependent anti-inflammatory effect, characterized by lower body weight loss, decreased anorexia (57%), colonic damage (65%), and weight to length ratio (32%), as well as a reduction in colonic alkaline phosphatase activity (42%) and interleukin 1, trefoil factor 3, and inducible nitric oxide synthase mRNA levels (P < 0.05). The mechanism of action of glycomacropeptide is unknown but is consistent with an inhibition of the activation of immune cells. The magnitude of the anti-inflammatory effect was generally comparable to that of sulfasalazine, an established drug used in the treatment of inflammatory bowel disease. Bovine glycomacropeptide may play a role in the management of patients with inflammatory bowel disease.     

Age-related differences in vasoconstrictor responses to isoprostanes in piglet pulmonary and mesenteric vascular smooth muscle

Isoprostanes are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonic acid. Isoprostanes evoke potent vascular effects but their actions in the neonatal vasculature are poorly known. We aimed to study the effects of 8-iso-PGE(1), 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) in pulmonary arteries (PA), pulmonary veins (PV), and mesenteric arteries (MA) from newborn and 2-wk-old piglets. Isoprostanes produced concentration-dependent contractions of PA, PV, and MA (magnitudes up to 1.5- to 2-fold greater than the responses to 62.5 mM KCl) but they were markedly less potent vasoconstrictors than the thromboxane A(2) (TXA(2)) mimetic U46619. Neonatal PA were more sensitive to 8-iso-PGF(1alpha), 8-iso-PGF(1beta), and 8-iso-PGF(2beta) than 2-wk-old PA. Neonatal PV were more sensitive to 8-iso-PGE(2) and 8-iso-PGF(1alpha), and neonatal MA were more sensitive to 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) than the corresponding 2-wk-old vessels. The sensitivity to U46619 decreased with postnatal age in MA but did not change in PA and PV. The contractile responses to all the isoprostanes and to U46619 were reverted by the TXA(2) receptor (TP) antagonist SQ 29,548. Moreover, isoprostane-evoked contractions in 2-wk-old PA were reduced by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and hydroxyfasudil) but not by inhibitors of protein kinase C (chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). In conclusion, isoprostanes produced compound-, tissue-, and age-dependent constriction of neonatal porcine pulmonary and mesenteric vascular smooth muscle. Isoprostane-evoked PA vasoconstriction involved TP receptors and activation of tyrosine kinases and Rho kinases.     

Genetic structure of a Cuban population based on nine short tandem repeat loci

Cuba is a multiethnic and multiracial society. Here we describe the genetic variation of a sample of the Cuban population, which include the three most common racial groups, Caucasians, Negroids and Mestizos, by means of a set of nine microsatellites (HUMTH01, HUMTPOX, HUMCFS1PO, HUMVWA, HUMFESFPS, HUMF13A, HUMF13B, HUMLPL and HUMHPRTB). The analysis presented here indicates that these STR loci are highly informative for forensic purposes. The genetic data on the major racial groups is in good agreement with current demographic tendencies and with historic events that took place during the formation of the Cuban population.     

TiA1 in advanced-stage classical Hodgkin’s lymphoma: no prognostic impact for positive tumour cells or number of cytotoxic cells

No reliable marker still exists for predicting those patients with Hodgkins lymphoma (HL) who may experience a fatal outcome. Among the factors tested in the literature, it has been suggested that the number of activated cytotoxic T cells may represent a prognostic marker in HL. In 244 samples from patients with stage-IIIB/IV HL issued from the GELA H89 trial, we have analysed TiA1 expression on Reed Sternberg (RS) cells as well as the percentage of positive reactive lymphocytes. There were 34 cases (13.7%) that showed TiA1 expression on tumour cells; whereas, in 32 cases (13.1%), TiA1-positive reactive lymphocytes represented more than 30% of the reactive lymphocytes. LMP-1 was found co-expressed with TiA1 in 10 of the 22 positive cases tested. Our study confirms that a subset of classical HL expresses cytotoxic proteins, with occasional co-expression of CD20. In stage-IIIB/IV disease, neither TiA1 expression by RS cells nor a high percentage of TiA1-positive reactive lymphocytes have a prognostic impact on outcome.     

Outcome of elderly patients with aggressive Non-Hodgkin's lymphoma refractory to or relapsing after first-line CHOP or CHOP-like chemotherapy: a low probability of cure

We retrospectively evaluated the outcome of 94 consecutive elderly patients treated at our center for an aggressive lymphoma without a low-grade component. Median survival was 26 months and 5-year overall survival was 39% (27 - 50%). We then evaluated the outcome of patients refractory to or relapsing after CHOP or CHOP-like chemotherapy. Twenty patients were refractory to first-line therapy and only 1/20 is alive with active lymphoma. Eight patients achieved a partial response and only 3 maintained the partial response while the other 5 patients died. Only 2 of the 27 patients who relapsed after a first complete remission achieved a second sustained complete remission. This study suggests that conventional-dose second-line chemotherapy yields disappointing results in elderly patients with aggressive lymphomas.     

the role of radiotherapy for limited stage Hodgkin's disease in 1999: limitations and perspectives]

The role of radiotherapy in limited stage Hodgkin's disease (HD) has been gradually changing in the past few decades, resulting in the almost complete disappearance of exclusive irradiation treatment. In reality, exclusive radiotherapy yielded satisfactory results in terms of long-term survival, but in 1999 it was becoming impossible not to take into account the late mortality rates observed in all large cohorts of HD patients. This increased mortality rate has been shown to be related to 1) cardiac toxicity of irradiation, and 2) secondary radiation-induced solid tumors. Thus, the search for efficient but less toxic new strategies can no longer be avoided. For clinically staged, limited HD, precisely defined according to specific prognostic factors, the association of chemotherapy and radiotherapy appears more and more as a standard, and with this therapeutic burden comes parallel efforts for its alleviation. The Previous Radiotherapy experience has shown that, after a chemotherapy-induced complete remission, irradiation of only the initially involved areas was enough. Ongoing trials are now exploring the possibility of a dose de-escalation, from the conventional 36 Gy to 20 Gy (as for children HD), and to maybe 0 Gy (no radiotherapy at all). In parallel, deescalation in the number of chemotherapy cycles is also being investigated. For unfavorable cases, the problem is slightly different, as a higher percentage of cases still appears to be refractory to treatment in this subgroup. Thus, while chemo-radiotherapy has clearly became the standard strategy, efforts are essentially being devoted to identify new--and hopefully more efficient--chemotherapy schemes. In Europe, most of these pending questions will be addressed in the recently initiated trials of the EORTC/GELA and of the GHSG (German Hodgkin Study Group), with the aim of offering to patients treatment which could be at least as efficient as the present schedules, and less toxic in the long term.     

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

BackgroundLoss-of-function progranulin gene (GRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein 43 (TDP-43) pathology (frontotemporal lobar degeneration [FTLD]-TDP); however, little is known about the association between progranulin (PGRN) deficiency and neuronal loss in individuals with FTLD-TDP. Previously we reported enhanced proliferative activity associated with the activation of WNT5A/CDK6/pRb signalling in PGRN-deficient cells. The objective of this work was to elucidate the association between PGRN deficiency, WNT5A signalling and cell proliferation in immortalized lymphoblasts from carriers of the c.709–1G > A GRN mutation (asymptomatic and FTLD-TDP).MethodsWe assessed cell proliferation in carriers of the c.709–1G > A GRN gene mutation and controls without GRN mutation and without sign of neurologic degeneration by cell counting or using an MTT assay. We used a luciferase assay to measure the nuclear factor-κ (NF-κ) activity. We evaluated messenger RNA levels using quantitative real-time polymerase chain reaction and protein levels by immunoblotting. Co-immunoprecipitation was used to analyze the interaction between PGRN and its receptors.ResultsWe enrolled 19 carriers of the GRN gene mutation and 10 controls in this study. The PGRN-deficient cells showed increased expression of WNT5A due to NF-κB signalling overactivation. We observed a competition between PGRN and tumour necrosis factor-α (TNF-α) for binding both TNF receptors (TNFR) I and II. Blocking NF-κB signalling using wedelolactone or specific antibodies against TNFRs inhibited WNT5A overexpression and proliferation of PGRN-deficient cells. Conversely, the activation of NF-κB signalling by TNF-α increased WNT5A-dependent proliferation of control cells.LimitationsAll cell lines were derived from individuals harboring the same splicing GRN mutation. Nevertheless, most of the known GRN mutations lead to haploinsufficiency of the protein.ConclusionOur results revealed an important role of NF-κB signalling in PGRN-associated FTLD-TDP and confirm that PGRN can bind to TNF-α receptors regulating the expression of WNT5A, suggesting novel targets for treatment of FTLD-TDP linked to GRN mutations.     

Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group

Background

Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement.

Design and Methods

Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2^nd generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response.

Results

Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2–78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%.

Conclusions

These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00390897","term_id":"NCT00390897"}}NCT00390897).