Study of molecular mechanisms of pro-apoptotic activity of NCX 4040, a novel nitric oxide-releasing aspirin, in colon cancer cell lines

Background  

Despite numerous studies aimed at verifying the antitumor activity of nitric oxide-releasing nonsteroidal antiflammatory drugs (NO-NSAIDs), little is known about the molecular targets responsible for their antineoplastic properties. In the present study, we investigated the mechanisms underlying the cytotoxicity of NCX 4040, a novel NO-aspirin with promising antineoplastic action, in in vitro human colon cancer models.     

Identification of two distinct CD5- B cell subsets from human tonsils with different responses to CD40 monoclonal antibody

This study investigated the response of different CD5^? B cell subsets to CD40 monoclonal antibody (mAb) in various combinations with interleukin (IL)-4 or rabbit anti-human μ chain antibody (a-μ-Ab). The different CD5 B cell subsets were isolated from tonsillar B cell suspensions depleted of CD5⁺ B cells and subsequently fractionated on Percoll density gradients. While resting CD5⁺ B cells proliferated and produced IgM molecules in response to a-μ-Ab, IL-4 and CD40 mAb as well as to Staphylococcus aureus Cowan strain I (SAC) and IL-2, resting CD5^? B cells, which were co-purified in the same 60% Percoll fractions, consistently failed to respond. These cells were, however, activated by the stimuli employed, as demonstrated by their capacity to express the surface activation markers CD69, CD25 and CD71. Resting CD5⁺ B cells had the typical phenotype of mantle zone B cells (IgM⁺ IgD⁺ CD39+ CD38^? CD10^? CDw75^dim), whereas resting CD5^? B cells were CD38^? CD39^? CD 10^? CDw75 intermediate and expressed surface IgM but relatively little surface IgD and could not be classified as mantle zone or germinal center cells. The finding that purified germinal center cells (CD38⁺ CD10⁺ CD39^? CDw75^bright, IgG⁺) responded to CD40 mAb and IL-4 and also to SAC plus IL-2 further underlined the differences to resting CD5^? B cells. However, some of the data collected suggest possible relationships between CD5^? B cells and germinal center cells. The CD5^? B cells isolated from the 50 % Percoll fraction proliferated in response to a-μ-Ab, CD40 mAb and IL-4 as well as to SAC and IL-2. These cells had the same mantle zone B cell phenotype as the CD5⁺ B cells, but their capacity to respond to the stimuli in vitro was unrelated to a possible contamination with CD5⁺ B cells, as documented by the appropriate controls. Furthermore, upon exposure to SAC or phorbol esters, the large majority of CD5^? B cells from the 50 % Percoll fraction did not express surface CD5 and there was very little if any accumulation of CD5 mRNA. Finally, most of the cycling cells in the stimulated CD5^? B cells did not express CD5. The CD5^? B cells from the 50 % Percoll fraction were comprised of a consistent proportion of cells that expressed surface activation markers. The removal of these cells abrogated the capacity of the suspensions to respond to the stimuli in vitro, possibly suggesting that these cells additional activation signals in vivo which were essential to acquire the capacity to respond and that could not be reproduced in vitro. The present study underlines the phenotypic and functional heterogeneity of CD5^? B cells and contributes to the identification of two subsets of these cells which differ in phenotype, tissue distribution and in vitro responses to different stimuli.     

Public health challenges and opportunities after COVID-19

With hindsight, the main weakness behind the ineffective response to the coronavirus disease 2019 (COVID-19) pandemic in some countries has been the failure to understand, and take account of, the multilayered systemic interdependencies that spread the effects of the pandemic across social, technological, economic and health-care dimensions. For example, to respond to the COVID-19 pandemic, all people were required to rapidly adjust to social distancing and travel restrictions. Such a complex behavioural response entails adaptation to achieve a full recovery from the systemic shock. To capitalize on the positive effects of disruption to the status quo, much more complex socioeconomic modelling needs to be considered when designing and evaluating possible public health interventions that have major behavioural implications. We provide a simple example of how this reasoning may highlight generally unacknowledged connections and interdependencies and guide the construction of scenarios that can inform policy decisions to enhance the resilience of society and tackle existing societal challenges.     

Medical treatment reverses cytokine pattern in allergic and nonallergic chronic rhinosinusitis in asthmatic children

A Th2 cytokine pattern has recently been reported both in allergic and nonallergic chronic rhinosinusitis in asthmatic children. The aim of the study was to evaluate the cytokine pattern in chronic rhinosinusitis in allergic and nonallergic asthmatic children before and after medical treatment. Thirty asthmatic children were evaluated, 18 males and 12 females (mean age 9.1 years). Sixteen were allergic and 14 were nonallergic. All children were asthmatic and suffered from chronic rhinosinusitis, whose diagnosis was confirmed by endoscopy. All of them were treated with amoxicilline-clavulanate (20 mg/kg b.i.d.) and fluticasone propionate aqueous nasal spray (100 µg daily) for 14 days; a short course of oral corticosteroid was also prescribed (deflazacort 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage and nasal cytology were performed in all subjects before and after medical treatment. IL4 and IFNγ were measured by immunoassay and inflammatory cells were counted by conventional staining. Thirteen allergic children and 12 nonallergic children showed a negative endoscopy after the treatment. Allergic subjects showed a significant decrease of IL4 (p = 0.0002) and a significant increase of IFNγ (p = 0.03) after the treatment. Nonallergic children showed a significant decrease of IL4 (p = 0.0007) and a nonsignificant increase of IFNγ. A significant reduction of the inflammatory infiltrate was detected in all asthmatic children (p < 0.05). This study confirms a Th2 polarization in chronic rhinosinusitis both in allergic and nonallergic asthmatic children. Moreover, the medical treatment of chronic rhinosinusitis reversed the cytokine pattern from a Th2 towards a Th1 profile both in allergic and nonallergic children.     

Evaluation of the Maruyama Computer Program Accuracy for Preoperative Estimation of Lymph Node Metastases from Gastric Cancer

Controversy still exists about the optimal lymph node (LN) dissection for potentially curable gastric cancer. For rational LN dissection it is important to know the incidence of metastasis at each LN station. For this purpose a computer program was developed using data from 4302 primary gastric cancers treated at the National Cancer Center Hospital in Tokyo between 1969 and 1989. To evaluate the accuracy of the computer program, the differences between the individual reports generated by the computer and the stored data were investigated in 282 Italian patients submitted to curative gastrectomy and D₂ or more extended LN dissections for gastric cancer. Receiver operating characteristic (ROC) analysis was used to assess the sensitivity and specificity of the program for predicting LN metastases in each of the 16 regional LN stations. The computer program showed good predictive ability for LN metastases in most of the 16 LN stations, as the areas under the curve ranged from 0.741 (station 15) to 0.944 (station 8), with a mean of 0.856. A critical cutoff point of 18% of the program's expected percentage was the value maximizing the validity of the prediction. Using an “absolute” cutoff point of 0%, the overall rate of false-negative (FN) predictions in 176 N+ patients was 11.9%; of these, 11 (6.2%) were absolute FNs, in which the program totally failed to estimate LN metastases; the remaining 10 cases (5.7%) were relative FNs because the specific prediction was positive for a different depth of stomach invasion. The low number of D₃/D₄ lymphadenectomies in the historical database may affect the low estimate of metastases to N₃/N₄ nodes generated by the program. Based on these data, the program predicts with good accuracy the extent of LN metastases from gastric cancer, but it is not recommended for directing the surgeon to perform more extensive lymphadenectomy.     

Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.     

Bacteriology of the anal wound after open hemorrhoidectomy

The purpose of this study is to analyze the size of the bacterial colonies in anal wounds after open hemorrhoidectomy. Twenty patients were studied during predetermined postoperative time periods. Material was collected from the surface and from within the tissue of each patient's three open wounds, intraoperatively, on the 6th, 13th and 20th postoperative days for bacteriologic examination in aerobic, microaerophilic, and anaerobic media. The bacterium most commonly identified was Escherichia coli,followed by Staphylococcus aureus and Staphylococcus epidermidis. Pseudomonas aeruginosa, Enterococcus faecalis, Klebsiella pneumoniae, Proteus vulgaris,and Proteus mirabilis were also identified. Critical indexes of colonization were present since the intraoperative stage (>10 ⁵ bacteria/g of tissue and >10 ⁶ bacteria/ml); obligate anaerobic bacteria were not identified; neither the species nor the number of bacteria, even when critical indexes were present, prevented proper healing. The same bacteria were not necessarily present on the surface and in the tissue; the bacterial load observed among the three wounds (left lateral, right posterior, and right anterior), was the same.Presented at the Postgraduate Course, Surgical Technique and Experimental Surgery, offered by the Escola Paulista de Medicina (Paulista Medical School) and the Department of Biomedical Sciences of the University of Taubaté, São Paulo, Brazil.     

Effect of angiotensin blockade on the orthostatic response in patients with systemic arterial hypertension

INTRODUCTION AND OBJECTIVES: The effect of the treatment of arterial hypertension with angiotensin inhibitors on the autonomic response to orthostatism was studied. PATIENTS AND METHOD: In 20 hypertensive patients, enalapril (10 to 20 mg) was administered daily for four weeks. Then, irbesartan (150 to 300 mg) was given for four weeks. Finally, 10 mg of enalapril combined with 150 mg of irbesartan was prescribed for another four weeks. Heart rate variability at rest and during the head-up tilt test with controlled respiration was assessed at the beginning and end of each period. RESULTS: Mean arterial pressure showed a similar reduction in the three treatment periods. There were no changes in heart rate. Heart rate variability at rest showed differences in the spectral high-frequency component between the control and the treatment periods (p = 0.10). There was an increase in the high-frequency component between the control and the third (p = 0.047) and the fourth periods (p = 0.03). In the head-up tilt test there was a decrease in total spectral high-frequency power. CONCLUSIONS: There was no increase in orthostatic intolerance with these drugs in hypertensive patients. The absence of changes in heart rate in spite of a decrease in blood pressure suggests resetting of the baroreflex function. The long-term control of hypertension with these drugs may have a favorable effect on heart rate variability, with an increase in parasympathetic activity.