Selective targeted delivery of TNFalpha to tumor blood vessels

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.     

New technique for assessing fetal heart growth using three-dimensional ultrasonography: description of the technique and reference curves

Objective: To describe a new technique for assessing fetal growth using three-dimensional ultrasonography (3DUS) using the extended imaging virtual organ computer-aided analysis (XI VOCAL) software and its respective reference curves.

Methods: We conducted a cross-sectional study on 303 normal singleton pregnancies between their 20th and 34th weeks. To assess fetal heart growth, we used the XI VOCAL software with 10 planes in which the reference lines (beginning and end) were placed at the cardiac apex, the output level of the vessels and the base above the diaphragm, respectively. To assess the correlation between distance and interval, polynomial regressions were performed with adjustments using the coefficient of determination (R²). To assess the inter-observer reproducibility, we used the intraclass correlation coefficient (ICC).

Results: The mean distance between the apex and the base of the fetal heart ranged from 14.41?±?1.24?mm to 26.24?±?2.62?mm between the 20th and 34th weeks, respectively. The mean interval between the apex and the base of the fetal heart ranged from 1.56?±?0.13?mm and 2.94?±?0.30?mm between the 20th and 34th weeks, respectively. We observed good correlation of distance and interval with the gestational age, with R²?=?0.73 and 0.74, respectively. We observed a good inter-observer to the interval and distance with ICC?=?0.983 and 0.996, respectively.

Conclusion: We described a new technique for assessing fetal heart growth using 3DUS and determined reference curves for the distance and interval between the 20th and 34th weeks of pregnancy.     

Myocardial Salvage Imaging: Where Are We and Where Are We Heading? A Cardiac Magnetic Resonance Perspective

Purpose of Review

Cardiac magnetic resonance (CMR) has emerged in recent years as a reliable tool to assess, in a single examination after a reperfused myocardial infarction, the initially area at risk (AAR), the final infarct size (IS), and from their difference the salvaged myocardium (SM). The aim of the present review is to summarize recent advances in the CMR imaging of SM.

Recent Findings

While there is consensus on the use of late gadolinium enhancement (LGE) to calculate IS, how to assess the AAR is a debated topic. The use of T2-weighted short-TI inversion recovery (T2W-STIR) is to date supported by a large amount of data, but it is affected by several limitations. Newer techniques have been developed to overcome T2W-STIR limitations, some of them have been already used in randomized clinical trials (RCTs) while others are showing promising results. The use of CMR to generate surrogate endpoints in RCTs is gaining attention; in this context, analysis of data from recent RCTs suggests that the assessment of SM as outcome measure could be useful to reduce sample sizes and costs of trials.

Summary

CMR is a reliable technique for the assessment of SM. LGE is the gold standard for IS measurement, while which is the best technique for the evaluation of AAR is still debated. When using CMR-derived endpoints in RCTs, the assessment of SM is advisable.

     

Rituximab in the management of acute lymphoblastic leukemia

Introduction: The anti-CD20 chimeric monoclonal antibody rituximab has revolutionized the treatment of B-cell malignancies, significantly improving patient clinical outcome. Recently, some single-group studies have suggested that adding rituximab to chemotherapy can improve the outcome of CD20-positive B-cell acute lymphoblastic leukemia (ALL) patients.

Areas covered: An overview of the current insights of rituximab in adult ALL patients is presented here. In particular, we focused on results of multicenter randomized phase III trial (GRAALL-2005 – Group for Research on Adult Acute Lymphoblastic Leukemia) that evaluated the benefit of associating rituximab to chemotherapy in Ph-negative, B-lineage ALL expressing the CD20 antigen.

Expert opinion: Data from clinical trials confirm that rituximab enhances the efficacy of chemotherapy without additive toxicity in ALL. However, results of GRAAL 2005 study represent only a modest incremental improvement in the treatment of ALL. Other promising compounds as single agent or in combination with chemotherapy are currently in different stages of clinical development. The GRAALL 2005 study sets the stage for other prospective studies which will further elucidate the role of monoclonal antibodies in the management of ALL.     

Increased risk of death and readmission after hospital discharge of critically ill patients in a developing country: a retrospective multicenter cohort study

Purpose

To describe long-term mortality and hospital readmissions of patients admitted to Brazilian intensive care units (ICU).

Methods

Retrospective cohort study of adult patients admitted to Brazilian hospitals affiliated to the Public Healthcare System from 10 state capitals. ICU patients were paired to non-ICU patients by frequency matching (ratio 1:2), according to postal code and admission semester. Hospitalization records were linked through deterministic linkage to national mortality data. Primary outcome was mortality up to 1 year. Other outcomes were mortality and readmissions at 30 and 90 days and 3 years. Multiple Cox regressions were used adjusting for age, sex, cancer diagnosis, type of hospital, and surgical status.

Results

We included 324,594 patients (108,302 ICU and 216,292 non-ICU). ICU patients had increased hospital length of stay [9 (5–17) vs. 3 (1–6) days, p?<?0.001] and mortality (18.5 vs. 3.6%, p?<?0.001) versus non-ICU patients. One year after discharge, ICU patients were more frequently readmitted to hospital (25.4 vs. 17.4%, p?<?0.001) and to ICU (31.4 vs. 7.3%, p?<?0.001) than controls. Mortality up to 1 year was also higher for ICU patients (14.3 vs. 3.9%, p?<?0.001). A significant interaction between surgical status and mortality was found, with adjusted hazard ratios (HRs) up to 1 year of 2.7 [95% confidence interval (CI) 2.5–2.9] for surgical patients, and 3.4 (95%CI 3.3–3.5) for medical patients. The risk for death and readmission diminished over time up to 3 years.

Conclusions

In a public healthcare system of a developing country, ICU patients have excessive long-term mortality and frequent readmissions. The ICU burden tended to reduce over time after hospital discharge.

     

Spiritual/religious coping and depressive symptoms in informal caregivers of hospitalized older adults

This aim of this study was assess whether positive and negative spiritual/religious coping (SRC) strategies are associated with depressive symptoms (DS) of informal caregiver (IC) of hospitalized older adults. A cross-sectional study was conducted among 98 IC of hospitalized older adults in the medical clinic of a Brazilian School Hospital. The functionality, Positive and Negative SRC strategies and DS were evaluated. The IC had high average use of SRC, with Positive SRC being more used than Negative SRC. In the unadjusted regression model, Positive and Negative SRC were associated with DS. However, when adjusted for confounding factors, only Negative SRC remained associated with DS. The IC had used their religious and spiritual beliefs as a way to cope with the stress that comes from caring for hospitalized older adults. Although the positive strategy use of these beliefs was more common, only the negative strategies were associated with a higher DS.     

Rational design,preparation and characterization of recombinant Ag85B variants and their glycoconjugates with T-cell antigenic activity against Mycobacterium tuberculosis

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from Mycobacterium tuberculosis. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.

Recombinant Ag85B variants were designed and prepared to improve the immunogenicity of a potential glycoconjugate vaccine against tuberculosis.     

Comparative toxicity of physiological and biochemical parameters in Euglena gracilis to short-term exposure to potassium sorbate

Ecotoxicology - Potassium sorbate is the potassium salt of sorbic acid, is a widespread and efficient antioxidant that has multiple functions in plants, traditionally associated with the reactions...