The iron chelator deferasirox synergises with chemotherapy to treat triple‐negative breast cancers

To ensure their high proliferation rate, tumor cells have an iron metabolic disorder causing them to have increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple‐negative tumors, which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this study, we demonstrated that deferasirox (DFX) synergises with standard chemotherapeutic agents such as doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple‐negative breast cancer (TNBC) cells. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient‐derived xenografts without increasing the side‐effects of chemotherapies alone or altering the global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve downregulation of the phosphoinositide 3‐kinase and nuclear factor‐κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Cytoprotective and Antioxidant Effects of the Methanol Extract of Eremomastax Speciosa in Rats

Background

Ethno-botanical information shows that Eremomastax speciosa is used in the traditional management of various stomach complaints including gastro-duodenal ulcers.

Materials and Methods

In this study, we tested the cytoprotective potential of the whole plant methanol extract (100–200 mg/kg, p.o), against HCl/ethanol, absolute ethanol, cold/restraint stress rats, and pylorus legated rats pre-treated with indomethacin. The effects of the extract on gastric lesion inhibition, the volume of gastric juice, gastric pH, gastric acid output, mucus production and gastric peptic activity were recorded. Oxidative stress parameters were measured in blood and gastric tissue samples obtained from the animals in all the models tested.

Results

The extract significantly (p<0.05), reduced the formation of cold/restraint ulcers by (31–60%, inhibition), completely inhibited (100%) the formation of lesions induced by HCl/ethanol at the highest dose, but was less effective against absolute ethanol (22–46% inhibition). The extract (200 mg/kg), significantly reduced lesion formation (P<0.01), gastric acidity (P<0.01), and volume of gastric secretions (P<0.05), in the indomethacin/pylorus ligation model, and did not affect the activity of pepsin in gastric juice. Blood concentrations of antioxidant enzymes (catalase, SOD and GSH), increased significantly and MDA concentrations decreased in all models tested.

Conclusion

Cytoprotection by E. speciosa methanol extract was attributed to its ability to reduce acid secretion, and to enhance mucosal defence and in vivo antioxidant status.     

Decreased Peripheral Dendritic Cell Numbers in Dengue Virus Infection

Laboratory predictors of severe forms of dengue virus (DENV) infection are needed. These clinical forms seem to be associated with high viremia, stressing the importance of immune responses, which could involve dendritic cells (DC). Yet, very few studies have evaluated DC after DENV infection. We assessed peripheral blood DC subset numbers in mild and severe forms of dengue in 44 patients, older than 15 years old, infected with serotypes DENV-2, 3 or 4. Patients were divided in high, intermediate and no detectable viremia according to results of molecular biology amplification of DENV. Serological status of anti-DENV IgG or IgM determined primary or secondary infections. Plasmacytoid and myeloid DC absolute and relative numbers were reduced in infected patients when compared to an age-matched healthy control group, but no significant differences in DC numbers were observed between mild or severe forms of disease. A severe disease was more frequent in patients infected with DENV-2 serotype and with secondary infection but no significant differences in DC subset numbers were found related to these variables. Viremia levels did not correlate to disease severity yet were associated to lower DC numbers. Plasmacytoid DC numbers were significantly lower in high and intermediate viremia groups compared to non-infected controls, but not in no detectable viremia patients. Myeloid DC numbers were also significantly lower than controls, even in no detectable viremia patients. These results confirm that circulating DC subset numbers are reduced after DENV infection, although this is not a biomarker of severe forms of dengue in adults.     

Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology,DNA content,and chromatin texture

A number of noninvasive fiber optic optical technologies are under development for real-time diagnosis of neoplasia. We investigate how the light scattering properties of cervical cells are affected by changes in nuclear morphology, DNA content, and chromatin texture, which occur during neoplastic progression. We used a Cyto-Savant computer-assisted image analysis system to acquire quantitative nuclear features measurements from 122 Feulgen-thionin-stained histopathologic sections of cervical tissue. A subset of the measured nuclear features was incorporated into a finite-difference time-domain (FDTD) model of cellular light scattering. The magnitude and angular distribution of scattered light was calculated for cervical cells as a function of pathologic grade. The nuclear atypia strongly affected light scattering properties. The increased size and elevated DNA content of nuclei in high-grade lesions caused the most significant changes in scattering intensity. The spatial dimensions of chromatin texture features and the amplitude of refractive index fluctuations within the nucleus impacted both the angular distribution of scattering angles and the total amount of scattered light. Cellular scattering is sensitive to changes in nuclear morphology that accompany neoplastic progression. Understanding the quantitative relationships between nuclear features and scattering properties will aid in the development of noninvasive optical technologies for detection of precancerous conditions.     

Myocardial lactate metabolism at rest and during exercise in ischemic heart disease

Cardiac dynamics and myocardial extraction of oxygen and lactate were investigated at rest in subjects with normal coronary arteries and in patients with coronary heart disease. Coronary artery disease was considered significant when there was obstruction or more than 50 per cent narrowing of one or more coronary arteries. Half of the patients were also studied during moderate exercise. The hemodynamic findings were almost comparable in all cases. On exercise, in patients with significant coronary disease, there was evidence of abnormal left ventricular function, and increases in cardiac index were mediated through a much higher left ventricular end-diastolic pressure.

Coronary arteriovenous difference and the myocardial extraction of oxygen were normal at rest and unchanged on exercise in all cases. Marked rise in the arterial level and a significant increase in the arteriovenous difference of lactate were present in all cases. The extraction ratio of lactate by the myocardium remained normal and increased only slightly in control subjects. However, this ratio increased to normal levels during exercise in all patients with significant coronary artery disease. Possible explanations for the increased coronary arteriovenous difference and myocardial extraction ratio of lactate on exercise in these patients are discussed.     

Doping test reveals high concentrations of salbutamol in a Swiss track and field athlete.

Beta-2 agonists are on the list of prohibited substances in sport. Salbutamol by inhalation is permitted to treat allergic asthma, and/or exercise-induced asthma or exercise-induced bronchoconstriction. If the level of salbutamol in urine exceeds 1000 ng/mL, the result is considered as a doping violation with an anabolic steroid. We report a case of a track and field athlete who tested well above this limit during a competition. He had a valid therapeutic use exemption for the use of salbutamol by inhalation and he claimed that he never used salbutamol orally. Further studies under controlled application by inhalation showed that this limit was exceeded. We propose that sanctioning bodies in sport should consider this possibility before taking into account a two-year ban for the use of an anabolic steroid.     

The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia–reperfusion autotransplant model

The aims of this study were to determine the most optimal timing to start machine perfusion during kidney preservation to improve early graft function and to evaluate the impact of temperature and oxygen supply during machine perfusion in a porcine ischemia–reperfusion autotransplant model. The left kidney of an approximately 40‐kg female Belgian Landrace pig was exposed to 30 minutes of warm ischemia via vascular clamping and randomized to 1 of 6 study groups: (1) 22‐hour static cold storage (SCS) (n = 6), (2) 22‐hour hypothermic machine perfusion (HMP) (n = 6), (3) 22‐hour oxygenated HMP (n = 7), (4) 20‐hour HMP plus 2‐hour normothermic perfusion (NP) (n = 6), (5) 20‐hour SCS plus 2‐hour oxygenated HMP (n = 7), and (6) 20‐hour SCS plus 2‐hour NP (n = 6). Graft recovery measured by serum creatinine level was significantly faster for continuous HMP preservation strategies compared with SCS alone and for all end‐ischemic strategies. The active oxygenated 22‐hour HMP group demonstrated a significantly faster recovery from early graft function compared with the 22‐hour nonactive oxygenated HMP group. Active oxygenation was also found to be an important modulator of a faster increase in renal flow during HMP preservation. Continuous oxygenated HMP applied from the time of kidney procurement until transplant might be the best preservation strategy to improve early graft function.     

Somatodendritic ion channel expression in substantia nigra pars compacta dopaminergic neurons across postnatal development

Dopaminergic neurons of the substantia nigra pars compacta (SNc) are involved in the control of movement, sleep, reward, learning, and nervous system disorders and disease. To date, a thorough characterization of the ion channel phenotype of this important neuronal population is lacking. Using immunohistochemistry, we analyzed the somatodendritic expression of voltage‐gated ion channel subunits that are involved in pacemaking activity in SNc dopaminergic neurons in 6‐, 21‐, and 40‐day‐old rats. Our results demonstrate that the same complement of somatodendritic ion channels is present in SNc dopaminergic neurons from P6 to P40. The major developmental changes were an increase in the dendritic range of the immunolabeling for the HCN, T‐type calcium, Kv4.3, delayed rectifier, and SK channels. Our study sheds light on the ion channel subunits that contribute to the somatodendritic delayed rectifier (Kv1.3, Kv2.1, Kv3.2, Kv3.3), A‐type (Kv4.3) and calcium‐activated SK (SK1, SK2, SK3) potassium currents, I_H (mainly HCN2, HCN4), and the L‐ (Cav1.2, Cav1.3) and T‐type (mainly Cav3.1, Cav3.3) calcium currents in SNc dopaminergic neurons. Finally, no robust differences in voltage‐gated ion channel immunolabeling were observed across the population of SNc dopaminergic neurons for each age examined, suggesting that differing levels of individual ion channels are unlikely to distinguish between specific subpopulations of SNc dopaminergic neurons. This is significant in light of previous studies suggesting that age‐ or region‐associated variations in the expression profile of voltage‐gated ion channels in SNc dopaminergic neurons may underlie their vulnerability to dysfunction and disease. © 2014 Wiley Periodicals, Inc.