Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating p21 and ROS levels

Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone (LHRH) analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108, consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog, AEZS-108, on LHRHR positive castration-resistant prostate cancer cells.     

Physical and Chemical Methods for Reduction in Aflatoxin Content of Feed and Food

Aflatoxins (AFs) are among the most harmful fungal secondary metabolites imposing serious health risks on both household animals and humans. The more frequent occurrence of aflatoxins in the feed and food chain is clearly foreseeable as a consequence of the extreme weather conditions recorded most recently worldwide. Furthermore, production parameters, such as unadjusted variety use and improper cultural practices, can also increase the incidence of contamination. In current aflatoxin control measures, emphasis is put on prevention including a plethora of pre-harvest methods, introduced to control Aspergillus infestations and to avoid the deleterious effects of aflatoxins on public health. Nevertheless, the continuous evaluation and improvement of post-harvest methods to combat these hazardous secondary metabolites are also required. Already in-use and emerging physical methods, such as pulsed electric fields and other nonthermal treatments as well as interventions with chemical agents such as acids, enzymes, gases, and absorbents in animal husbandry have been demonstrated as effective in reducing mycotoxins in feed and food. Although most of them have no disadvantageous effect either on nutritional properties or food safety, further research is needed to ensure the expected efficacy. Nevertheless, we can envisage the rapid spread of these easy-to-use, cost-effective, and safe post-harvest tools during storage and food processing.     

CMT Additive Manufacturing Parameters Defining Aluminium Alloy Object Geometry and Mechanical Properties

Additive manufacturing technologies based on metal melting use materials mainly in powder or wire form. This study focuses on developing a metal 3D printing process based on cold metal transfer (CMT) welding technology, in order to achieve enhanced productivity. Aluminium alloy test specimens have been fabricated using a special 3D printing technology. The probes were investigated to find correlation between the welding parameters and geometric quality. Geometric measurements and tensile strength experiments were performed to determine the appropriate welding parameters for reliable printing. The tensile strength of the product does not differ significantly from the raw material. Above 60 mm height, the wall thickness is relatively constant due to the thermal balance of the welding environment. The results suggest that there might be a connection between the welding parameters and the printing accuracy. It is demonstrated that the deviation of ideal geometry will be the smallest at the maximum reliable welding torch movement speed, while printing larger specimens. As a conclusion, it can be stated that CMT-based additive manufacturing can be a reliable, cost-effective and rapid 3D printing technology with enhanced productivity, but without significant decrease in mechanical stability.     

Mesenchymal stem cells and the immune system--immunosuppression without drugs?

Mesenchymal stem cells (MSC) - isolated from various tissues in humans and other species - are one of the most promising adult stem cell types due to their availability and the relatively simple requirements for in vitro expansion. They have the capacity to differentiate into several tissues, including bone, cartilage, tendon, muscle and adipose, and produce growth factors and cytokines that promote hematopoietic cell expansion and differentiation. In vivo, MSCs are able to repair damaged tissue from kidney, heart, liver, pancreas and gastrointestinal tract. Furthermore, they also have anti-proliferative, immunomodulatory and anti-inflammatory effects, but evoke only little immune reactivity. Although the mechanism underlying the immunosuppressive effects of MSCs has not been clearly defined, their immunosuppressive properties have already been exploited in the clinical setting. Therefore, in the future, MSCs might have implications for treatment of allograft rejection, graft-versus-host disease, rheumatoid arthritis, autoimmune inflammatory bowel disease and other disorders in which immunomodulation and tissue repair are required. The aim of this review is to critically analyze the field of MSC biology, particularly with respect to their immunomodulatory properties and potential clinical use in the future.     

Correlation between risk factors and mortality in elderly patients with femoral neck fracture with 5-year follow-up

Hip fractures are associated with increased mortality in the elderly. There are only a few studies based on large patient number covering a nationwide health care system. AIM: The aim of this study was to investigate the mortality following primary treatment in patients over 60 with acute, monotraumatic femoral neck fracture on monthly and annual base during a 5-year follow-up period; and to evaluate the effect of different risk factors on mortality during the follow-up. METHODS: Data were derived from the nationwide database of the National Health Insurance Fund Administration. The evaluation includes patients with femoral neck fracture discharged from inpatient care institutions in 2000 following a primary surgical treatment. Weekly, monthly and annual mortality rates, and its monthly and annual trends according to risk factors were calculated. Logistic and Cox regression analysis was performed to evaluate the correlation between risk factors and mortality. RESULTS: 3783 patients were involved in the study with a mean age of 77,97 years (SD 8,52). The mortality rates were 1,71% (during the first week), 8,99% (30 days), 30,74% (first year) and 61,88% (in 5 years). Mortality showed a declining trend up to the 5th month, and is stagnant after the first year. Risk factor analysis showed that higher risk of mortality is associated with male sex and higher age group up to 5 years, co-morbidities up to 4 years, lateral type femoral neck fracture and 12 hours delay of primary treatment up to 2 years, early local complications up to 1 year and surgical treatment during week-end up to 1 month. Surgical treatment delivered in national health institutes and university clinics resulted in a lower mortality risk up to 1 year. CONCLUSIONS: In order to reduce mortality during the management of hip fractures, the authors emphasize the importance of delay of treatment within 12 hours, appropriate selection of methods corresponding to fracture type, providing the same conditions for primary treatment during all days of the week, to organize the treatment to special centres, appropriate acute care and follow-up corresponding to the general health status and co-morbidities of patients.     

Novel bradykinin-1 antagonists containing a (1,2,3,4-tetrahydro-isoquinolin-1-yl)acetic acid scaffold

A novel B(1) antagonist core was utilized and the effects of modification of its amide side chain on the biological activity were tested. The imino functional group of isoquinolin-1-ylacetic acid and its 6,7-dimethoxy variant was sulfonylated (4-toluenesulfonyl), while the acetyl side chain was converted to amides. Three of the synthesized compounds exhibited significant activity at the recombinant human B(1) receptors in binding tests and also in a functional assay.     

Acetazolamide induces indomethacin and ischaemia-sensitive pial arteriolar vasodilation in the piglet

AIM: Acetazolamide (AZD) produces cerebral vasodilation. The underlying mechanism is unclear, but it is assumed to be largely due to CO2 retention and acidosis. We tested if cerebrovascular effects of AZD were similar to hypercapnia in the newborn pig. METHODS: We used the closed cranial window/intravital microscopy technique to determine pial arteriolar diameters simultaneously with laser-Doppler flowmetry (LDF) to monitor cortical blood perfusion. Anaesthetized (Na-thiopenthal +alpha-chloralose), ventilated, 1-day-old instrumented piglets (n=38) were divided into five experimental groups: time control (n=11), indomethacin, ibuprofen, Nomega-nitro-L-arginine methyl ester (L-NAME) treatments (1, 30, 15 mg/kg, i.v., n=6, 6, 4, respectively), and global ischaemia/reperfusion (I/R, 10 min induced by elevated intracranial pressure, n=11). Responses to 5-10% inhaled CO2 were recorded before and after the treatments, and then in a similar manner to AZD (10-20 mg/kg, i.v.). RESULTS: Hypercapnia and AZD produced pial arteriolar vasodilation and increases in cortical perfusion. Consistent with previous data, hypercapnia-induced changes were abolished by indomethacin, unaltered by ibuprofen and L-NAME and were significantly attenuated after I/R. AZD-induced vasodilation was also sensitive to indomethacin and I/R and was unaltered by ibuprofen or L-NAME. CONCLUSION: The mechanism of AZD-induced vasodilation appears to be similar/identical to hypercapnia, and pial arteriolar diameter changes reflect changes in cortical perfusion.