Liver, gastrointestinal and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: Results from the PRECISION V randomized trial : B-240

Purpose: To evaluate the toxicity focussing on hepatic, gastrointestinal and cardiac parameters following PRECISION TACE with DC Bead? versus conventional transarterial chemoembolization (cTACE) in the treatment of intermediate-stage hepatocellular carcinoma (HCC). Methods and Materials: This prospective, randomized, multicentre study was conducted under best practice trial management and authorized by local institutional review boards. Informed consent was obtained. 212 patients (185 men/27 women; mean: 67 years) were randomized to be treated with DC Beads? or cTACE. The majority of both groups presented in a more advanced stage. Safety was measured by rate of adverse events (South West Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed by means of left ventricular ejection fraction (LVEF) in MRI or echocardiography. The results of the two groups were compared using the chi-square test and Student`s t-test. Results: Mean maximum alanine transaminase increase in the DC Bead group was 50% in the cTACE group (p < 0.001) and 59% for aspartate transaminase (p < 0.001). For bilirubin, mean increase was 5.30±15.13 vs. 13.53±73.89 µmol/L. Concerning gastrointestinal disorders, 120 adverse events (AEs) occurred in 57/93 (61.3%) patients in the DC Bead group vs. 114 in 49/108 (45.4%) in cTACE. Concerning hepatobiliary disorders, serious AEs occurred in 8/93 (8.6%) vs. 11/108 (10.2%) patients. LVEF showed an increase in the DC Bead group by +2.7±10.1 percentage points and a small decrease by -1.5±7.6 in the cTACE group, p=0.018. Conclusion: PRECISION TACE is safe, even in more advanced HCC patients. Serious liver and cardiac toxicity were significantly lower in the DC Bead group.

Biochemical changes associated to soybean seeds osmoconditioning during storage

A work was carried out with the purpose of verifying the biochemical changes associated to soybean (Glycine max (L.) Merrill) seeds osmoconditioning. Seeds of the UFV 10, IAC 8 and Doko RC cultivars harvested at R8 development stage and submitted to different treatments were used. The biochemical evaluations were performed during seed storage, after the hydration-dehydration process. Initially, seeds were osmoconditioned in a polyethylene glycol (PEG 6000) solution, with the osmotic potential of -0.8 MPa and 20ºC, for a period of four days. After that, seeds were dried back until the initial moisture content (10-11%) and stored in natural conditions for three and six months. Two controls were used: untreated seeds (dry seeds) and water soaked seeds. Seed changes in protein and lipid, hexanal accumulation and fatty acids contents were evaluated. The results showed that seed storage under laboratory natural conditions caused reduction in protein, lipid and polyunsaturated fatty acids content and promoted hexanal production. Storage periods reduced protein levels for all treatments, however the PEG 6000 treatment showed lower protein reduction. The soybean seed storage increased hexanal production, but hexanal levels were smaller with osmoconditioning comparing to the other imbibition treatments.

Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia.

OBJECTIVE: Targeting neuroprotectants specifically to the cells that need them is a major goal in biomedical research. Many peptidic protectants contain an active sequence linked to a carrier such as the transactivator of transcription (TAT) transduction sequence, and here we test the hypothesis that TAT-linked peptides are selectively endocytosed into neurons stressed by excitotoxicity and focal cerebral ischemia. METHODS: In vivo experiments involved intracerebroventricular injection of TAT peptides or conventional tracers (peroxidase, fluorescein isothiocyanate-dextran) in young rats exposed to occlusion of the middle cerebral artery at postnatal day 12. Cellular mechanisms of uptake were analyzed in dissociated cortical neuronal cultures. RESULTS: In both models, all tracers were taken up selectively into stressed neurons by endocytosis. In the in vivo model, this was neuron specific and limited to the ischemic area, where the neurons displayed enhanced immunolabeling for early endosomal antigen-1 and clathrin. The highly efficient uptake of TAT peptides occurred by the same selective mechanism as for conventional tracers. All tracers were targeted to the nucleus and cytoplasm of neurons that appeared viable, although ultimately destined to die. In dissociated cortical neuronal cultures, an excitotoxic dose of N-methyl-D-aspartate induced a similar endocytosis. It was 100 times more efficient with TAT peptides than with dextran, because the former bound to heparan sulfate proteoglycans at the cell surface, but it depended on dynamin and clathrin in both cases. INTERPRETATION: Excitotoxicity-induced endocytosis is the main entry route for protective TAT peptides and targets selectively the neurons that need to be protected.

Consumer Advisory: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones, June 2014

The Attorney General’s Consumer Protection Division receives hundreds of calls and consumer complaints every year. Follow these tips to avoid unexpected expense and disappointments. This record is about: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones

The effect of storage ageing and spring sprouting of seed tubers on the yield of three potato varieties in the Finnish Lapland : Research Note

Selostus: Siemenmukuloiden varastointiaikaisen lämpökäsittelyn ja kevätidätyksen vaikutus kolmen perunalajikkeen satoon Lapissa

Effect of harvest time on storage loss and sprouting in onion

Selostus: Sadonkorjuuajan vaikutus sipulin varastohävikkiin ja varastoinnin jälkeiseen versomiseen

Cardiovascular drug interactions with tyrosine kinase inhibitors

Imatinib mesylate, a selective inhibitor of tyrosine kinases, has excellent efficacy in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). Inducing durable responses and achieving prolonged survival, it has become the standard of care for the treatment of these diseases. It has opened the way to the development of additional tyrosine kinase inhibitors (TKIs), including sunitinib, nilotinib, dasatinib and sorafenib, all indicated for the treatment of various haematological malignancies and solid tumours. TKIs are prescribed for prolonged periods and are often taken by patients with - notably cardiovascular - comorbidities. Hence TKIs are regularly co-administered with cardiovascular drugs, with a considerable risk of potentially harmful drug-drug interactions due to the large number of agents used in combination. However, this aspect has received limited attention so far, and a comprehensive review of the published data on this important topic has been lacking. We review here the available data and pharmacological mechanisms of interactions between commonly prescribed cardiovascular drugs and the TKIs marketed at present. Regular updating of the literature on this topic will be mandatory, as will the prospective reporting of unexpected clinical observations, given the fact that these drugs have been only recently marketed.

Residual antimalarial concentrations before treatment in patients with malaria from Cambodia: indication of drug pressure.

BACKGROUND: The Thai-Cambodian border has been known as the origin of antimalarial drug resistance for the past 30 years. There is a highly diverse market for antimalarials in this area, and improved knowledge of drug pressure would be useful to target interventions aimed at reducing inappropriate drug use. METHODS: Baseline samples from 125 patients with falciparum malaria recruited for 2 in vivo studies (in Preah Vihear and Pursat provinces) were analyzed for the presence of 14 antimalarials in a single run, by means of a liquid chromatography-tandem mass spectrometry assay. RESULTS: Half of the patients had residual drug concentrations above the lower limit of calibration for at least 1 antimalarial at admission. Among the drugs detected were the currently used first-line drugs mefloquine (25% and 35% of patients) and piperaquine (15% of patients); the first-line drug against vivax malaria, chloroquine (25% and 41% of patients); and the former first-line drug, quinine (5% and 34% patients). CONCLUSIONS: The findings demonstrate that there is high drug pressure and that many people still seek treatment in the private and informal sector, where appropriate treatment is not guaranteed. Promotion of comprehensive behavioral change, communication, community-based mobilization, and advocacy are vital to contain the emergence and spread of parasite resistance against new antimalarials.

Association between nonmedical prescription drug use and health status among young swiss men.

PURPOSE: To examine the relationship between the nonmedical prescription drug use (NMPDU) of six drug classes and health. METHODS: Data on young adults males (mean age, 19.96 years) from the baseline and follow-up of the Cohort Study on Substance Use Risk Factors (C-SURF) were used (n = 4,958). Two sets of logistic regression models were fitted to examine the associations between NMPDU of opioid analgesics, sedatives or sleeping pills, anxiolytics, antidepressants, beta blockers and stimulants, and health status (assessed using the Medical Outcomes Study 12-Item Short Form Survey Instrument [SF-12 v2]). We first computed odds ratios between NMPDU at baseline and poor mental and physical health at follow-up, adjusting for poor mental or physical health at baseline. We then computed odds ratios between poor mental and physical health at baseline and NMPDU at follow-up, adjusting for NMPDU at baseline. RESULTS: Three key findings regarding mental health were (1) there was a reciprocal risk between poor mental health and sedatives and anxiolytics; (2) poor mental health increased NMPDU of opioid analgesics and antidepressants but not vice versa; and (3) there were no associations with stimulants. Three key findings regarding physical health were (1) poor physical health increased the risk of NMPDU of anxiolytics; (2) the only reciprocal risk was between physical health and NMPDU of opioid analgesics; and (3) there were no associations with stimulants. CONCLUSION: These results, among the first ever on reciprocal effects between NMPDU and mental and physical health status, give unique information concerning the adverse effects of NMPDU on health and vice versa. The study shows that NMPDU is not only a sign of self-medication but may induce health problems.

Lipophilicity and its relationship with passive drug permeation.

In this review, we first summarize the structure and properties of biological membranes and the routes of passive drug transfer through physiological barriers. Lipophilicity is then introduced in terms of the intermolecular interactions it encodes. Finally, lipophilicity indices from isotropic solvent systems and from anisotropic membrane-like systems are discussed for their capacity to predict passive drug permeation across biological membranes such as the intestinal epithelium, the blood-brain barrier (BBB) or the skin. The broad evidence presented here shows that beyond the predictive power of lipophilicity parameters, the various intermolecular forces they encode allow a mechanistic interpretation of passive drug permeation.

The glucose transporter 4 FQQI motif is necessary for Akt Substrate of 160-Kilodalton-dependent plasma membrane translocation but not Golgi-localized g-ear-containing Arf-binding protein-dependent entry into the insulin-responsive storage compartment.

Newly synthesized glucose transporter 4 (GLUT4) enters into the insulin-responsive storage compartment in a process that is Golgi-localized γ-ear-containing Arf-binding protein (GGA) dependent, whereas insulin-stimulated translocation is regulated by Akt substrate of 160 kDa (AS160). In the present study, using a variety of GLUT4/GLUT1 chimeras, we have analyzed the specific motifs of GLUT4 that are important for GGA and AS160 regulation of GLUT4 trafficking. Substitution of the amino terminus and the large intracellular loop of GLUT4 into GLUT1 (chimera 1-441) fully recapitulated the basal state retention, insulin-stimulated translocation, and GGA and AS160 sensitivity of wild-type GLUT4 (GLUT4-WT). GLUT4 point mutation (GLUT4-F5A) resulted in loss of GLUT4 intracellular retention in the basal state when coexpressed with both wild-type GGA and AS160. Nevertheless, similar to GLUT4-WT, the insulin-stimulated plasma membrane localization of GLUT4-F5A was significantly inhibited by coexpression of dominant-interfering GGA. In addition, coexpression with a dominant-interfering AS160 (AS160-4P) abolished insulin-stimulated GLUT4-WT but not GLUT4-F5A translocation. GLUT4 endocytosis and intracellular sequestration also required both the amino terminus and large cytoplasmic loop of GLUT4. Furthermore, both the FQQI and the SLL motifs participate in the initial endocytosis from the plasma membrane; however, once internalized, unlike the FQQI motif, the SLL motif is not responsible for intracellular recycling of GLUT4 back to the specialized compartment. Together, we have demonstrated that the FQQI motif within the amino terminus of GLUT4 is essential for GLUT4 endocytosis and AS160-dependent intracellular retention but not for the GGA-dependent sorting of GLUT4 into the insulin-responsive storage compartment.