AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis.

BACKGROUND: MSB11022 is a proposed adalimumab biosimilar. OBJECTIVES: To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. METHODS: AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). RESULTS: In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. CONCLUSIONS: Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.

Effect of ozonation on table grapes preservation in cold storage.

Table grapes artificially inoculated with B. Cinerea were tested under four different ozonation strategies in order to achieve prolongation of table grapes' shelf-life time. Decay incidence, external disease appearance, number of infected grapes, weight loss and a variety of quality parameters such as sugars and proteins content were checked after every 3 days. No significant alteration of table grapes quality characteristics was observed after their exposure to ozone atmosphere. Moreover, the low ozone dosage process (0.3 ppm) caused sufficient restriction of fruit decay due to fungal contamination and secured a 40-days-period of storage time. However, the observed weight loss was somewhat higher on the treated samples compared to the untreated ones. From technical and economical point of view the low dosage (0.3 ppm) ozonation process on a daily basis combined with the cold storage appears to a very promising method for table grapes preservation.

p57(KIP2) control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effect.

p57 (Kip2, cyclin-dependent kinase inhibitor 1C), often found downregulated in cancer, is reported to hold tumor suppressor properties. Originally described as a cyclin-dependent kinase (cdk) inhibitor, p57(KIP2) has since been shown to influence other cellular processes, beyond cell cycle regulation, including cell death and cell migration. Inhibition of cell migration by p57(KIP2) is attributed to the stabilization of the actin cytoskeleton through the activation of LIM domain kinase-1 (LIMK-1). Furthermore, p57(KIP2) is able to enhance mitochondrial-mediated apoptosis. Here, we report that the cell death promoting effect of p57(KIP2) is linked to its effect on the actin cytoskeleton. Indeed, whereas Jasplakinolide, an actin cytoskeleton-stabilizing agent, mimicked p57(KIP2)'s pro-apoptotic effect, destabilizing the actin cytoskeleton with cytochalsin D reversed p57(KIP2)'s pro-apoptotic function. Conversely, LIMK-1, the enzyme mediating p57(KIP2)'s effect on the actin cytoskeleton, was required for p57(KIP2)'s death promoting effect. Finally, p57(KIP2-)mediated stabilization of the actin cytoskeleton was associated with the displacement of hexokinase-1, an inhibitor of the mitochondrial voltage-dependent anion channel, from the mitochondria, providing a possible mechanism for the promotion of the mitochondrial apoptotic cell death pathway. Altogether, our findings link together two tumor suppressor properties of p57(KIP2), by showing that the promotion of cell death by p57(KIP2) requires its actin cytoskeleton stabilization function.

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide.

Various inhibitors of histone deacetylase (HDAC) activity can sensitize drug resistant cancer cells to chemotherapeutic agents. However, the mechanisms underlying such effects of distinct HDAC inhibitors (HDACi) remain poorly understood. Here we show that both the HDACi trichostatin A and valproic acid induced a sensitization of multidrug-resistant cancer cells to the topoisomerase II inhibitor etoposide/VP16. This effect was associated with increased acetylation of certain lysines on histones H3 and H4, including lysine 16 on histone H4 (H4K16). Overexpression of the histone acetyltransferase hMOF, known to target H4K16, was sufficient to mimic HDACi treatment on sensitization and H4K16 acetylation, and importantly, small-interfering RNA (siRNA)-mediated knockdown of hMOF abolished the HDACi-mediated sensitizing effects as well as the increase in H4K16 acetylation. Conversely, siRNA-mediated knockdown of the H4K16 deacetylase SIRT1 mimicked HDACi treatment whereas overexpression of SIRT1 abolished H4K16 acetylation and significantly reduced the sensitizing effects of HDACi. Interestingly, the effects of hMOF on H4K16 acetylation and sensitization to the topoisomerase II inhibitor could be directly counteracted by exogenous expression of increasing amounts of SIRT1 and vice versa. Our study results suggest that hMOF and SIRT1 activities are critical parameters in HDACi-mediated sensitization of multidrug-resistant cancer cells to topoisomerase II inhibitor and increased H4K16 acetylation.

The Cdk inhibitor p57(Kip2) controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics.

The cyclin-dependent kinase inhibitor p57(Kip2) gene has been suggested to be a tumor suppressor gene, being inactivated in various cancer types, linked to tumor progression and poor patient outcome. Here, we report that p57(Kip2) interacts with the actin cytoskeleton modifying enzyme, LIM-kinase 1 (LIMK-1) but not LIMK-2. This interaction enhances activity of LIMK-1, independently of its activator Rho-associated kinase. This resulted in an increased phosphorylation and consequent inactivation of the actin depolymerization factor, cofilin. In accordance, selective p57(Kip2) expression promotes actin stress fiber formation in cancer cells. Fluorescence recovery after photobleaching analysis of fluorescent-labeled actin further demonstrated that p57(Kip2) expression results in reduction of actin protein mobile fraction, which affects its turnover rate in cell. Finally, we present evidence that the p57(Kip2) control of LIMK-1 ultimately affects cell mobility negatively. Thus, in addition to its established function in control of proliferation and cell death, these results indicate that p57(Kip2) is critical in the regulation of actin cytoskeleton dynamic and by this means migration ability of cancer cells.

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells.

Mammalian central nervous system (CNS) development is a highly organized process involving the precise and coordinated timing of cell-cycle exit, differentiation, survival, and migration. These events require proper expression of pro-neuronal genes but also repression of alternative cell fates and restriction of cell-type-specific gene expression. Here, we show that the cyclin-dependent kinase (CDK) inhibitor p57Kip2 interacted with pro-neuronal basic helix-loop-helix (bHLH) factors such as Mash1, NeuroD, and Nex/Math2. Increased levels of p57Kip2 inhibited Mash1 transcriptional activity independently of CDK interactions and acted as a direct repressor in transcriptional assays. Proliferating telencephalic neural progenitors co-expressed basal levels of Mash1 and p57Kip2, and endogenous p57Kip2 accumulated transiently in the nuclei of neural stem cells (NSCs) during early stages of astrocyte differentiation mediated by ciliary neurotrophic factor (CNTF), independent of cell-cycle exit and at times when Mash1 expression was still prominent. In accordance with these observations, gain- and loss-of-function studies showed that p57Kip2 repressed neuronal differentiation after mitogen withdrawal, but exerted little or no effect on CNTF-mediated astroglial differentiation of NSCs. Our data suggest a novel role for p57Kip2 as a context-dependent repressor of neurogenic transcription factors and telencephalic neuronal differentiation.

Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells.

Commonly used regimens in cancer therapy rely on the induction of apoptotic cell death, and drug resistance can be attributed, at least in part, to a disabled apoptotic program. Non-small cell lung carcinomas (NSCLC), exhibit an intrinsic resistance to chemotherapy. Here, we show that co-treatment with etoposide (VP16) and the pan-histone deacetylase (HDAC) inhibitor trichostatin A (TSA), but not valproic acid (VPA), induced apoptotic cell death in drug-resistant NSCLC cells. Co-treatment, but not single treatment, with VP16 and TSA induced apoptosis in a caspase-dependent manner accompanied by a crucial decrease in Bcl-xL expression allowing Bax activation and subsequent initiation of the apoptosis inducing factor (AIF)-dependent death pathway. Importantly, AIF proved to be required for the effects of TSA/VP16 as RNA knockdown of AIF resulted in a complete abolishment of TSA/VP16-induced apoptotic cell death in drug-resistant NSCLC cells. Our results thus provide evidence for the requirement of both caspase-dependent and caspase-independent apoptotic pathways in TSA/VP16-mediated death of drug-resistant NSCLC cells, and extend previous suggestions that HDAC inhibitors in combination with conventional chemotherapeutic drugs could be valuable in the treatment of NSCLC cancer and other malignancies in which Bcl-xL is overexpressed.

The cell cycle inhibitor p57(Kip2) promotes cell death via the mitochondrial apoptotic pathway.

The p57(Kip2) gene belongs to the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors and has been suggested to be a tumor suppressor gene, being inactivated in various types of human cancers. However, little is known concerning p57(Kip2) possible interplay with the apoptotic cell death machinery and its possible implication for cancer. Here, we report that selective p57(Kip2) expression sensitizes cancer cells to apoptotic agents such as cisplatin, etoposide and staurosporine (STS) via a mechanism, which does not require p57(Kip2)-mediated inhibition of CDK. Translocation of p57(Kip2) to mitochondria occurs within 20 min after STS application. In fact, p57(Kip2) primarily promotes the intrinsic apoptotic pathways, favoring Bax activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation. In accordance, Bcl2 overexpression or voltage-dependent anion channel (VDAC) inhibition is able to inhibit p57(Kip2) cell death promoting effect. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57(Kip2) influences the mitochondrial apoptotic cell death pathway in cancer cells.

A Full-Color Electroluminescent Device and Patterned Photoalignment Using Light-Emitting Liquid Crystals.

Blue, green, and red polymerizable light-emitting liquid crystals have been patterned photolithographically in a full-color liquid-crystal electroluminescent display. A new hole-transporting photoalignment copolymer is also reported and the spatial patterning of the polarization direction of emission is demonstrated.

Paraquat poisoning in a family.

A familial occurrence of acute paraquat (PQ) poisoning is reported. The mother administered a PQ solution to their 3 children aged 8 y, 6 y and 15 mo and then ingested an unknown amount of the herbicide herself. In the absence of history or diagnostic signs, the poisoning was initially misdiagnosed as gastroenteritis. Thirty h after the ingestions, serum PQ concentrations of the children were 60, <6 and 25 ng/ml respectively. Hemoperfusion was performed on all patients, and 2 of the children also received plasmapheresis and erythropheresis. The 3 children recovered fully but the mother died. According to these patients' data, the extracorporeal techniques had little effect on PQ removal, and the decreases in serum PQ were related to its urinary excretion.

Household bleaches based on sodium hypochlorite: review of acute toxicology and poison control center experience.

Bleaches based on solutions of sodium hypochlorite (NaOCl) are widely used in the household to disinfect and clean hard surfaces and to bleach the laundry. A review of both published and unpublished toxicological data is presented. In addition, the results of a survey of human accidents with hypochlorite bleaches by the Poison Control Centers of France, Italy, Belgium, Greece, Turkey, Spain and Portugal for the period 1989-1992 are presented. The data show that acute accidental exposure to household bleach in use or in foreseeable misuse situations results, in the great majority of the cases, in minor, transient adverse effects on health, with no permanent sequelae. Ingestion is the most frequent route of exposure, followed by inhalation of gases evolved by mixing sodium hypochlorite bleach with acid or alkaline products. All evidence presented confirms the normal safety profile of hypochlorite-based bleaches to be similar to that of other 'generally recognized as safe' household products.

Vincristine overdose: experience with 3 patients.

Vincristine overdose (7.5 mg/m2) was accidentally administered to 3 children with acute lymphoblastic leukemia. Treatment included double-volume exchange transfusion, phenobarbital administered prophylactically, and folinic acid rescue 18 mg every 3 hours for 16 doses. Vincristine levels were also assayed and showed a dramatic decline in postexchange levels in the 2 patients who survived and an almost unchanged value in the patient who succumbed. Early signs of toxicity in the 2 survivors were peripheral neuropathy (day 4), bone marrow toxicity (day 5), gastrointestinal toxicity (days 6 and 7), and hypertension (days 7 and 8). Marrow aplasia lasted for 4 and 10 days, peripheral neuropathy for 15 and 42 days, gastrointestinal toxicity for 3 and 5 days, and hypertension for 5 and 14 days. The 2 children were discharged on days 13 and 16 and cytostatic therapy was restarted on days 18 and 25. Both are alive without evidence of leukemia. The third patient developed liver and marrow toxicity on day 3 and died on day 9. Postmortem examination showed leukemia infiltration of the liver and spleen.

Suicidal attempts by ingestion of various substances in 2050 children and adolescents in Greece.

This study investigates suicidal attempts by ingestion of drugs or other chemicals in 2050 children and adolescents (312 boys and 1738 girls) under seventeen years of age as seen over a six year period, 1977-1982, at the Poison Control Center, "P.A. Kyriakou" Children's Hospital, Athens, Greece. Demographic, clinical, psychosocial and cultural data were presented and discussed. It is the authors' opinion that more attention should be paid to the increased incidence of suicidal attempts in younger persons and therefore the urgent need for early recognition and prevention of this event is necessary. This is the first broad study of its kind in Greece which reflects a segment of the psycho-biosocial developments in this country.

Knee joint injury by mercury from a broken thermometer: case report and review of the literature.

An 11-year-old boy injured the inner side of his left knee when accidentally breaking a mercury thermometer. He immediately developed an acute synovitis. Soft tissues and synovium containing metallic mercury droplets were completely removed at operation. The patient recovered within five weeks. Symptoms and signs of acute or chronic mercury poisoning were not observed. However, because injury by a mercury thermometer may become very serious if the metal is absorbed by the tissues and disseminated through the circulatory system, immediate local excision of tissue is necessary. Interestingly, the histologic appearance of the synovial membrane was remarkable by the lack of any foreign body giant cell reaction.

Effect of ascorbic acid (vitamin C) on the epiphyseal plate of young guinea pigs receiving prednisolone.

The effect of excess ascorbic acid on the epiphyseal plate of young guinea pigs receiving prednisolone over a period of 28 days has been investigated. The results show that the structural and morphologic changes caused in the epiphyseal plate of the animals receiving prednisolone are prevented by the simultaneous administration of excess ascorbic acid. These data are consistent with the hypothesis that pharmacological doses of ascorbic acid given concurrently to children receiving prolonged treatment with corticosteroids may prevent suppression of growth in these children.