A phase i study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates

Background

Defects in skin barrier function are associated with an increase risk of eczema and atopic sensitisation. Ceramide-dominant triple lipid mixture may improve and maintain the infant skin barrier function, and if shown to be safe and feasible, may therefore offer an effective approach to reduce the incidence of eczema and subsequent atopic sensitisation. We sort to assess the safety and compliance with daily application of a ceramide-dominant triple lipid formula (EpiCeram?) commencing in the neonatal period for the prevention of eczema.

Methods

Ten infants (0-4 weeks of age) with a family history of allergic disease were recruited into an open-label, phase one trial of daily application of EpiCeram? for six weeks. The primary outcomes were rate of compliance and adverse events. Data on development of eczema, and physiological properties of the skin (transepidermal water loss, hydration, and surface pH) were also measured.

Results

Eighty percent (8/10) of mothers applied the study cream on 80% or more of days during the six week intervention period. Though a number of adverse events unrelated to study product were reported, there were no adverse skin reactions to the study cream.

Conclusions

These preliminary results support the safety and parental compliance with daily applications of a ceramide-dominant formula for the prevention of eczema, providing the necessary ground work for a randomised clinical trial to evaluate EpiCeram? for the prevention of eczema.

Trial registration

The study was listed at the Australian/New Zealand Clinical Trial Registry (ANZCTR): reg. no. ACTRN12609000727246.     

Employment and self-management: a meta-evaluation of seven literature reviews

Efforts focused on teaching individuals with intellectual disabilities to manage their own affairs have evolved over the past 30 years. Self-management strategies, in particular, hold much promise when the goal is to promote self-determination. In this article, the authors describe trends in the evolution of self-management strategies by analyzing seven literature reviews. The authors conclude with thoughts related to jump-starting an intervention that has appeared to lose momentum, namely, self-management.     

Successful Treatment of Esophageal Cancer with Airway Invasion with Induction Chemotherapy and Concurrent Chemoradiotherapy

Esophageal cancer with airway invasion with or without fistula presents a challenging therapeutic dilemma with no standard therapy. Recent studies in Japan have focused on the use of definitive chemoradiotherapy. However, this approach is associated with significant treatment-related morbidity and mortality. We present a case report of a patient with thoracic esophageal squamous cell carcinoma with bronchial invasion who was treated to a clinical complete response with induction chemotherapy followed by consolidation with concurrent chemoradiotherapy. The patient also underwent restaging with a positron emission tomography scan after induction chemotherapy. Such a staged approach may reduce the morbidity of upfront radiation. The use of an interim positron emission tomography scan may also identify early treatment failure.     

Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma

Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non-small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal-regulated kinase (ERK)-1/2 in human 293T cells and to growth factor-independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma.     

Multiple high-grade bronchial dysplasia and squamous cell carcinoma: concordant and discordant mutations.

Loss of heterozygosity (LOH) involving chromosomes 3p, 5q, 9p, or 17p and aberrant expression or mutation of p53 are reported previously in selected bronchial dysplasias and squamous cell cancers (SCCs). Yet, comprehensive analyses of LOH patterns at these chromosomal sites and of p53 alterations are not reported for histologically normal bronchial epithelium, high-grade bronchial dysplasia, and SCC present in the same pulmonary resections. Whether concordant or discordant genetic changes are detected in these bronchial tissues, especially when multiple high-grade dysplastic bronchial lesions are present, was studied. Genomic DNA was microdissected from eight pulmonary SCCs and high-grade dysplastic lesions that were associated with SCC. In four cases, two independent high-grade dysplastic bronchial lesions were identified. When available, histologically normal bronchial epithelium was microdissected. Germ-line genomic DNA was isolated from normal lymph nodes. LOH was assessed for 15 microsatellite markers on chromosomes 3p, 5q, 9p, or 17p, sites frequently deleted in lung cancers. Immunohistochemical p53 expression was studied and correlated with p53 DNA sequence analyses. Progressive LOH for these markers was found when SCCs were compared with high-grade dysplasia and histologically normal bronchial epithelium present in the same resections. Histologically normal bronchial specimens had LOH in up to 27% of informative markers. High-grade dysplastic lesions exhibited LOH for 18-45% and SCC had LOH for 18-73% of the markers. Common regions of LOH were found in some dysplasias compared with SCCs. In other dysplasias, discordance was found relative to SCCs, especially for p53 mutations. In cases with a single or second high-grade dysplasia associated with SCC, heterogeneity in LOH markers was detected. These concordant and discordant changes were consistent with convergent and divergent clonal selection pathways in pulmonary squamous cell carcinogenesis. Some histologically normal bronchial epithelial tissues had genetic changes more similar to those in the SCCs than in dysplastic lesions. DNA loss or mutations accumulate in SCC, but discordant genetic changes can exist in the same carcinogen-exposed bronchial tissues. These findings have implications for lung cancer prevention trials.     

RAGE interacts with the necroptotic protein RIPK3 and mediates transfusion-induced danger signal release

RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage-associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC transfusion. Mounting evidence implicates the pro-inflammatory pattern recognition receptor, Receptor for Advanced Glycation End Products (RAGE), in initiating cell death programmes such as necroptosis. Here, we demonstrate the role of RAGE in endothelial necroptosis, as deletion of RAGE attenuates necroptotic cell death in response to TNFα, LPS or CpG-DNA. We show direct interaction of RAGE with the critical mediator of necroptosis, Receptor Interacting Protein Kinase 3 (RIPK3), during necroptosis. Furthermore, we observe decreased plasma High Mobility Group Box 1 (HMGB1) and RIPK3 levels in RAGE deficient mice compared to WT mice post-transfusion, substantiating the role for RAGE in transfusion-induced DAMP release in vivo. Collectively, these findings underscore RAGE as an essential mediator of regulated necrosis and post-transfusion DAMP release. Further studies to understand the role of RAGE and the necroptotic pathway in transfusion-induced organ injury may offer key targets to mitigate transfusion-related risks, including the risk of ARDS, in susceptible hosts.     

Effects of Three Consecutive Days of Morphine or Methadone Administration on Analgesia and Open-Field Activity in Mice with Ehrlich Carcinoma

This study assessed the exploratory behavioral responses in BALB/c mice inoculated with Ehrlich ascitic carcinoma after 3 consecutive days of treatment with morphine or methadone. Fifty-three female mice, 60 ± 10 d old, were used. Seven days after intraperitoneal tumor inoculation (2 × 10⁶ cells), the animals were randomized into 7 groups: morphine 5 mg/kg (MO₅), morphine 7.5 mg/kg (MO_7.5), morphine 10 mg/kg (MO₁₀), methadone 2.85 mg/kg (ME_2.85), methadone 4.3 mg/kg (ME_4.3), methadone 5.7 mg/kg (ME_5.7), and 0.9% NaCl (Saline) (n = 7). Drug treatments were administered subcutaneously every 6 h for 3 d. The animals were evaluated for analgesia using the mouse grimace scale (MGS) and for general activity using the open field test. The MGS was performed before tumor inoculation (day 0), on day 7 at 40, 90, 150, 240, and 360 min after drug injection, and on days 8 and 9 at 40, 150, 240, and 360 min after drug injection. The open field test was performed before tumor inoculation (day 0), on day 7 after inoculation at 40, 90, 150, 240, and 360 min after drug injection, and on days 8 and 9 after inoculation at 40, 150, and 360 min after drug injection. MGS results indicated that administration of morphine promoted analgesia for up to 240 min. Conversely, methadone reduced MGS scores only at 40 min. All tested doses promoted a significant dose-dependent increase in the total distance traveled and the average speed, and increase that was markedly pronounced on days 8 and 9 as compared with day 7. The frequencies of rearing and self-grooming decreased significantly after morphine or methadone administration. Despite the difference in analgesia, both drugs increased locomotion and reduced the frequency of rearing and self-grooming as compared with the untreated control animals.

Ehrlich carcinoma is a well-known transplantable tumor in which cells from mammary adenocarcinoma are inoculated subcutaneously or intraperitoneally, and grow into either solid or ascitic tumors, respectively.^6,8 This tumor is considered to cause pain yet is widely used to determine the influence of drugs and other therapeutic substances on the inhibition of tumor growth.^23,27,33 The ascitic form of Ehrlich carcinoma is characterized by a proinflammatory response induced by tumor cells in the peritoneum and increased vascular permeability.⁴¹ Tumor cells promote a progressive increase in the secretion of interleukin-1β (IL1β),¹⁶ monocyte chemoattractant protein-1 (MCP-1)⁵⁴ and prostaglandin E2 (PGE-2),²⁸ substances all related to the phenomenon of hyperalgesia.¹⁵Recognition and management of pain are an important component of international standards designed to ensure the welfare of research animals. These factors are closely related to the survival and quality of life.^34,55 Although a test to directly measure pain in animals is currently unavailable, changes in behavioral patterns can indicate pain (for example, agitation, reduced ambulation, and changes in the sequence and frequency of self-grooming and vocalization).⁹ Opioid analgesics, such as morphine and methadone, although frequently regarded as the most effective treatment of cancer pain,^12,38,53 tend to alter locomotor activity and exploratory behavior in mice.^22,43,47 Although morphine alters behavioral patterns, it does not interfere with facial expression in the absence of pain.³⁰Morphine is a potent opioid that acts mainly through the occupation of pre- and postsynaptic µ-opioid receptors, which modulate the perception of pain.⁵² Methadone has affinity for µ-receptors, is also an antagonist of N-methyl-D-Aspartate receptors (NMDA), and is considered an ideal treatment choice in cases of tolerance to morphine.²⁰ The condition of cancer pain requires long-term analgesic treatment. However, some disagreement remains regarding the optimal doses and frequency of administration of morphine and methadone in mice, and few studies have evaluated the effects of these drugs on cancer pain in mice or the effect of long-term administration.^35,39,43,46The current study aimed to evaluate the analgesic effect of morphine and methadone in BALB/c mice with Ehrlich ascitic carcinoma by observing the influence of these opioids on behavior. The hypothesis was that morphine and methadone would provide analgesia and mitigate pain-related behavioral changes in mice with Ehrlich ascitic carcinoma in a dose-dependent manner.     

How Effective Is Neoadjuvant Therapy Followed by Surgery for Pathologic Single-Station N2 Non–Small Cell Lung Cancer?

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Morphologie

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