Keren Cohen

Paclitaxel-clusters coated with hyaluronan as selective tumor-targeted nanovectors

Paclitaxel (PTX) is a widely used anti-tumor agent in the treatment of solid tumors. Lack of selective strategies to target PTX into tumor cells together with poor solubility necessitating detergent, are severe clinical limitations. To address these hurdles, we devised a strategy that utilized PTX insolubility, mixing it with lipids that self-assemble into nanoparticle-like clusters. These clusters were then coated with hyaluronan, a glycosaminoglycan (GAG), and termed PTX-GAGs. These particles, delivered PTX selectively into tumor cells in a CD44-dependent manner. Injected systemically to mice bearing solid tumors, the PTX-GAGs showed high safety profile and tumor accumulation. Tumor progression was exponential upon treatment with free PTX or PTX in albumin nanoparticles (the FDA-approved Taxol and Abraxane, respectively). Under the same conditions, PTX-GAGs induced tumor arrest and were as potent as a 4-fold higher Taxol dose. Our findings suggest GAGs merit further investigation as vehicles for taxanes, and may be applicable as carriers in other therapeutic settings.

Theories of Posttraumatic Growth: Cross-Cultural Perspectives

Posttraumatic growth is a concept that has been established within a Western cultural framework. This review examines whether there is a Western cultural bias in this concept, and related processes and outcomes, and whether any cultural bias has been incorporated into associated psychometric tools. It is concluded that, although at an abstract level the concept of posttraumatic growth appears cross-culturally valid, the operationalization of the concept may serve to impose assumptions of a Western individualistic society. The impact of this for the emerging cross-cultural literature on posttraumatic growth is discussed, alongside recommendations for future research.

Reviewing evidence for the cognitive model of auditory hallucinations: The relationship between cognitive voice appraisals and distress during psychosis

Individuals who hear voices during psychosis may be vulnerable to increased distress. Cognitive models place emphasis on the role of subjective and cognitive appraisals of voices in influencing different emotional reactions. This paper systematically reviewed literature investigating the relationship between appraisals of voices and distress. The review included 26 studies, published between 1990 and 2008. Several types of appraisals were found to be linked to higher levels of distress in voice hearers, including voices appraised as malevolent, voices appraised as high in supremacy, voices appraised to have personal acquaintance with the individual, and attitudes of disapproval and rejection towards voices. However, results from cognitive therapy trials did not consistently report significant improvements in voice related distress post-intervention. One explanation for this finding is that mediating variables, such as social schemata, exist within the appraisal-distress relationship, variables which were not targeted in the cognitive therapy trials. Areas for future investigation may include developing a greater understanding of mediating variables, such as social schemata, within the appraisal-distress relationship, carrying out interventions aimed at addressing these mediating variables using randomized controlled trial designs, and understanding the relationship between positive affect and voice appraisals.

Vicarious Posttraumatic Growth Among Interpreters

An emerging evidence base indicates that posttraumatic growth might be experienced vicariously by those working alongside trauma survivors. In this study we explored the vicarious experiences of eight interpreters working in a therapeutic setting with asylum seekers and refugees. We adopted a qualitative approach, using semistructured interviews and interpretative phenomenological analysis. Four interrelated themes emerged from the findings: feeling what your client feels, beyond belief, finding your own way to deal with it, and a different person. Although all participants experienced distress, they also perceived themselves to have grown in some way. The implications for a theory of vicarious posttraumatic growth are discussed, along with clinical applications.

Thyroid Hormone Is a MAPK-Dependent Growth Factor for Human Myeloma Cells Acting via αvβ3 Integrin

Experimental and clinical observations suggest that thyroid hormone [l-thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3)] can support cancer cell proliferation. T3 and T4 promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the αvβ3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several MM cell lines to T3 and T4 and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T3 (1–100 nmol/L) and T4 (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), MM cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T3 and T4 increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T3 and T4. Antibodies to the integrin αvβ3 dimer and αv and β3 monomers (but not β1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T4 analogue previously shown to selectively block T3/T4 binding to αvβ3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for MM cells may offer novel therapeutic approaches. Mol Cancer Res; 9(10); 1385–94. ©2011 AACR.

BurnEd: parental, psychological and social factors influencing a burn-injured child's return to education.

Childhood burns are painful and traumatic and impact the child and their family. For the child, part of the returning to wellness process involves successfully returning to school, a process in which parents play a vital role. This qualitative research aimed to examine how influential parental and other factors were in the return to school process. Data was collected through semi-structured interviews and was analysed using a social-constructivist Grounded Theory approach. The analysis revealed that parental confidence-in themselves, their children and their childrens schools; role adaptation, skill acquisition and flexibility; and school receptivity, were pivotal in the return to school process.

Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4 -related deafness

Thyroid hormone is essential for inner ear development and is required for auditory system maturation. Human mutations in SLC26A4 lead to a syndromic form of deafness with enlargement of the thyroid gland (Pendred syndrome) and non-syndromic deafness (DFNB4). We describe mice with an Slc26a4 mutation, Slc26a4loop/loop, which are profoundly deaf but show a normal sized thyroid gland, mimicking non-syndromic clinical signs. Histological analysis of the thyroid gland revealed defective morphology, with a majority of atrophic microfollicles, while measurable thyroid hormone in blood serum was within the normal range. Characterization of the inner ear showed a spectrum of morphological and molecular defects consistent with inner ear pathology, as seen in hypothyroidism or disrupted thyroid hormone action. The pathological inner ear hallmarks included thicker tectorial membrane with reduced β-tectorin protein expression, the absence of BK channel expression of inner hair cells, and reduced inner ear bone calcification. Our study demonstrates that deafness in Slc26a4loop/loop mice correlates with thyroid pathology, postulating that sub-clinical thyroid morphological defects may be present in some DFNB4 individuals with a normal sized thyroid gland. We propose that insufficient availability of thyroid hormone during inner ear development plays an important role in the mechanism underlying deafness as a result of SLC26A4 mutations.

Caloric restriction ameliorates cardiomyopathy in animal model of diabetes

Background: The db/db mouse is an animal model of diabetes in which leptin receptor activity is deficient resulting accelerated cardiomyopathy when exposed to angiotensin (AT). Toll‐like receptors 4 and 2 (TLR4, TLR2) are pattern recognition receptors, that recognize pathogen‐associated molecular patterns and exacerbate and release inflammatory cytokines. Fetuin A (Fet A) is a fatty acid carrier which affects inflammation and insulin resistance in obese humans and animals through TLRs. The aim of this study was to investigate the effect of caloric restriction (CR) on free fatty acids (FFA) level and the inflammatory response in diabetic cardiomyopathy. Methods and results: Left ventricular hypertrophy, increased fibrosis and leukocytes infiltration were observed in db/db AT treated hearts. Serum glucose, FFA, and cholesterol levels were elevated in db/db AT treated mice. Cardiac expression of PPAR&agr; increased while AKT phosphorylation was decreased. Conclusions: Cumulatively, CR elevated cardiac PPAR&agr; improved the utilization of fatty acids, and reduced myocardial inflammation as seen by reduced levels of Fet A. Thus CR negated cardiomyopathy associated with AT in an animal model of diabetes suggesting that CR is an effective therapeutic approach in the treatment of diabetes and associated cardiomyopathy.

Incidence and Expression of Circulating Cell Free p53-Related Genes in Acute Myocardial Infarction Patients

AIM The circulating RNA levels are predictive markers in several diseases. We determined the levels of circulating p53-related genes in patients with acute ST-segment elevation myocardial infarction (STEMI), indicating major heart muscle damage. METHODS Plasma RNA was extracted from the patients (n=45) upon their arrival to the hospital (STEMI 0h) and at four hours post-catheterization (STEMI 4h) as well as from controls (n=34). RESULTS Of 18 circulating p53-related genes, nine genes were detectable. A significantly lower incidence of circulating p21 (p ＜ 0.0001), Notch1 (p=0.042) and BTG2 (p ＜ 0.0001) was observed in the STEMI 0h samples in comparison to the STEMI 4h and control samples. Lower expression levels (2.1-fold) of circulating BNIP3L (p=0.011), p21 (3.4-fold, p=0.005) and BTG2 (6.3-fold, p=0.0001) were observed in the STEMI 0h samples in comparison to the STEMI 4h samples, with a 7.4-fold lower BTG2 expression (p ＜ 0.001) and 2.6-fold lower p21 expression (p=0.034) compared to the control samples. Moreover, the BNIP3L expression (borderline significance, p=0.0655) predicted the level of peak troponin, a marker of myocardial infarction. In addition, the BNIP3L levels on admission (p=0.0025), at post-catheterization (p=0.020) and the change between the groups (p=0.0079) were inversely associated with troponin. The BNIP3L (p=0.0139) and p21 levels (p=0.0447) were also associated with a longer time to catheterization. CONCLUSIONS Our results suggest that circulating downstream targets of p53 are inhibited during severe AMI and subsequently re-expressed after catheterization, uncovering possible novel death-or-survival decisions regarding the fate of p53 in the heart and the potential use of its target genes as prognostic biomarkers for oxygenation normalization.

A pilot study evaluating care staffs’ perceptions of their experience of psychological consultation within a mental health setting

The aim of this study was to conduct a preliminary evaluation of a mental health consultation process provided to staff working in residential care settings for young people. Using a semi-structured interview approach, qualitative information was gathered from six participants about their experiences of the consultation. A thematic analysis of the interviews generated four key themes, which appear to reflect the different stages of consultation. These included: initiating consultation; building the consultative relationship; overcoming obstacles; and seeing the value of consultation. These themes, along with prevalent sub-themes, are discussed with reference to the effectiveness of the consultation process and the implications for use of psychological consultation in clinical practice. Implications for future practice include providing information to potential consultees before the consultation process, being accessible informally to the consultee and adopting a variety of approaches based on the consultees needs. The limitations of this study and recommendations for future research are also discussed.