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See detailTargeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab.
Chen, Gang; Kronenberger, Peter; Teugels, Erik et al

in BMC Medicine (2012), 10

BACKGROUND: The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal ... [more ▼]

BACKGROUND: The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs) or a monoclonal antibody cetuximab. METHODS: NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index. RESULTS: EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines. Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic. The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines, independent of the EGFR mutation status (wild-type or sensitizing mutation or resistant mutation). The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA. CONCLUSIONS: EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone, confirming that single agent drug targeting does not achieve a maximal biological effect. The siRNA inhibits EGFR oncogenic activity that bypasses downstream "resistance" mutations such as KRAS and PTEN. The combined treatment of siRNA and EGFR inhibitory agents is additive. The combination of a potent, irreversible kinase inhibitor such as afatinib, with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers, including those with downstream resistance mutations. [less ▲]

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See detailMuscle: a source of progenitor cells for bone fracture healing.
Henrotin, Yves ULg

in BMC Medicine (2011), 9

Bone repair failure is a major complication of open fracture, leading to non-union of broken bone extremities and movement at the fracture site. This results in a serious disability for patients. The role ... [more ▼]

Bone repair failure is a major complication of open fracture, leading to non-union of broken bone extremities and movement at the fracture site. This results in a serious disability for patients. The role played by the periosteum and bone marrow progenitors in bone repair is now well documented. In contrast, limited information is available on the role played by myogenic progenitor cells in bone repair. In a recent article published in BMC Musculoskeletal Disorders, Liu et al. compared the presence of myogenic progenitor (MyoD lineage cells) in closed and open fractures. They showed that myogenic progenitors are present in open, but not closed fractures, suggesting that muscle satellite cells may colonize the fracture site in the absence of intact periosteum. Interestingly, these progenitors sequentially expressed a chondrogenic and, thereafter, an osteoblastic phenotype, suggestive of a functional role in the repair process. This finding opens up new perspectives for the research of orthopedic surgical methods, which could maximize myogenic progenitor access and mobilization to augment bone repair. Please see related article: http://www.biomedcentral.com/1471-2474/12/288. [less ▲]

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See detailUnresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome.
Laureys, Steven ULg; Celesia, Gastone G; Cohadon, Francois et al

in BMC Medicine (2010), 8

BACKGROUND: Some patients awaken from coma (that is, open the eyes) but remain unresponsive (that is, only showing reflex movements without response to command). This syndrome has been coined vegetative ... [more ▼]

BACKGROUND: Some patients awaken from coma (that is, open the eyes) but remain unresponsive (that is, only showing reflex movements without response to command). This syndrome has been coined vegetative state. We here present a new name for this challenging neurological condition: unresponsive wakefulness syndrome (abbreviated UWS). DISCUSSION: Many clinicians feel uncomfortable when referring to patients as vegetative. Indeed, to most of the lay public and media vegetative state has a pejorative connotation and seems inappropriately to refer to these patients as being vegetable-like. Some political and religious groups have hence felt the need to emphasize these vulnerable patients' rights as human beings. Moreover, since its first description over 35 years ago, an increasing number of functional neuroimaging and cognitive evoked potential studies have shown that physicians should be cautious to make strong claims about awareness in some patients without behavioral responses to command. Given these concerns regarding the negative associations intrinsic to the term vegetative state as well as the diagnostic errors and their potential effect on the treatment and care for these patients (who sometimes never recover behavioral signs of consciousness but often recover to what was recently coined a minimally conscious state) we here propose to replace the name. CONCLUSION: Since after 35 years the medical community has been unsuccessful in changing the pejorative image associated with the words vegetative state, we think it would be better to change the term itself. We here offer physicians the possibility to refer to this condition as unresponsive wakefulness syndrome or UWS. As this neutral descriptive term indicates, it refers to patients showing a number of clinical signs (hence syndrome) of unresponsiveness (that is, without response to commands) in the presence of wakefulness (that is, eye opening). [less ▲]

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See detailVaricella vaccination in Europe – taking the practical approach
Bonanni, Paolo; Breuer, Judith; Gershon, Anne A. et al

in BMC Medicine (2009), 7(26), 1-38

Varicella is a common viral disease affecting almost the entire birth cohort. Although usually self-limiting, some cases of varicella can be serious, with 2 to 6% of cases attending a general practice ... [more ▼]

Varicella is a common viral disease affecting almost the entire birth cohort. Although usually self-limiting, some cases of varicella can be serious, with 2 to 6% of cases attending a general practice resulting in complications. The hospitalisation rate for varicella in Europe ranges from 1.3 to 4.5 per 100,000 population/year and up to 10.1% of hospitalised patients report permanent or possible permanent sequelae (for example, scarring or ataxia). However, in many countries the epidemiology of varicella remains largely unknown or incomplete. In countries where routine childhood vaccination against varicella has been implemented, it has had a positive effect on disease prevention and control. Furthermore, mathematical models indicate that this intervention strategy may provide economic benefits for the individual and society. Despite this evidence and recommendations for varicella vaccination by official bodies such as the World Health Organization, and scientific experts in the field, the majority of European countries (with the exception of Germany and Greece) have delayed decisions on implementation of routine childhood varicella vaccination, choosing instead to vaccinate high-risk groups or not to vaccinate at all. In this paper, members of the Working Against Varicella in Europe group consider the practicalities of introducing routine childhood varicella vaccination in Europe, discussing the benefits and challenges of different vaccination options (vaccination vs. no vaccination, routine vaccination of infants vs. vaccination of susceptible adolescents or adults, two doses vs. one dose of varicella vaccine, monovalent varicella vaccines vs. tetravalent measles, mumps, rubella and varicella vaccines, as well as the optimal interval between two doses of measles, mumps, rubella and varicella vaccines). Assessment of the epidemiology of varicella in Europe and evidence for the effectiveness of varicella vaccination provides support for routine childhood programmes in Europe. Although European countries are faced with challenges or uncertainties that may have delayed implementation of a childhood vaccination programme, many of these concerns remain hypothetical and with new opportunities offered by combined measles, mumps, rubella and varicella vaccines, reassessment may be timely. In countries where routine childhood vaccination against varicella has been implemented, it has had a positive effect on disease prevention and control. Furthermore, mathematical models indicate that this intervention strategy may provide economic benefits for the individual and society. Despite this evidence and recommendations for varicella vaccination by official bodies such as the World Health Organization, and scientific experts in the field, the majority of European countries (with the exception of Germany and Greece) have delayed decisions on implementation of routine childhood varicella vaccination, choosing instead to vaccinate high-risk groups or not to vaccinate at all. In this paper, members of the Working Against Varicella in Europe group consider the practicalities of introducing routine childhood varicella vaccination in Europe, discussing the benefits and challenges of different vaccination options (vaccination vs. no vaccination, routine vaccination of infants vs. vaccination of susceptible adolescents or adults, two doses vs. one dose of varicella vaccine, monovalent varicella vaccines vs. tetravalent measles, mumps, rubella and varicella [MMRV] vaccines, as well as the optimal interval between two doses of MMRV vaccines). Assessment of the epidemiology of varicella in Europe and evidence for the effectiveness of varicella vaccination provides support for routine childhood programmes in Europe. Although European countries are faced with challenges or uncertainties that may have delayed implementation of a childhood vaccination programme, many of these concerns remain hypothetical and with new opportunities offered by combined MMRV vaccines, reassessment may be timely. [less ▲]

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