The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Left main bronchus resection and reconstruction. A single institution experience

<p>Abstract</p> <p>Background</p> <p>Left main bronchus resection and reconstruction (LMBRR) is a complex surgical procedure indicated for management of inflammatory, benign and low grade malignant lesions. Its application provides maximal parenchymal sparing.</p> <p>Methods</p> <p>Out of 98 bronchoplastic procedures performed at the Authors' Institution in the 1995-2011 period, 4 were LMBRR. Indications were bronchial carcinoid in 2 cases, inflammatory pseudotumor in 1 case, TBC stricture in 1 case. All patients underwent preoperatively a rigid bronchoscopy to restore the airway lumen patency. At surgery a negative resection margin was confirmed by frozen section in the neoplastic patients. In all patients an end-to-end bronchial anastomosis was constructed according to Grillo.</p> <p>Results</p> <p>There were neither mortality nor major complications. Airway lumen was optimal in 3 patients, good in 1.</p> <p>Conclusion</p> <p>LMBRR is a valuable option for the thoracic surgeon. It maximizes the parenchyma-sparing philosophy, broadening the spectrum of potential candidates for cure. It remains a technically demanding procedure, to be carried out by an experienced surgical team. Correct surgical planning affords excellent results, both in the short and long term.</p

Youth’s narratives about family members smoking: parenting the parent- it’s not fair!

<p>Abstract</p> <p>Background</p> <p>Successful cancer prevention policies and programming for youth must be based on a solid understanding of youth’s conceptualization of cancer and cancer prevention. Accordingly, a qualitative study examining youth’s perspectives of cancer and its prevention was undertaken. Not surprisingly, smoking (i.e., tobacco cigarette smoking) was one of the dominant lines of discourse in the youth’s narratives. This paper reports findings of how youth conceptualize smoking with attention to their perspectives on parental and family-related smoking issues and experiences.</p> <p>Methods</p> <p>Seventy-five Canadian youth ranging in age from 11–19 years participated in the study. Six of the 75 youth had a history of smoking and 29 had parents with a history of smoking. Youth were involved in traditional ethnographic methods of interviewing and photovoice. Data analysis involved multiple levels of analysis congruent with ethnography.</p> <p>Results</p> <p>Youth’s perspectives of parents and other family members’ cigarette smoking around them was salient as represented by the theme: <it>It’s not fair.</it> Youth struggled to make sense of why parents would smoke around their children and perceived their smoking as an unjust act. The theme was supported by four subthemes: <it>1) parenting the parent about the dangers of smoking; 2) the good/bad parent; 3) distancing family relationships; and 4) the prisoner</it>. Instead of being <it>talked to</it> about smoking it was more common for youth to share stories of <it>talking to</it> their parents about the dangers of smoking. Parents who did not smoke were seen by youth as the good parent, as opposed to the bad parent who smoked. Smoking was an agent that altered relationships with parents and other family members. Youth who lived in homes where they were exposed to cigarette smoke felt like a trapped prisoner.</p> <p>Conclusions</p> <p>Further research is needed to investigate youth’s perceptions about parental cigarette smoking as well as possible linkages between youth exposed to second hand smoke in their home environment and emotional and lifestyle-related health difficulties. Results emphasize the relational impact of smoking when developing anti-tobacco and cancer prevention campaigns. Recognizing the potential toll that second-hand smoke can have on youth’s emotional well-being, health care professionals are encouraged to give youth positive messages in coping with their parents’ smoking behaviour.</p

A longitudinal study of environmental tobacco smoke exposure in children: Parental self reports versus age dependent biomarkers

<p>Abstract</p> <p>Background</p> <p>Awareness of the negative effects of smoking on children's health prompted a decrease in the self-reporting of parental tobacco use in periodic surveys from most industrialized countries. Our aim is to assess changes between ETS exposure at the end of pregnancy and at 4 years of age determined by the parents' self-report and measurement of cotinine in age related biological matrices.</p> <p>Methods</p> <p>The prospective birth cohort included 487 infants from Barcelona city (Spain). Mothers were asked about maternal and household smoking habit. Cord serum and children's urinary cotinine were analyzed in duplicate using a double antibody radioimmunoassay.</p> <p>Results</p> <p>At 4 years of age, the median urinary cotinine level in children increased 1.4 or 3.5 times when father or mother smoked, respectively. Cotinine levels in children's urine statistically differentiated children from smoking mothers (Geometric Mean (GM) 19.7 ng/ml; 95% CI 16.83–23.01) and exposed homes (GM 7.1 ng/ml; 95% CI 5.61–8.99) compared with non-exposed homes (GM 4.5 ng/ml; 95% CI 3.71–5.48). Maternal self-reported ETS exposure in homes declined in the four year span between the two time periods from 42.2% to 31.0% (p < 0.01). Nevertheless, most of the children considered non-exposed by their mothers had detectable levels of cotinine above 1 ng/mL in their urine.</p> <p>Conclusion</p> <p>We concluded that cotinine levels determined in cord blood and urine, respectively, were useful for categorizing the children exposed to smoking and showed that a certain increase in ETS exposure during the 4-year follow-up period occurred.</p

Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function

BACKGROUND: Neurodegeneration in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against neurodegenerative insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined, mitochondrial dysfunction, including altered calcium homeostasis and Bcl-2 expression, are involved in neurodegenerative vulnerability. RESULTS: In this study, we investigated the mechanism of 17β-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E(2 )pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function. CONCLUSION: Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8&nbsp;% in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat