Optimising cardiovascular care of patients with multiple myeloma

Multiple myeloma (MM) is the third most common haematological malignancy, with increasing prevalence over recent years. Advances in therapy have improved survival, changing the clinical course of MM into a chronic condition and meaning that management of comorbidities is fundamental to improve clinical outcomes. Cardiovascular (CV) events affect up to 7.5% of individuals with MM, due to a combination of patient, disease and treatment-related factors and adversely impact survival. MM typically affects older people, many with pre-existing CV risk factors or established CV disease, and the disease itself can cause renal impairment, anaemia and hyperviscosity, which exacerabate these further. Up to 15% of patients with MM develop systemic amyloidosis, with prognosis determined by the extent of cardiac involvement. Management of MM generally involves administration of multiple treatment lines over several years as disease progresses, with many drug classes associated with adverse CV effects including high rates of venous and arterial thrombosis alongside heart failure. Recommendations for holistic management of patients with MM now include routine baseline risk stratification including ECG and echocardiography and administration of thromboprophylaxis drugs for patients treated with immunomodulatory drugs. Close surveillance of high-risk patients with collaboration between haematology and cardiology is required, with prompt investigation in the event of CV symptoms, in order to identify and treat complications early. Decisions regarding discontinuation of cardiotoxic therapies should be made in a multidisciplinary setting, taking into account the severity of the complication, prognosis, expected benefits and the availability of effective alternatives

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Three- dimensional assessment of craniofacial asymmetry in children with transverse maxillary deficiency after rapid maxillary expansion: A prospective study

ObjectiveThe aim of this study was to evaluate craniofacial asymmetry in children with transverse maxillary deficiency, with or without functional unilateral posterior crossbite (UPC), before and after rapid maxillary expansion (RME).Setting and sample populationA sample of 51 children with cone beam computed tomography scans obtained before RME (T1) and a year after RME (T2).Material and methodsThis prospective study consisted of 2 groups: 25 children with functional UPC (6.77 ± 1.5 years) and 26 children without UPC (7.41 ± 1.31 years). Linear and angular measurements were obtained from zygomatic, maxilla, glenoid fossa and mandible, using original and mirrored 3D overlapped models. All right and left side comparisons in both groups and intergroups asymmetries were compared using MANOVA and t test for independent samples, respectively, statistically significant at P < .05.ResultsThe UPC group showed no side differences, but mandibular horizontal rotation at T1, and this asymmetry was improved in T2. The non- UPC group showed at baseline significant lateral asymmetry in orbitale, position of palatine foramen, respectively, in average 2.95 mm and 1.16 mm, and 0.49 mm of average asymmetry in condylar height. The glenoid fossa was symmetric in both groups at T1 and T2.ConclusionsChildren with transverse maxillary deficiency showed slight morphological asymmetry, located in the mandible position in cases of UPC, and in the orbital and maxillary regions in cases without UPC. One year after RME, patients improved their craniofacial asymmetry, with significant changes in the mandible and correction of the mandibular rotation in patients who presented UPC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156195/2/ocr12370_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156195/1/ocr12370.pd

The interaction between a sexually transferred steroid hormone and a female protein regulates oogenesis in the malaria mosquito anopheles gambiae

Molecular interactions between male and female factors during mating profoundly affect the reproductive behavior and physiology of female insects. In natural populations of the malaria mosquito Anopheles gambiae, blood-fed females direct nutritional resources towards oogenesis only when inseminated. Here we show that the mating-dependent pathway of egg development in these mosquitoes is regulated by the interaction between the steroid hormone 20-hydroxy-ecdysone (20E) transferred by males during copulation and a female Mating-Induced Stimulator of Oogenesis (MISO) protein. RNAi silencing of MISO abolishes the increase in oogenesis caused by mating in blood-fed females, causes a delay in oocyte development, and impairs the function of male-transferred 20E. Co-immunoprecipitation experiments show that MISO and 20E interact in the female reproductive tract. Moreover MISO expression after mating is induced by 20E via the Ecdysone Receptor, demonstrating a close cooperation between the two factors. Male-transferred 20E therefore acts as a mating signal that females translate into an increased investment in egg development via a MISO-dependent pathway. The identification of this male–female reproductive interaction offers novel opportunities for the control of mosquito populations that transmit malaria

High connectivity of the Crocodile Shark between the Atlantic and Southwest Indian Oceans: highlights for conservation

Among the various shark species that are captured as bycatch in commercial fishing operations, the group of pelagic sharks is still one of the least studied and known. Within those, the crocodile shark, Pseudocarcharias kamoharai, a small-sized lamnid shark, is occasionally caught by longline vessels in certain regions of the tropical oceans worldwide. However, the population dynamics of this species, as well as the impact of fishing mortality on its stocks, are still unknown, with the crocodile shark currently one of the least studied of all pelagic sharks. Given this, the present study aimed to assess the population structure of P. kamoharai in several regions of the Atlantic and Indian Oceans using genetic molecular markers. The nucleotide composition of the mitochondrial DNA control region of 255 individuals was analyzed, and 31 haplotypes were found, with an estimated diversity Hd = 0.627, and a nucleotide diversity pi = 0.00167. An analysis of molecular variance (AMOVA) revealed a fixation index phi(ST) = -0.01118, representing an absence of population structure among the sampled regions of the Atlantic Ocean, and between the Atlantic and Indian Oceans. These results show a high degree of gene flow between the studied areas, with a single genetic stock and reduced population variability. In panmictic populations, conservation efforts can be concentrated in more restricted areas, being these representative of the total biodiversity of the species. When necessary, this strategy could be applied to the genetic maintenance of P. kamoharai.Foundation for Research Support of the Sao Paulo State - FAPESP [2011/23787-0, 2010/51903-2]; Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/93936/2013]; Foundation for Research Support of the Sao Paulo State - FAPESP [2011/23787-0, 2010/51903-2]; Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/93936/2013]info:eu-repo/semantics/publishedVersio