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Sporadic cancer develops from the accrual of somatic mutations. Out of all small-scale somatic aberrations in coding regions, 95% are base substitutions, with 90% being missense mutations. While multiple studies focused on the importance of this mutation type, a machine learning method based on the number of protein-protein interactions (PPIs) has not been fully explored. This study aims to develop an improved computational method for driver identification, validation and evaluation (DRIVE), which is compared to other methods for assessing its performance. DRIVE aims at distinguishing between driver and passenger mutations using a feature-based learning approach comprising two levels of biological classification for a pan-cancer assessment of somatic mutations. Gene-level features include the maximum number of protein-protein interactions, the biological process and the type of post-translational modifications (PTMs) while mutation-level features are based on pathogenicity scores. Multiple supervised classification algorithms were trained on Genomics Evidence Neoplasia Information Exchange (GENIE) project data and then tested on an independent dataset from The Cancer Genome Atlas (TCGA) study. Finally, the most powerful classifier using DRIVE was evaluated on a benchmark dataset, which showed a better overall performance compared to other state-of-the-art methodologies, however, considerable care must be taken due to the reduced size of the dataset. DRIVE outlines the outstanding potential that multiple levels of a feature-based learning model will play in the future of oncology-based precision medicine.

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2 -/- Vav3 -/- Tiam1 -/- ), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it., (© 2016 The authors.)

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone Morphogenic Protein 2 (BMP2) is a multipurpose cytokine, important in the development of bone and cartilage, and with a role in tumour initiation and progression. BMP2 signal transduction is dependent on two distinct classes of serine/threonine kinase known as the type I and type II receptors. Although the type I receptors (BMPR1A and BMPR1B) are largely thought to have overlapping functions, we find tissue and cellular compartment specific patterns of expression, suggesting potential for distinct BMP2 signalling outcomes dependent on tissue type. Herein, we utilise large publicly available datasets from The Cancer Genome Atlas (TCGA) and Protein Atlas to define a novel role for BMP2 in the progression of dedifferentiated liposarcomas. Using disease free survival as our primary endpoint, we find that BMP2 confers poor prognosis only within the context of high BMPR1A expression. Through further annotation of the TCGA sarcoma dataset, we localise this effect to dedifferentiated liposarcomas but find overall BMP2/BMP receptor expression is equal across subsets. Finally, through gene set enrichment analysis we link the BMP2/BMPR1A axis to increased transcriptional activity of the matrisome and general extracellular matrix remodelling. Our study highlights the importance of continued research into the tumorigenic properties of BMP2 and the potential disadvantages of recombinant human BMP2 (rhBMP2) use in orthopaedic surgery. For the first time, we identify high BMP2 expression within the context of high BMPR1A expression as a biomarker of disease relapse in dedifferentiated liposarcomas.

Background: Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing., Methods: Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci., Results: We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma., Conclusion: With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner.

Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non-cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed., (©2015 American Association for Cancer Research.)

Modern medicine faces a growing crisis as demand for organ transplantations continues to far outstrip supply. By stimulating the body's own repair mechanisms, regenerative medicine aims to reduce demand for organs, while the closely related field of tissue engineering promises to deliver "off-the-self" organs grown from patients' own stem cells to improve supply. To deliver on these promises, we must have reliable means of generating complex tissues. Thus far, the majority of successful tissue engineering approaches have relied on macroporous scaffolds to provide cells with both mechanical support and differentiative cues. In order to engineer complex tissues, greater attention must be paid to nanoscale cues present in a cell's microenvironment. As the extracellular matrix is capable of driving complexity during development, it must be understood and reproduced in order to recapitulate complexity in engineered tissues. This review will summarize current progress in engineering complex tissue through the integration of nanocomposites and biomimetic scaffolds.

The differentiation of progenitor cells is dependent on more than biochemical signalling. Topographical cues in natural bone extracellular matrix guide cellular differentiation through the formation of focal adhesions, contact guidance, cytoskeletal rearrangement and ultimately gene expression. Osteoarthritis and a number of bone disorders present as growing challenges for our society. Hence, there is a need for next generation implantable devices to substitute for, or guide, bone repair in vivo. Cellular responses to nanometric topographical cues need to be better understood in vitro in order to ensure the effective and efficient integration and performance of these orthopedic devices. In this study, the FDA-approved plastic polycaprolactone was embossed with nanometric grooves and the response of primary and immortalized osteoprogenitor cells observed. Nanometric groove dimensions were 240 nm or 540 nm deep and 12.5 μm wide. Cells cultured on test surfaces followed contact guidance along the length of groove edges, elongated along their major axis and showed nuclear distortion; they formed more focal complexes and lower proportions of mature adhesions relative to planar controls. Down-regulation of the osteoblast marker genes RUNX2 and BMPR2 in primary and immortalized cells was observed on grooved substrates. Down-regulation appeared to directly correlate with focal adhesion maturation, indicating the involvement of ERK 1/2 negative feedback pathways following integrin-mediated FAK activation., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to examine different protocols with regard to the presentation of music stimuli and compare gender differential reactions to those stimuli. Subjects for this study (N = 63) were premature infants in the Neonatal Intensive Care Unit (NICU) between the gestational ages of 28 and 33 weeks. Half of the experimental infants listened to 20 mins of lullaby music (female voice with orchestral background) on 2 days followed by 20 mins of classical music (Mozart string music) on 2 days. The other half listened to the same music in the reverse order. One quarter of the males and one quarter of the females listened to music presented at an average of 65 dB, one quarter at an average of 70 dB, one quarter at an average of 75 dB, and one quarter did not listen to any music and served as control subjects. Head circumference data were collected four times by the researcher: (a) upon receipt of parental consent, (b) on the first day of music presentation (1 week after consent), (c) on the last day of music presentation, and (d) 1 week after music presentation. Physiological data (heart rate, respiratory rate, oxygen saturation) were recorded by the researcher at 2-minute intervals starting 4 minutes prior to and ending 4 minutes after music presentation. There was a significant difference (p < .0001) in average daily head growth across time, but this seems unrelated to the music condition as the same curvilinear trend (larger gain during days of treatment, smaller gain during baseline before and after treatment) was noted for control infants who did not listen to music. Results indicate a significant (p = .002), but biologically unimportant, decrease in heart rate over the course of data collection. No differences due to gender were noted.

The purpose of this study was to examine gender differences with regard to cochlea sensitivity as measured by the transient evoked otoacoustic emissions hearing screening procedure. During this test, a sudden burst of sound is presented at between 78 and 83 dB SPL which stimulates the entire basilar membrane. This in turn excites the outer hair cells in the cochlea and causes an echo-type response which is recorded by a microphone in a probe placed in the ear canal. This test is used to screen for peripheral hearing loss. Subjects ( N = 350) for this project were healthy, full-term newborns (38-42 weeks gestation) in the first 48 hours of life who had bilaterally passed the transient evoked otoacoustic emissions (TEOAE) screening test. Male (n = 170) and female (n = 180) infants were selected randomly from all babies born during a 3-month period who met the criteria at a large birthing hospital. Responses to TEOAE stimuli were recorded at 1.6 kHz, 2.4 kHz, 3.2 kHz, and 4.0 kHz. The responses were recorded as decibel levels indicating a signal-to-noise ratio. These decibel levels were used in a three-way ANOVA with repeated measures comparing gender, ear, and frequency level. Results indicated significant differences due to gender (female hearing more sensitive than male) and frequency (least sensitive hearing recorded at 1.6 kHz, most sensitive hearing recorded at 3.2 kHz). A significant two-way interaction indicated that differences in hearing sensitivity between genders increased as the frequency increased.

The purpose of this study was twofold: (a) to examine extant research in the field of music with premature and full term infants in order to identify protocols being used in the presentation of musical stimuli to neonates and (b) to use knowledge gleaned from audiology as a basis for suggesting a standardized protocol for use of musical stimuli with infants. Articles considered appropriate for inclusion in the analysis met the following criteria: (a) presented data for the effects of music on a dependent measure, (b) had subjects who were identified as either premature or term newborns receiving treatment after birth and prior to discharge from the hospital, and (c) used music for some or all of the aural stimuli. Articles (N = 20) were categorized by demographic information, types of aural stimuli, independent variables, dependent measures, and protocol used to present the musical stimuli. Of primary importance to this study was the protocol used in each study to present musical stimuli. Data regarding total duration of stimuli per day, longest duration of stimuli per day, method of stimuli presentation, placement of speakers, decibel level of stimuli, and where;he decibel level was measured reveal that there is no standard protocol being followed with regard to the presentation of aural stimuli. Recommendations include future research on (a) determining a minimum gestational age where music therapy may be appropriate, (b) determining the frequency spectrum perceived by a premature infant, (c) determining the decibel levels reaching the ear drum and assessing appropriate levels for minimum stimulation with maximum results, and (d) carefully considering the method of stimulus presentation as it will have an impact on the decibel level reaching the ear drum of these infants.

All children seen by a pediatrician in a suburban practice during an 18-month interval were examined carefully for the presence of an abnormal uvula. Isolated bifid uvula, without overt cleft palate, was detected among 44 children who had been followed in the practice during the first three years of life. A chart review was performed to determine the frequency of acute otitis media (AOM) and of insertion of tympanostomy tubes among these study patients and among age-matched controls with normal uvulas. Compared to control children, a slightly higher proportion of children with bifid uvulas had experienced more than one episode of AOM (64% vs. 49%) and more than three episodes of AOM (16% vs. 8%) during the first year of life, but these differences were not statistically significant. By age 3 years, the incidences of AOM in the compared groups were more nearly equal. Insertion of tympanostomy tubes during the first three years of life for persistent middle ear effusion was slightly more common among the bifid uvula group than among the controls (14% vs. 10%), but this difference again was not statistically significant. Children with bifid uvula may be at slightly increased risk of middle ear problems during the first years of life, but the magnitude of this increase, if any, appears small.

Three patients with recurrent affective disorders experienced polydipsia and the syndrome of inappropriate secretion of antidiuretic hormone in association with acute exacerbations of their affective disorders. These disturbances of water homeostasis responded to treatment of the affective disorders.