Development of Technologies for Separation and Functional Improvement of Individual Milk Protein Fractions

End of Project ReportMilk proteins can be hydrolysed (i.e. fragmented) using proteolytic enzymes to give enhanced functional and nutritional properties. There is an increasing demand for hydrolysed protein ingredients with specific properties for nutrition of individuals with specialised dietary requirements including infants, the critically ill, the immuno-compromised and athletes. Such hydrolysed proteins can be specifically designed to provide distinctive tailor-made solutions to meet customer needs in these areas. This project explored the technologies for the production of two types of hydrolysates i.e. acid-soluble and glutamine-rich. Acid-soluble protein hydrolysates have potential in the fortification of acidic beverages, including soft drinks. Glutamine-rich hydrolysates are suggested as an optimal glutamine source for administration during periods of stress, such as recovery from strenuous exercise, or from surgery. Casein was selected as the protein for development of acid-soluble product and cereal protein for the glutamine-rich product. The main conclusions were as follows: A number of protein hydrolysate products with value added properties and the processes required for their manufacture have been developed and are available for uptake by the food industry. Laboratory investigations identified conditions for the generation of two casein hydrolysates with desirable functional properties. Scale-up conditions for the manufacture of these hydrolysates in the pilot plant were successfully developed. Both hydrolystates were 100% soluble at pH 4.6, exhibited clarity in solution at low pH in clear soft drinks and in caramelised beverages and were stable in solution over a wide temperature range (from 4 to 30ºC) for extended periods. Solutions containing these hydrolysates exhibited no foaming properties and had acceptable sensory properties, being considered as weakly bitter compared to unsupplemented solutions. These performance characteristics make the acid-soluble hydrolysates useful supplements for caramelised beverages, such as colas, and clear soft drinks. Six glutamine-enriched peptide products were produced at laboratory scale using two commercially available enzyme preparations. These products had desirable characteristics such as increased levels of peptide bound glutamine, low free amino acid and free pyroglutamate levels. Pilot plant processes were developed for manufacture of the two glutamine-rich hydrolysates with most suitable compositional properties and these were fully characterised chemically. The manufacturing process was modified to enable industrial scale batches (5,000 litres) to be produced.Department of Agriculture, Food and the Marin

Fistula awareness among sisters of women with fistula

ObjectiveTo determine whether sisters of women with obstetric fistula (OF) were aware of their sisters’ condition, in order to inform the development of survey questions that adapt the sister‐based method to fistula rate estimation.MethodsTwelve women with OF and 20 of their sisters were interviewed using semi‐structured questionnaires in rural Uganda in 2007. Topics included fistula awareness and perceptions of causality.ResultsEleven women had vesicovaginal fistula and 1 had rectovaginal fistula. Three were primiparous at time of fistula occurrence; 6 had a parity of 6 or more. Nineteen sisters were aware their sister had OF; 12 became aware at the time of occurrence. The majority of participants (fistula patients and their sisters) associated OF with mistakes made by hospital personnel or problems during procedures.ConclusionSisters were generally aware of OF within their family. Larger studies are needed to assess the validity and reliability of the sister‐based method in capturing fistula through household surveys. In the present study, there was a widespread perception among fistula patients and their sisters that fistula is caused by medical procedures. More research is needed to understand this perception, and program development efforts are required to improve patient perceptions of hospital care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135323/1/ijgo232.pd

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types