COEVOLUTION AND GENETIC DIVERSITY IN GRASS-ENDOPHYTE SYMBIOSES

Symbioses between cool-season grasses (Subfamily Pooideae) and endophytic fungi in the genera Epichlo and Neotyphodium straddle a continuum of interactions from antagonistic to highly mutualistic. Although these two genera of endophytes are closely related, Neotyphodium endophytes are strictly seed-transmitted and provide many physiological and defensive benefits to their hosts, while Epichlo spp. have an obligately sexual contagious stage wherein host inflorescences are replaced by fungal sexual structures (stromata), effectively sterilizing the plant. Between these two extremes of interactions are Epichlo spp. with a mixed strategy, where some grass tillers are sterilized while others develop normally and yield healthy endophyte-infected seeds. These symbioses offer a unique opportunity to dissect evolutionary mechanisms that may drive movement along this continuum. The research presented characterizes distinct hybridization processes in endophytes and grasses that result in the generation of astounding genetic diversity for the symbiosis. Interspecific hybridization via hyphal anatomosis is a common feature of Neotyphodium endophytes, and may promote mutualism by combining suites of defensive alkaloid genes and ameliorating the adverse evolutionary effects of an asexual lifestyle. My results demonstrate that several genetically distinct hybrid endophytes infect grass species in tribe Poeae. Further, I show that a highly mutualistic asexual endophyte infecting tall fescue (=Festuca arundinaceum Schreb.), Neotyphodium coenophialum, also infects two closely related and interfertile relatives of this host. My findings suggest that this seed-borne endophyte may have been introgressed into these grasses through sexual grass hybridization events. These findings highlight interspecific hybridization as a means of generating tremendous genetic variability in both endophytes and their hosts, thus magnifying the adaptive evolutionary potential of these symbioses. Further, I establish a phylogenetic framework for grasses naturally harboring Epichlo and Neotyphodium endophytes. I show that patterns of genetic divergence among grass lineages are emulated by those of their fungal symbionts. These results suggest that endophytes have co-evolved with grasses in subfamily Pooideae, and may have played a critical role in the evolutionary success and radiation of this group of grasses

A systematic review and meta-analysis of the criterion validity of nutrition assessment tools for diagnosing protein-energy malnutrition in the older community setting

Background: Accurate diagnosis is a key step in managing protein-energy malnutrition. This review seeks to determine the criterion (concurrent and predictive) validity and reliability of nutrition assessment tools in making a diagnosis of protein-energy malnutrition in community-living older adults. Methods: A systematic literature review was undertaken using six electronic databases in September 2016. Studies in any language were included which measured malnutrition via a nutrition assessment tool in adults ≥65 years living in their own homes. Data relating to the predictive validity of tools were analysed via meta-analyses. GRADE was used to evaluate the body of evidence. Results: There were 6,412 records identified, of which eight papers were included. Two studies evaluated the concurrent validity of the Mini Nutritional Assessment (MNA) and Subjective Global Assessment (SGA) and six evaluated the predictive validity of the MNA. The quality of the body of evidence for the concurrent validity of both the MNA andSGA was very low. The quality of the body of evidence for the predictive validity of the MNA in detecting risk of death was moderate (RR: 1.92 [95%CI: 1.55-2.39]; P Conclusions: Due to the small number of studies identified and no evaluation of the predictive validity of tools other than the MNA, there is insufficient evidence to recommend a particular nutrition assessment tool for diagnosing protein-energy malnutrition in older adults in the community setting. High quality diagnostic accuracy studies are needed for all nutrition assessment tools used in older community samples, including measuring of health outcomes subsequent to nutrition assessment by the SGA and PG-SGA

A systematic review and meta-analysis of the criterion validity of nutrition assessment tools for diagnosing protein-energy malnutrition in the older community setting (the MACRo Study)

Background & aims: Malnutrition is a significant barrier to healthy and independent ageing in older adults who live in their own homes, and accurate diagnosis is a key step in managing the condition. However, there has not been sufficient systematic review or pooling of existing data regarding malnutrition diagnosis in the geriatric community setting. The current paper was conducted as part of the MACRo (Malnutrition in the Ageing Community Review) Study and seeks to determine the criterion (concurrent and predictive) validity and reliability of nutrition assessment tools in making a diagnosis of protein-energy malnutrition in the general older adult community. Methods: A systematic literature review was undertaken using six electronic databases in September 2016. Studies in any language were included which measured malnutrition via a nutrition assessment tool in adults ≥65 years living in their own homes. Data relating to the predictive validity of tools were analysed via meta-analyses. GRADE was used to evaluate the body of evidence. Results: There were 6412 records identified, of which 104 potentially eligible records were screened via full text. Eight papers were included; two which evaluated the concurrent validity of the Mini Nutritional Assessment (MNA) and Subjective Global Assessment (SGA) and six which evaluated the predictive validity of the MNA. The quality of the body of evidence for the concurrent validity of both the MNA and SGA was very low. The quality of the body of evidence for the predictive validity of the MNA in detecting risk of death was moderate (RR: 1.92 [95% CI: 1.55–2.39]; P < 0.00001; n = 2013 participants; n = 4 studies; I2: 0%). The quality of the body of evidence for the predictive validity of the MNA in detecting risk of poor physical function was very low (SMD: 1.02 [95%CI: 0.24–1.80]; P = 0.01; n = 4046 participants; n = 3 studies; I2:89%). Conclusions: Due to the small number of studies identified and no evaluation of the predictive validity of tools other than the MNA, there is insufficient evidence to recommend a particular nutrition assessment tool for diagnosing PEM in older adults in the community. High quality diagnostic accuracy studies are needed for all nutrition assessment tools used in older community samples, including measuring of health outcomes subsequent to nutrition assessment by the SGA and PG-SGA

Physiological Monitoring of the Cardiovascular System During a One-Rep Max Bench Press Using the Zephyr Bioharness

While much is known about the muscular and neurological responses in the body during a one rep max (1RM) bench press test, there is little research regarding the cardiovascular response. The purpose of this study was to investigate the physiological response, specifically in the cardiopulmonary system, during 1RM testing in real-time using the Zephyr Bioharness. Thirty college undergraduates who were enrolled in beginning weight training for three months were asked to wear a BioHarness device during a 1RM bench test. Individual 1RM was found one week prior to test. Prior to testing, subjects followed a standardized warm-up and protocol to obtain 1RM. Subjects instantaneous peak and average heart rate and respiratory rate during, prior to, and following the lift were recorded. Data showed instantaneous heart rate was correlated to the amount of weight successfully lifted (p\u3c.05). There were no significant correlations between weight lifted and average heart rate or respiratory rate. Post lift heart rate and respiratory rate had no correlation to amount of weight lifted. Because intensity is highly subjective and the cardiovascular system and its kinetics limit meaningful research on instantaneous cardiovascular response in the field, the correlations found and relationships between variables in this study may be limited. Cardiovascular fitness is an important aspect of recovery in all activities and the ability to recover from maximal lifting is related to and limited by circulation. Future studies should focus on other power activities and the often neglected relationship between those activities and cardiovascular recovery

Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma

The importance of angiogenesis in pancreatic ductal adenocarcinoma (PDAC) and its therapeutic potential have been explored in both pre-clinical and clinical studies. Human PDACs overexpress a number of angiogenic factors and their cognate high-affinity receptors, and anti-angiogenic agents reduce tumor volume, metastasis, and microvessel density (MVD), and improve survival in subcutaneous and orthotopic pre-clinical models. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful. This review will focus on these pre-clinical and clinical studies, the potential reasons for failure in the clinical setting, and ways these shortcomings could be addressed in future investigations of angiogenic mechanisms in PDAC

Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes

Indiana University-Purdue University Indianapolis (IUPUI)Pancreatic ductal adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival rate of 8%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density (MVD), and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting. In an effort to compare and contrast the angiogenic transcriptomes of these two tumor types, we analyzed RNA-Sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA) and found that a pro-angiogenic gene signature is present in 35% of PDACs and that it is mostly distinct from the angiogenic signature present in PNETs. The pro-angiogenic PDAC subgroup also exhibits a transcriptome that reflects active TGF-β signaling, less frequent SMAD4 inactivation than PDACs without the signature, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Consequently, targeting the TGF-β receptor type-1 kinase with SB505124 and JAK1/2 with ruxolitinib blocks proliferative crosstalk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs). Additionally, treatment of the KRC (oncogenic Kras, homozygous deletion of Rb1) and KPC (oncogenic Kras, mutated Trp53) genetically engineered PDAC mouse models with ruxolitinib suppresses murine PDAC (mPDAC) progression only in the KRC model, which shows superior enrichment and differential expression of the human pro-angiogenic gene signature as compared to KPC tumors. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an pro-angiogenic gene signature should be explored in a clinical trial

Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes

Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ~12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ~35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti-proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-β and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature

Combined targeting of TGF-beta, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

Pancreatic ductal adenocarcinomas (PDAC) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ∼35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatanib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures