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Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease., Through X-ray crystallography and NMR, Hosszu et al. show that V127 mutation in the human prion protein induces structural changes, leading to conformational restrictions in key regions of the protein associated with prion disease. These may prevent prion formation and explain this mutation′s profound effect on prion disease.

Summary Background & aims Pre-clinical studies suggest that 16:4(n-3) in purified form or as a component of fish oil might induce platinum-based chemotherapy resistance. Our aim was to determine plasma total and free 16:4(n-3) before and during platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients supplemented with fish oil or provided standard care, and to explore relationships between plasma 16:4(n-3) levels and tumor response to treatment. Methods In a retrospective, secondary data analysis of a prior clinical trial, plasma from patients with NSCLC (n = 21) who underwent platinum-based chemotherapy and were assigned to 2.2 g/day of eicosapentaenoic (EPA) plus 1.1 g DHA/day as fish oil (FO; n = 12) or received no intervention (standard care; SC; n = 9). Plasma 16:4(n-3) was quantified as free and esterified (total) fatty acid using HPLC-MS/MS. Plasma 16:4(n-3) levels were evaluated over time in relation to fish oil supplementation and response to platinum-based therapy, and compared with a group of healthy subjects (REF; n = 11). Results Plasma 16:4(n-3) was detected in all samples. The percentage change/day in plasma esterified (total) 16:4(n-3) was higher for FO versus SC group (2.7 versus −1.8%/d, U = 20, p = 0.02), but change in plasma free 16:4(n-3) was not different between FO and SC. Median plasma free and esterified 16:4(n-3) were similar between responders and non-responders to platinum-based chemotherapy. Total and free plasma 16:4(n-3) fatty acids were similar between NSCLC patients and REF (NSCLC vs REF: total 16:4(n-3): 122.9 vs. 95.2 nM and free 16:4(n-3) 23.9 vs. 27.6 nM). Conclusions This first of its kind study that evaluated plasma 16:4(n-3) in NSCLC patients showed that 16:4 (n-3) was elevated during FO supplementation, independent of fish oil supplementation or platinum-based chemotherapy.

Colorectal cancer is one of the most common malignancies diagnosed in Canada. Currently, adjuvant colorectal cancer treatment primarily includes chemotherapeutic regimens such as FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin), as well as alternative regimens such as TOMOX (raltitrexed, oxaliplatin). However, the prevalence of drug shortages in today’s society may make these preferred regimens inaccessible. The purpose of this case report is to highlight the tolerability of an alternative adjuvant regimen (pemetrexed plus oxaliplatin) that has undergone both phase I and II clinical trials for the treatment of colorectal cancer. The patient presented in this case report is a 57-year-old female diagnosed with Stage III colon cancer. This patient received seven cycles of pemetrexed plus oxaliplatin and experienced several adverse events, with the majority of them being mild in nature including fatigue and cold dysesthesia. However, the patient also experienced progressive neuropathy which required a dose reduction and subsequent discontinuation of oxaliplatin. Overall, pemetrexed and oxaliplatin’s tolerability seems comparable to other regimens used to treat colorectal cancer and could potentially be an option to consider in the future for alternative treatment of colorectal cancer pending further trials.

Mycobacterium tuberculosis, which causes tuberculosis, expresses a large proportion of leaderless transcripts lacking the canonical bacterial translation initiation signals. The role leaderless genes play in the physiology of this pathogen, which can undergo prolonged periods of non-replicating persistence in the host, is currently unknown. We have previously demonstrated that levels of leaderless transcription increase under conditions of nutrient starvation. However, little is known about the implications of this for persistent infection. Here, we performed ribosome profiling to characterise the translational landscape ofM. tuberculosis in vitro. Our data reveals robust leaderless translation in the pathogen and points towards different mechanisms for their initiation of translation compared to canonical Shine-Dalgarno genes. Furthermore, under conditions of nutrient starvation, we found a significant global up-regulation of leaderless genes in the translatome. Our data represents a rich resource for others seeking to understand translational regulation not only inM. tuberculosisbut in bacterial pathogens.

Retinoic acid (RA) is a well-known morphogen in human development. However, how an RA gradient distribution influences cardiac development remains obscure due to the lack of appropriate experimental apparatus. To address this issue, a polymeric micelle system with covalently attached RA was engineered to deliver gradient quantities of RA upon photo-irradiation. A photo-degradable polymeric nanoparticle (NP) composed of an amphiphilic methoxy(polyethylene glycol)-b-poly(e-caprolactone)-co-poly(azido-e-caprolactone-g-ortho nitrobenzyl retinoic ester) copolymer was synthesized, and hanging RA was covalently attached through a photo-sensitive o-nitrobenzyl (ONB) linker. The ONB linker was efficiently cleaved when exposed to a light (365 nm)-gradient, and the consequent gradient release of RA from the micelles was demonstrated. The efficacy of the photo-gradient-mediated RA release was validated across different concentrations of polymer micelles over varied irradiation periods. It was confirmed that polymer micelles demonstrated minimal cytotoxicity when exposed to mouse embryoid bodies (EBs). Finally, when the photo-gradient release of polymer micelles was applied, GFP-cardiac troponin T reporter mouse EBs demonstrated a concurrent gradient-like pattern of cardiac differentiation, verifying the utility of our novel photo-gradient approach to study morphogen gradients not only for cardiac development but also for other potential biological microenvironments subject to morphogen presentation with highly defined spatial and temporal geometries.

We draw on data from the Online Labour Index and interviews with freelancers in the United States securing work on online platforms, to illuminate effects of the COVID‐19 pandemic. The pandemic's global economic upheaval is shuttering shops and offices. Those able to do so are now working remotely from their homes. They join workers who have always been working remotely: freelancers who earn some or all of their income from projects secured via online labour platforms. Data allow us to sketch a first picture of how the initial months of the COVID‐19 pandemic have affected the livelihoods of online freelancers. The data shows online labour demand falling rapidly in early March 2020, but with an equally rapid recovery. We also find significant differences between countries and occupations. Data from interviews make clear jobs are increasingly scarce even as more people are creating profiles and seeking freelance work online., We draw on data from the Online Labour Index and interviews with freelancers in the United States securing work on online platforms, to illuminate effects of the COVID‐19 pandemic. Data allow us to sketch a first picture of how the initial month of the COVID‐19 pandemic has affected the livelihoods of online freelancers. The data show online labour demand falling rapidly in early March 2020, but with an equally rapid recovery. Interviews make clear jobs are increasingly scarce even as more people are creating profiles and seeking freelance work online.

Water quality monitoring and predicting the changes in water characteristics require the collection of water samples in a timely manner. Water sample collection based on in situ measurable water quality indicators can increase the efficiency and precision of data collection while reducing the cost of laboratory analyses. The objective of this research was to develop an adaptive water sampling device for an aerial robot and demonstrate the accuracy of its functions in laboratory and field conditions. The prototype device consisted of a sensor node with dissolved oxygen, pH, electrical conductivity, temperature, turbidity, and depth sensors, a microcontroller, and a sampler with three cartridges. Activation of water capturing cartridges was based on in situ measurements from the sensor node. The activation mechanism of the prototype device was tested with standard solutions in the laboratory and with autonomous water sampling flights over the 11-ha section of a lake. A total of seven sampling locations were selected based on a grid system. Each cartridge collected 130 mL of water samples at a 3.5 m depth. Mean water quality parameters were measured as 8.47 mg/L of dissolved oxygen, pH of 5.34, 7 &micro, S/cm of electrical conductivity, temperature of 18 &deg, C, and 37 Formazin Nephelometric Unit (FNU) of turbidity. The dissolved oxygen was within allowable limits that were pre-set in the self-activation computer program while the pH, electrical conductivity, and temperature were outside of allowable limits that were specified by Environmental Protection Agency (EPA). Therefore, the activation mechanism of the device was triggered and water samples were collected from all the sampling locations successfully. The adaptive water sampling with Unmanned Aerial Vehicle-assisted water sampling device was proved to be a successful method for water quality evaluation.

The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time., We describe the co‐occurrence of cancer and heart failure (HF), their potential shared risk factors, and their pathophysiological mechanisms. We advocate intense interaction between cardiologists and oncologists to achieve unifying hypotheses and collaborative pre‐clinical and clinical studies.

We focus on networked arrangements of digital resources that are shared among otherwise independent units to advance conceptual and empirical insights about their governance. We are motivated by the simple observation that, increasingly, independent organizations are engaging in shared activities, often relying on purpose-built digital infrastructures to support this move to inter-dependence. To advance current conceptualizations of networked governance, we draw on data from 42 public safety networks and use fuzzy-set qualitative comparative analysis. We do so because fsQCA allows us to account for the realities of inter-dependence among the concepts and variables we consider and to illuminate the multiple viable governance patterns that are possible. The results show the importance of network-level governance competencies to manage stakeholders and information infrastructure to achieve high effectiveness of PSN. Analysis makes clear that there exist five configurations of PSN governance practices that enable high levels of network governance effectiveness. Common to all these configurations are the network-level competence in managing both stakeholders and the digital infrastructure, suggesting these are necessary (but not sufficient) network-level governance competencies. Building from the analysis, we advance the role of specific network-level governance competencies, and the current conceptualization of network governance more broadly.

Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment and prognosis but have also resulted in adverse effects such as fatigue, diarrhea, hypothyroidism, and other toxicities. We investigated TKI effects on skeletal muscle as a possible explanation of TKI induced fatigue. Changes in mitochondrial function due to inhibition of oxidative phosphorylation complexes, generation of superoxides, and inhibition of key transporters involved in uptake of glucose and/or nucleosides may result in alteration of energy metabolism and/or mitochondrial function. We investigated effects of imatinib, sorafenib and sunitinib on these processes in cultured C2C12 murine skeletal muscle cells. Imatinib, sorafenib and sunitinib were cytotoxic to C2C12 cells with IC50 values of 20, 8 and 8 µM, respectively. Imatinib stimulated glucose uptake and inhibited complex V activity by 35% at 50 µM. Sorafenib inhibited complex II/III and V with IC50 values of 32 and 28 µM, respectively. Sorafenib caused activation of caspase 3/7 and depolarization of mitochondrial membranes occurred very rapidly with complete loss at 5-10 µM. Sunitinib inhibited Complex I with an IC50 value of 38 µM and caused ATP depletion, caspase 3/7 activation, an increase in reactive oxygen species (ROS), and decreased nucleoside and glucose uptake. In conclusion, imatinib, sunitinib and sorafenib caused changes in mitochondrial complex activities, glucose and nucleoside uptake leading to decreased energy production and mitochondrial function in a skeletal muscle cell model, suggesting that these changes may play a role in fatigue, one of the most common adverse effects of TKIs.

Objectives The COU-AA-301 trial demonstrated that in men with metastatic castrate-resistant prostate cancer using abiraterone post-docetaxel increased overall survival. This study aims to assess this conclusion in a real world context. Design Retrospective chart review of a provincial Pharmacy BDM Database (a pharmacy dispensing software) and a provincial Electronic Chart (ARIA). Dispensing data, information on the state of the disease before and after abiraterone use, and information regarding effects of abiraterone were gathered. Setting Cancer centers in Alberta, Canada. Patients Metastatic castrate-resistant prostate cancer (CRPC) patients on abiraterone outside of a clinical trial who have previously had docetaxel chemotherapy for CRPC between February 2012 and May 2014. Primary outcome Overall survival from the time of abiraterone initiation. Results Overall survival increase of 17 months was consistent with the survival increase of 14.8 months observed in the pivotal trial. Conclusion Abiraterone is a valuable therapy post-docetaxel for metastatic CRPC, as in a real world context it demonstrated an increase in overall survival that was consistent with the findings of the clinical trial despite including a patient population of older age and lower performance status.

Use of cross-sectional imaging to identify whole-body lean soft-tissue mass has recently emerged as an attractive prognostic factor for chemotherapy toxicities. Beyond that, there is increasing interest in use of lean soft-tissue mass as a more accurate method for dosing chemotherapy, as compared to body surface area. In this review, we summarize the current evidence that supports interactions between skeletal muscle and chemotherapy, the role of lean soft tissue in predicting chemotherapy toxicities and potential use of an alternate method of chemotherapeutic dosing, all based on quantification of skeletal muscle mass by computed tomography.

Two field-programmable gate array (FPGA) designs are tested for dynamic single event upset (SEU) sensitivity on two different 28-nm static random access memory-based FPGAs—an Intel Stratix V and a Xilinx Kintex 7 FPGA. These designs were tested in both a conventional unmitigated version and a version to tolerate SEUs with feedback triple modular redundancy (TMR). The unmitigated design sensitivity and the low-level device sensitivity were found to be similar between the devices through neutron radiation testing. Results also show that feedback TMR and configuration scrubbing benefit both designs on both FPGAs. While TMR is helpful, the benefit of TMR depends on the design structure and the device architecture. TMR and scrubbing reduced dynamic SEU sensitivity by a factor of 4– $54\times $ .

Introduction: Gemcitabine (GEM) plus nab-paclitaxel (nab) has been shown to improve overall survival (OS) compared to GEM monotherapy in patients with metastatic pancreatic cancer. However, GEM/nab is associated with increased toxicity. Our study evaluated whether sarcopenia increased the likelihood of chemotherapy toxicity in pancreatic cancer treated with GEM/nab. Methods: A retrospective review was performed of all patients who received GEM/nab as first-line therapy for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014-2017. Patients were included if a computed tomography (CT) scan of the abdomen and pelvis was performed within 60 days of starting chemotherapy. Skeletal muscle surface area was measured at L3 on baseline CT scans and normalized for height to determine skeletal muscle index (SMI, cm2/m2). Dose-limiting toxicity (DLT) was defined as dose reduction or treatment discontinuation due to toxicity. Optimal stratification was used to establish sex-specific SMI cut-offs with DLT as an outcome. Results: 152 patients were included in the study. 88 patients (57.8%) were male and median age was 66.5 years (range 34-95). 62 patients (40.8%) experienced DLT. SMI cut-offs were determined as 65), sex, BMI category, and performance status (PS), sarcopenia significantly increased the likelihood of DLT (OR 7.21, 95% CI 3.02-17.24, p Conclusion: In pancreatic cancer treated with GEM/nab, sarcopenic patients are significantly more likely to experience DLT, independent of age, sex, BMI, and PS. These findings could have implications for reduced chemotherapy dosing in sarcopenic patients. Citation Format: Susie Youn, Angela Chen, Vincent Ha, Carole Chambers, Dean T. Eurich, Michael McCall, Michael B. Sawyer. Sarcopenia predicts dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 432.

This special issue advances the current, relatively lacking, empirical knowledge related to the experiences of employees who are sexual orientation and/or gender identity minorities. In this introduction to the special issue, we provide a brief but comprehensive review of the current literature focused on sexual orientation or gender identity published in 14 of the top organizational science, industrial-organizational psychology, and management journals. In so doing, we highlight what has been done and what opportunities remain in the current literature. We then provide a brief overview of the articles included in this special issue, highlighting the unique and collective contributions to the existing literature. We conclude by providing opportunities for further research in this field and a call to action for organizational scholars to continue to expand this important area of research.

Introduction: Body surface area dosing of chemotherapeutic agents is based on limited scientific data, and often results in unpredictable plasma drug levels. Cross-sectional computed tomography (CT) imaging provides an accurate measurement of lean mass. This review summarizes emerging roles of lean mass in predicting pharmacokinetics and drug toxicities in cancer patients.Areas covered: A concise review of body composition measurement with CT cross-sectional imaging and its relationship to drug pharmacokinetics and toxicities. A comprehensive review of the predictive value of low lean mass (sarcopenia) in dose-limiting toxicities is also included.Expert commentary: Drug dosing in medical oncology faces many challenges, including heterogeneous body composition profiles. The emerging role of sarcopenia in predicting lean mass may provide the tool needed to more accurately dose patients and prevent dose-limiting toxicities.

Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHY This study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.

Background Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction. Methods To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47–93 months) GRMD dogs, were assessed. Results GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a “metabolic crisis” seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction. Conclusions These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0257-2) contains supplementary material, which is available to authorized users.

Background Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non–small-cell lung cancer (NSCLC) enrolled onto randomized trials comparing first-line carboplatin-doublets. Patients and Methods Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m 2 , gemcitabine 1000 mg/m 2 , or vinorelbine 60 mg/m 2 . LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1. Results Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed ∼3-fold range: gemcitabine 38.0 (22.5-61.7) mg/kg LBM, pemetrexed 19.1 (8.1-27.9) mg/kg LBM, and vinorelbine 2.4 (1.4-3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models ( P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01-1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95-0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21-3.10) and halved (OR = 0.52; 95% CI, 0.32-0.83), respectively. Conclusion Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography–defined LBM may provide a future basis for better dose individualization.

Background The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. Methods and Results Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor–blocking therapy, were studied before and after 6–29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1 LL ). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m 2 ) decreased in all patients ( P LL ( r = −0.65; P = .02). Conclusion Myocardial T1 LL , in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen.

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.

Purpose Elastomeric pumps are used to administer 46-hour infusions of 5-fluorouracil (5FU). Baxter suggests patients visually monitor their pumps to ensure that infusions are proceeding correctly. This can be confusing and lead to concerns about under- or over-dosing. Baxter has not considered weighing pumps as a validated method for monitoring. This study aims to validate weighing as a more accurate method for patients and healthcare professionals, and describe real life Baxter Infusor™ variability. Methods Patients who had been started on a 46-hour 5FU infusion returned to the clinic approximately 24 h after starting treatment. The pump was weighed on a StarFrit kitchen scale, and date, time, and weights recorded. Patients were asked if they had a preference for weighing or visually inspecting their pump. Results Pumps ( n = 103) were weighed between 17.25 and 27.5 h after connection. The average weight of a pump was 189 g. Of 103 pumps weighed, 99 weighed less than expected, corresponding to average flow rates of 5.69 mL/h over the elapsed time. The expected flow rate is 5 mL/h with 10% variability. Average flow rates within the 17.25- to 27.5-hour window were 4.561 mL/h, which is 8.78% slower than expected, but within the 10% known variability. Forty-seven percent of patients didn’t have a preference for either method, but for those who did have a preference, more than twice as many preferred weighing. Conclusion With proper education, weighing Baxter Infusors at home with kitchen scales can be an accepted and objective alternative to the current recommendation of visual inspection.

Mammalian heart regeneration has been the subject of intense debate and investigation among cardiovascular scientists for more than a century (1). While it is now widely accepted that the mammalian heart does have the capacity for self-renewal, replacement of injured tissue with new cardiomyocytes happens at a very low rate in the adult heart, and is not sufficient for the recovery of cardiac function after massive loss of cells (2).

MRS of 13 C4 -labelled glutamate (13 C4 -Glu) during an infusion of a carbon-13 (13 C)-labelled substrate, such as uniformly labelled glucose ([U-13 C6 ]-Glc), provides a measure of Glc metabolism. The presented work provides a single-shot indirect 13 C detection technique to quantify the approximately 2.51 ppm 13 C4 -Glu satellite proton (1 H) peak at 9.4 T. The methodology is an optimized point-resolved spectroscopy (PRESS) sequence that minimizes signal contamination from the strongly coupled protons of N-acetylaspartate (NAA), which resonate at approximately 2.49 ppm. J-coupling evolution of protons was characterized numerically and verified experimentally. A (TE1 , TE2 ) combination of (20 ms, 106 ms) was found to be suitable for minimizing NAA signal in the 2.51 ppm 1 H 13 C4 -Glu spectral region, while retaining the 13 C4 -Glu 1 H satellite peak. The efficacy of the technique was verified on phantom solutions and on two rat brains in vivo during an infusion of [U-13 C6 ]-Glc. LCModel was employed for analysis of the in vivo spectra to quantify the 2.51 ppm 1 H 13 C4 -Glu signal to obtain Glu C4 fractional enrichment time courses during the infusions. Cramer-Rao lower bounds of about 8% were obtained for the 2.51 ppm 13 C4 -Glu 1 H satellite peak with the optimal TE combination.

This chapter advances an articulation of the contemporary knowledge worker as an infrastructural bricoleur. The practical and pragmatic intelligence of the contemporary knowledge worker, particularly those involved in project-based work, reflects an ability to build adaptable practices and routines, and to develop a set of working arrangements that is creative and event-laden. Like Ciborra’s octopi, workers augment infrastructures by drawing on certain forms of oblique, twisted, flexible, circular, polymorphic and ambiguous thinking until an accommodation can be found. These workers understand the non-linearity of work and working, and are artful in their pursuits around, through and beyond infrastructural givens. Modern knowledge work, then, when looked at through the lens of infrastructure and bricolage, is less a story of failure to understand, a limitation in training or the shortcomings of a system, but instead is more a mirror of the contemporary realities of today’s knowledge work drift as reflected in individuals’ sociotechnical practices.

Introduction: The human adult heart contains a subset of mesenchymal cells characterized by high proliferative potential and capability to differentiate into different cell types. We recently demonstrated that a high level of ErbB2 expression is associated with differentiation of human highly proliferative cells (hHiPC) into endothelial cells in vitro. Based on our findings, we hypothesized that ErbB2 high hHiPC play a critical role in early revascularization and repair of injured heart. To test this hypothesis, we performed xenotransplantation of human ERBB2 high hHiPC into mouse hearts and analyzed the phenotype of transplanted cells and cardiac function on day 7 after experimental myocardial infarction (MI). Methods: The effect of ErbB2 high hHiPC was tested in immunodeficient NSG mice. MI was induced by permanent ligation of the left coronary artery. Human ERBB2 high hHiPC (2.5 x 10 5 cells) were injected into the peri-infarct zone immediately after MI. Echocardiography was performed on unsedated mice before and on days 7 after MI. Examination of transplantation efficiency and hHiPC phenotype was performed using flow cytometric analysis of cell suspension obtained from left ventricles (LV). Results: We found that up to 25% of cardiac endothelial cells were represented by cells that originated from hHiPC, as identified by specific expression of human CD31, in mouse LV, on day 7 after MI. The total number of cells expressing mouse or human endothelial cell markers, CD31 and CD105, within non-immune cardiac cell population was higher in mice that received injection of hHiPC compared to control mice (PBS injection) (4.7 vs. 2.9 x 10 5 cells, hHiPC vs. PBS, p= 0.026 ). Echocardiographic analysis revealed that mice which received an injection of ERBB2 high cells demonstrated significantly improved cardiac function compared to control mice injected with PBS (fractional shortening: 21.6% vs. 15.3% for hHiPC vs. PBS, p=0.023 ). Conclusion: ERBB2 high hHiPC survive, undergo endothelial cell differentiation in vivo, and contribute to the pool of cardiac endothelial cells after experimental myocardial infarction. A population of ErbB2 high hHiPC obtained from adult human hearts can be used to improve the revascularization of injured myocardium or other tissues.

Background: \ud Total energy expenditure (TEE) data in patients with early-stage cancer are scarce, precluding an understanding of energy requirements.\ud \ud Objective: \ud The objective was to cross-sectionally characterize TEE in patients with colorectal cancer (CRC) and to compare measured TEE with energy recommendations. It was hypothesized that TEE would differ according to body mass, body composition, and physical activity level (PAL) and current energy recommendations would have poor individual-level accuracy.\ud \ud Methods: \ud Patients with newly diagnosed CRC had resting energy expenditure (REE) measured by indirect calorimetry and TEE by doubly labeled water. Hypermetabolism was defined as REE > 110% of that predicted from the Mifflin St.-Jeor equation. Body composition was assessed via DXA. Physical activity was determined as the ratio of TEE to REE (TEE:REE) (PAL) and residual activity energy expenditure (RAEE). TEE was compared with energy recommendations of 25–30 kcal/d and Dietary Reference Intakes (DRIs) using Bland–Altman analyses. Patients were stratified according to median BMI, PAL, and sex-specific ratio of fat mass (FM) to fat-free mass (FFM).\ud \ud Results: \ud Twenty-one patients (M:F 14:7; mean ± SD BMI: 28.3 ± 4.9 kg/m2, age: 57 ± 12 y) were included. Most (n = 20) had stage II–III disease; 1 had stage IV. Approximately half (n = 11) were hypermetabolic; TEE was not different in those with hypermetabolism and REE as a percentage of predicted was not correlated with TEE. Mean ± SD TEE was 2473 ± 499 kcal/d (range: 1562–3622 kcal/d), or 29.7 ± 6.3 kcal/kg body weight (range: 20.4–48.5 kcal/kg body weight). Mean ± SD PAL was 1.43 ± 0.27. The energy recommendation of 25 kcal/kg underestimated TEE (−12.6% ± 16.5%, P = 0.002); all energy recommendations had wide limits of agreement (the smallest was DRI with measured PAL: −21.2% to 29.3%). Patients with higher BMI and FM:FFM had higher bias using kilocalories per kilogram recommendations; bias from several recommendations was frequently lower (i.e. underestimation) in patients with higher PAL and RAEE.\ud \ud Conclusions: \ud TEE variability was not reflected in energy recommendations and error was related to body weight, body composition, and physical activity. This trial was registered at clinicaltrials.gov as NCT03131921.

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia‐reperfusion injuries. After the initial hypoxic‐ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5′‐nucleotidase), production of tumor necrosis factor‐α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73‐expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post‐ CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor‐α production and generation of reactive oxygen species. This effect was blocked by adenosine 5′‐(α, β‐methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP ‐dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73‐expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.

Anthracycline-associated cardiomyopathy and peripartum cardiomyopathy are nonischemic cardiomyopathies that often afflict previously healthy young patients; both diseases have been well described since at least the 1970s and both occur in the settings of predictable stressors (ie, cancer treatment and pregnancy). Despite this, the precise mechanisms and the ability to reliably predict who exactly will go on to develop cardiomyopathy and heart failure in the face of anthracycline exposure or childbirth have proven elusive. For both cardiomyopathies, recent advances in basic and molecular sciences have illuminated the complex balance between cardiomyocyte and endothelial homeostasis via 3 broad pathways: reactive oxidative stress, interference in apoptosis/growth/metabolism, and angiogenic imbalance. These advances have already shown potential for specific, disease-altering therapies, and as our mechanistic knowledge continues to evolve, further clinical successes are expected to follow.

Background Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. Objective This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer. Design This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival. Settings All patients were seen in a tertiary care cancer center. Patients Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included. Intervention Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity. Main outcome measures Primary outcome measures were overall, recurrence-free, and cancer-specific survival. Results In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model. Limitations The limitations of this study are inherent in retrospective observational studies. Conclusions Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

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635 Background: In the phase II CheckMate-142 trial, NIVO + low-dose IPI (1 mg/kg) provided meaningful clinical benefit in previously treated MSI-H/dMMR mCRC pts after a median follow-up of 13.4 mo. Here, we present long-term follow-up (median 25.4 mo) of these pts. Methods: Pts received NIVO 3 mg/kg + low-dose IPI Q3W (4 doses) followed by NIVO 3 mg/kg Q2W until disease progression. Primary endpoint was investigator (INV)-assessed objective response rate (ORR; RECIST v1.1). Results: Of 119 treated pts, 76% had ≥ 2 prior lines of therapy. ORR and disease control rates (DCR) were 58 and 81%, respectively (Table). Complete response (CR) rate increased with long-term follow-up from 3 (13.4 mo) to 6% (25.4 mo). Median duration of response (DOR) was not reached, with 68% of responses ongoing at data cutoff. At 24 mo, progression-free survival (PFS) and overall survival (OS) rates were 60 and 74%, respectively; OS rates were 96, 56, and 29% in pts with CR or partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 31% of pts; 10% (grade 3–4) and 13% (any grade) of pts had TRAEs leading to discontinuation. Conclusions: Long-term follow-up with NIVO + low-dose IPI provides durable clinical benefit with deepening of response and a manageable safety profile with no new safety signals, demonstrating long-term benefit of NIVO + low-dose IPI for previously treated pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]