Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase.

Oncotarget. 2017 Mar 27;:

Authors: Zheng M, Luan S, Gao S, Cheng L, Hao B, Li J, Chen Y, Hou X, Chen L, Li H

Abstract
T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.

PMID: 28388576 [PubMed - as supplied by publisher]

Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.

Sci Rep. 2017 Apr 06;7(1):682

Authors: Wang S, Wang L, Zhou Z, Deng Q, Li L, Zhang M, Liu L, Li Y

Abstract
Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.

PMID: 28386133 [PubMed - in process]

Using phase II data for the analysis of phase III studies: An application in rare diseases.

Clin Trials. 2017 Mar 01;:1740774517699409

Authors: Wandel S, Neuenschwander B, Röver C, Friede T

Abstract
BACKGROUND: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases.
METHODS: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data.
RESULTS: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence.
CONCLUSION: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

PMID: 28387537 [PubMed - as supplied by publisher]

Incidence and Clinical Features of Rare Cutaneous Malignancies in Olmsted County, Minnesota, 2000 to 2010.

Dermatol Surg. 2017 Jan;43(1):116-124

Authors: Tolkachjov SN, Schmitt AR, Muzic JG, Weaver AL, Baum CL

Abstract
BACKGROUND: The incidence of rare cutaneous malignancies is unknown. Current estimates of rare cutaneous malignancy incidences are based on broad epidemiologic data or single institution experiences, not population-based data.
OBJECTIVE: To determine the incidence of several rare nonmelanoma skin cancers.
MATERIALS AND METHODS: The authors conducted a retrospective chart review of a population-based cohort between the years 2000 and 2010. Residents of Olmsted County, Minnesota, who were diagnosed with a biopsy-proven nonmelanoma skin cancer-excluding basal cell carcinoma and squamous cell carcinoma-were included in this study. The primary outcome was tumor incidence. Additionally, the authors extracted patient demographics, tumor characteristics, treatment modalities, and outcomes.
RESULTS: The age-adjusted and sex-adjusted incidences per 100,000 persons of multiple rare cutaneous malignancies were: atypical fibroxanthoma (1.8), sebaceous carcinoma (0.8), dermatofibrosarcoma protuberans (0.4), microcystic adnexal carcinoma (0.7), eccrine carcinoma (0.4), eccrine porocarcinoma (0.2), and leiomyosarcoma (0.2).
CONCLUSION: The authors report population-based incidences and clinical characteristics for these rare cutaneous malignancies. The immune status and smoking status of patients and the treatment and outcomes of these tumors are reported. Additional studies in a broader population are needed to further define the epidemiology and outcomes of these malignancies.

PMID: 28027201 [PubMed - indexed for MEDLINE]

Subcutaneous nasal angioleiomyoma: Case of a rare tumor and review of the literature.

Ear Nose Throat J. 2016 Oct-Nov;95(10-11):E23-E25

Authors: Saadi R, Oberman BS, Crist H, Lighthall J

Abstract
We describe the case of a 46-year-old woman with a rare presentation of angioleiomyoma of the subcutaneous nasal tissue. The patient presented with pain and severe nasal obstruction. Her nasal deformity was sufficient to indicate an external rhinoplasty for both extirpation of the tumor and reconstruction of the defect with cartilage grafts. The procedure resulted in successful removal of the tumor and a satisfactory cosmetic outcome.

PMID: 27792829 [PubMed - indexed for MEDLINE]

Translating Aboriginal genomics - four letters Closing the Gap.

Med J Aust. 2016 Oct 17;205(8):379

Authors: Baynam GS, Pearson G, Blackwell J

PMID: 27736627 [PubMed - indexed for MEDLINE]

Pulmonary complications of type 1 neurofibromatosis.

Rev Mal Respir. 2016 Jun;33(6):460-73

Authors: Reviron-Rabec L, Girerd B, Seferian A, Campbell K, Brosseau S, Bergot E, Humbert M, Zalcman G, Montani D

Abstract
INTRODUCTION: Type 1 neurofibromatosis is one of the most common genetic diseases, with an incidence of 1/3500 live births. Its diagnosis primarily relies on the clinical features of the condition.
CURRENT KNOWLEDGE: The life expectancy of these patients is reduced by 10 years, on average, compared to the general population. Type 1 neurofibromatosis has been shown to increase the risk of various types of neoplasia, primarily those affecting the neural crest. In addition, interstitial lung disease, lung cancer, and pulmonary hypertension have been observed during the third or the fourth decade of an adult's life.
PERSPECTIVES: There are only few case reports available that address the pulmonary complications of neurofibromatosis type 1. It is thus crucial to fully understand this rare disease and its potential complications in order to allow for early diagnosis so we are able to improve the quality of life and survival of those suffering from the condition.
CONCLUSIONS: The pulmonary complications of type 1 neurofibromatosis can be severe and life-threatening. Patients with this condition should thus undergo regular clinical visits and examinations to allow pulmonary complications to be detected and treatment to be initiated as early as possible.

PMID: 26868668 [PubMed - indexed for MEDLINE]

The anatomy of phenotype ontologies: principles, properties and applications.

Brief Bioinform. 2017 Apr 06;:

Authors: Gkoutos GV, Schofield PN, Hoehndorf R

Abstract
The past decade has seen an explosion in the collection of genotype data in domains as diverse as medicine, ecology, livestock and plant breeding. Along with this comes the challenge of dealing with the related phenotype data, which is not only large but also highly multidimensional. Computational analysis of phenotypes has therefore become critical for our ability to understand the biological meaning of genomic data in the biological sciences. At the heart of computational phenotype analysis are the phenotype ontologies. A large number of these ontologies have been developed across many domains, and we are now at a point where the knowledge captured in the structure of these ontologies can be used for the integration and analysis of large interrelated data sets. The Phenotype And Trait Ontology framework provides a method for formal definitions of phenotypes and associated data sets and has proved to be key to our ability to develop methods for the integration and analysis of phenotype data. Here, we describe the development and products of the ontological approach to phenotype capture, the formal content of phenotype ontologies and how their content can be used computationally.

PMID: 28387809 [PubMed - as supplied by publisher]

Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21(st) International Symposium on Microsomes and Drug Oxidations (MDO).

Acta Pharm Sin B. 2017 Mar;7(2):241-248

Authors: Yu AM, Ingelman-Sundberg M, Cherrington NJ, Aleksunes LM, Zanger UM, Xie W, Jeong H, Morgan EM, Turnbaugh PJ, Klaassen CD, Bhatt AP, Redinbo MR, Hao P, Waxman DJ, Wang L, Zhong XB

Abstract
Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21(st) International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2-6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME) and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.

PMID: 28388695 [PubMed]

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs.

OMICS. 2017 Apr;21(4):207-216

Authors: Petros Z, Lee MT, Takahashi A, Zhang Y, Yimer G, Habtewold A, Schuppe-Koistinen I, Mushiroda T, Makonnen E, Kubo M, Aklillu E

Abstract
Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV- and ARV-ATD-induced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G→A, R919Q, p = 1.4 × 10(-6), odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH (p = 5.3 × 10(-7), OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

PMID: 28388302 [PubMed - in process]

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

Nat Commun. 2017 Apr 07;8:14907

Authors: Mauriac SA, Hien YE, Bird JE, Carvalho SD, Peyroutou R, Lee SC, Moreau MM, Blanc JM, Geyser A, Medina C, Thoumine O, Beer-Hammer S, Friedman TB, Rüttiger L, Forge A, Nürnberg B, Sans N, Montcouquiol M

Abstract
Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

PMID: 28387217 [PubMed - in process]

The Protective Effect of Aucubin from Eucommia ulmoides Against Status Epilepticus by Inducing Autophagy and Inhibiting Necroptosis.

Am J Chin Med. 2017 Apr 07;:1-17

Authors: Wang J, Li Y, Huang WH, Zeng XC, Li XH, Li J, Zhou J, Xiao J, Xiao B, Ouyang DS, Hu K

Abstract
Eucommia ulmoides Oliv. is a famous traditional Chinese medicine which exhibits anti-oxidative stress ability and neuro-protective effects. Aucubin is the predominant component of Eucommia ulmoides Oliv. Our present study is intended to investigate aucubin's potential protective effects on neurons against epilepsy in the hippocampus by establishing the lithium-pilocarpine induced status epilepticus (SE) rat model in vivo. Aucubin (at a low dose and a high dose of 5[Formula: see text]mg/kg and 10[Formula: see text]mg/kg, respectively) was administered through gavage for two weeks before lithium-pilocarpine injection. Rats were sacrificed at 4, 24 and 72[Formula: see text]h after SE induction. Pretreatment with both low-dose and high-dose aucubin significantly reduced the number of death neurons ([Formula: see text]) and increased the number of surviving neurons ([Formula: see text]) in DG, Hilus, CA1 and CA3 hippocampal regions post SE. Meanwhile, it significantly inhibited necroptosis proteins (MLKL and RIP-1) ([Formula: see text] or [Formula: see text]) and enhanced autophagy protein (Beclin-1 and LC3BII/LC3BI) prevalence in the hippocampus ([Formula: see text] or [Formula: see text]). In conclusion, aucubin appeared to ameliorate damages in lithium-pilocarpine induced SE in hippocampus, reduce the number of apoptotic neurons, and increased the number of survival neurons by inducing autophagy and inhibiting necroptosis. These original findings might provide an important basis for the further investigation of the therapeutic role of aucubin in treatment or prevention of epilepsy-related neuronal damages.

PMID: 28387136 [PubMed - as supplied by publisher]

Activation of the ventral tegmental area increased wakefulness in mice.

Sleep Biol Rhythms. 2017;15(2):107-115

Authors: Sun HX, Wang DR, Ye CB, Hu ZZ, Wang CY, Huang ZL, Yang SR

Abstract
The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic "designer receptors exclusively activated by designer drugs (DREADD)" approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited. The hM3Dq-expressing VTA neurons were excited confirmed by clozapine-N-oxide (CNO)-driven c-Fos expression and firing in patch-clamp recordings; whereas the hM4Di-expressing VTA neurons inhibited by reduction of firing. Compared with controls, the activation of VTA neurons at 9:00 (inactive period) produced a 120.1% increase in the total wakefulness amount for 5 h, whereas NREM and REM sleep were decreased by 62.5 and 92.2%, respectively. Similarly, when VTA neurons were excited at 21:00 (active period), the total wakefulness amount increased 81.5%, while NREM and REM sleep decreased 64.6 and 93.8%, respectively, for 8 h. No difference of the amount and EEG power density of the NREM sleep was observed following the arousal effects of CNO. The inhibition of VTA neurons during active or inactive periods gave rise to no change in the time spent in the wakefulness, REM, and NREM sleep compared with control. The results indicated that VTA neurons activated pharmacogentically played important roles in promoting wakefulness.

PMID: 28386207 [PubMed - in process]

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial-mesenchymal transition in vitro and predicts poor prognosis in glioma.

Tumour Biol. 2017 Mar;39(3):1010428317695022

Authors: Lv QL, Chen SH, Zhang X, Sun B, Hu L, Qu Q, Huang YT, Wang GH, Liu YL, Zhang YY, Zhou HH

Abstract
Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin β1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

PMID: 28349823 [PubMed - indexed for MEDLINE]

Evidence for circulating cancer stem-like cells and epithelial-mesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy.

Tumour Biol. 2017 Mar;39(3):1010428317695915

Authors: Mirza S, Jain N, Rawal R

Abstract
Lung cancer stem cells are supposed to be the main drivers of tumor initiation, maintenance, drug resistance, and relapse of the disease. Hence, identification of the cellular and molecular aspects of these cells is a prerequisite for targeted therapy of lung cancer. Currently, analysis of circulating tumor cells has the potential to become the main diagnostic technique to monitor disease progression or therapeutic response as it is non-invasive. However, accurate detection of circulating tumor cells has remained a challenge, as epithelial cell markers used so far are not always trustworthy for detecting circulating tumor cells, especially during epithelial-mesenchymal transition. As cancer stem cells are the only culprit to initiate metastatic tumors, our aim was to isolate and characterize circulating tumor stem cells rather than circulating tumor cells from the peripheral blood of NSCLC adenocarcinoma as limited data are available addressing the gene expression profiling of lung cancer stem cells. Here, we reveal that CD44(+)/CD24(-) population in circulation not only exhibit stem cell-related genes but also possess epithelial-mesenchymal transition characteristics. In conclusion, the use of one or more cancer stem cell markers along with epithelial, mesenchymal and epithelial mesenchymal transition markers will prospectively provide the most precise assessment of the threat for recurrence and metastatic disease and has a great potential for forthcoming applications in harvesting circulating tumor stem cells and their downstream applications. Our results will aid in developing diagnostic and prognostic modalities and personalized treatment regimens like dendritic cell-based immunotherapy that can be utilized for targeting and eliminating circulating tumor stem cells, to significantly reduce the possibility of relapse and improve clinical outcomes.

PMID: 28347243 [PubMed - indexed for MEDLINE]

Antioxidant polymorphisms do not influence the risk of epilepsy or its drug resistance after neonatal hypoxic-ischemic brain injury.

Seizure. 2017 Mar;46:38-42

Authors: Esih K, Goričar K, Dolžan V, Rener-Primec Z

Abstract
PURPOSE: The aim of this study was to investigate if common functional antioxidant polymorphisms are associated with epilepsy after neonatal hypoxic-ischemic encephalopathy (HIE). The antioxidant enzymes manganese superoxide dismutase (SOD2), glutathione peroxidase 1 (GPX1) and catalase (CAT) represent the primary defence mechanism against reactive oxygen species (ROS). Evidence suggests that genetic variants in antioxidant enzymes could influence susceptibility to epilepsy, but to date the relationship between them remains unclear.
METHODS: The study comprised 214 patients with epilepsy (64 with and 150 without neonatal HIE) as well as 95 healthy controls. Genomic DNA was isolated from buccal swabs or venous blood samples and genotyped for SOD2 rs4880, GPX1 rs1050450 and CAT rs1001179 using real-time PCR-based methods.
RESULTS: The investigated polymorphisms influenced neither the overall risk of epilepsy nor the risk of epilepsy after HIE in comparison with healthy controls. Furthermore, no significant difference in genotype distribution was observed between patients with drug-resistant epilepsy and patients in remission in either the group with epilepsy but without HIE or in the group with epilepsy and HIE, although the frequency of drug-resistant cases was higher in the latter group (p=0.009, OR=2.52; 95% CI=1.22-4.15).
CONCLUSION: According to this study, common GPX1, SOD2 and CAT polymorphisms do not influence the overall risk of epilepsy after HIE and its drug resistance.

PMID: 28222320 [PubMed - indexed for MEDLINE]

Critical evaluation of challenges and future use of animals in experimentation for biomedical research.

Int J Immunopathol Pharmacol. 2016 Dec;29(4):551-561

Authors: Singh VP, Pratap K, Sinha J, Desiraju K, Bahal D, Kukreti R

Abstract
Animal experiments that are conducted worldwide contribute to significant findings and breakthroughs in the understanding of the underlying mechanisms of various diseases, bringing up appropriate clinical interventions. However, their predictive value is often low, leading to translational failure. Problems like translational failure of animal studies and poorly designed animal experiments lead to loss of animal lives and less translatable data which affect research outcomes ethically and economically. Due to increasing complexities in animal usage with changes in public perception and stringent guidelines, it is becoming difficult to use animals for conducting studies. This review deals with challenges like poor experimental design and ethical concerns and discusses key concepts like sample size, statistics in experimental design, humane endpoints, economic assessment, species difference, housing conditions, and systematic reviews and meta-analyses that are often neglected. If practiced, these strategies can refine the procedures effectively and help translate the outcomes efficiently.

PMID: 27694614 [PubMed - indexed for MEDLINE]

Protein Requirements of the Critically Ill Pediatric Patient.

Nutr Clin Pract. 2017 Apr;32(1_suppl):128S-141S

Authors: Coss-Bu JA, Hamilton-Reeves J, Patel JJ, Morris CR, Hurt RT

Abstract
This article includes a review of protein needs in children during health and illness, as well as a detailed discussion of protein metabolism, including nitrogen balance during critical illness, and assessment and prescription/delivery of protein to critically ill children. The determination of protein requirements in children has been difficult and challenging. The protein needs in healthy children should be based on the amount needed to ensure adequate growth during infancy and childhood. Compared with adults, children require a continuous supply of nutrients to maintain growth. The protein requirement is expressed in average requirements and dietary reference intake, which represents values that cover the needs of 97.5% of the population. Critically ill children have an increased protein turnover due to an increase in whole-body protein synthesis and breakdown with protein degradation leading to loss of lean body mass (LBM) and development of growth failure, malnutrition, and worse clinical outcomes. The results of protein balance studies in critically ill children indicate higher protein needs, with infants and younger children requiring higher intakes per body weight compared with older children. Monitoring the side effects of increased protein intake should be performed. Recent studies found a survival benefit in critically ill children who received a higher percentage of prescribed energy and protein goal by the enteral route. Future randomized studies should evaluate the effect of protein dosing in different age groups on patient outcomes, including LBM, muscle structure and function, duration of mechanical ventilation, intensive care unit and hospital length of stay, and mortality.

PMID: 28388381 [PubMed - in process]

Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine.

Nutr Clin Pract. 2017 Apr;32(1_suppl):30S-47S

Authors: Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB

Abstract
Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

PMID: 28388380 [PubMed - in process]

WITHDRAWN: Interventions for fatigue and weight loss in adults with advanced progressive illness.

Cochrane Database Syst Rev. 2017 Apr 07;4:CD008427

Authors: Payne C, Wiffen PJ, Martin S

Abstract
BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress.
OBJECTIVES: To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews.
METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review.
MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies. Management of fatigueAmyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration. Management of weight lossALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition.
AUTHORS' CONCLUSIONS: There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.

PMID: 28387447 [PubMed - as supplied by publisher]