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Dorsoradial Instability of the Thumb Metacarpophalangeal Joint: A Biomechanical Investigation.
J Hand Surg Am. 2017 Aug 11;
To define the role of the dorsal capsule and associated dorsal fibrocartilage (DFC) and their interactions with the radial collateral ligament (RCL) as a thumb metacarpophalangeal (MCP) joint stabilizer.
Aburjania Z,Jang S,Montemayor-Garcia C,Lloyd RV,Schneider DF,Sippel RS,Chen H,Elfenbein DM
Encapsulated follicular variant of papillary thyroid cancer: are these tumors really benign?
J Surg Res. 2017 Aug;216:138-142
Recent studies suggest that the encapsulated form of follicular variant of papillary thyroid cancer (eFVPTC) behaves more similarly to benign lesions and can be treated with thyroid lobectomy alone instead of total thyroidectomy. To distinguish aggressive cancers from more benign lesions more clearly, the objective of this study was to determine if the eFVPTC behaves less aggressively than the nonencapsulated variant (neFVPTC).
Arbuckle C,Greenberg M,Bergh A,German R,Sirago N,Linstead E
T-Time: A data repository of T cell and calcium release-activated calcium channel activation imagery.
BMC Res Notes. 2017 Aug 15;10(1):408
A fundamental understanding of live-cell dynamics is necessary in order to advance scientific techniques and personalized medicine. For this understanding to be possible, image processing techniques, probes, tracking algorithms and many other methodologies must be improved. Currently there are no large open-source datasets containing live-cell imaging to act as a standard for the community. As a result, researchers cannot evaluate their methodologies on an independent benchmark or leverage such a dataset to formulate scientific questions.
Rock EM,Moreno-Sanz G,Limebeer CL,Petrie GN,Angelini R,Piomelli D,Parker LA
Suppression of acute and anticipatory nausea by peripherally restricted FAAH inhibitor in animal models: Role of PPARα and CB1 receptors.
Br J Pharmacol. 2017 Aug 14;
To evaluate the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) to suppress acute and anticipatory nausea in rats, and to examine the pharmacological mechanism of such an effect.
Gu S,Sayad A,Chan G,Yang W,Lu Z,Virtanen C,Van Etten RA,Neel BG
SHP2 is required for BCR-ABL1-induced hematologic neoplasia.
Leukemia. 2017 Aug 14;
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph(+)) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1(+) B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1(+) B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1(+), but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1(+) pre-B cells, but is only required for the proliferation of BCR-ABL1(+) cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1(+) pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1(+) and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.Leukemia accepted article preview online, 14 August 2017. doi:10.1038/leu.2017.250.
Bernhardt J,Borschmann K,Boyd L,Carmichael ST,Corbett D,Cramer SC,Hoffmann T,Kwakkel G,Savitz S,Saposnik G,Walker M,Ward N
Moving Rehabilitation Research Forward: Developing Consensus Statements for Rehabilitation and Recovery Research.
Neurorehabil Neural Repair. 2017 Aug;31(8):694-698
Stroke recovery is the next frontier in stroke medicine. While growth in rehabilitation and recovery research is exponential, a number of barriers hamper our ability to rapidly progress the field. Standardized terminology is absent in both animal and human research, methods are poorly described, recovery biomarkers are not well defined, and we lack consistent timeframes or measures to examine outcomes. Agreed methods and conventions for developing, monitoring, evaluating and reporting interventions directed at improving recovery are lacking, and current approaches are often not underpinned by biology. We urgently need to better understand the biology of recovery and its time course in both animals and humans to translate evidence from basic science into clinical trials. A new international partnership of stroke recovery and rehabilitation experts has committed to advancing the research agenda. In May 2016, the first Stroke Recovery and Rehabilitation Roundtable will be held, with the aim of achieving an agreed approach to the development, conduct and reporting of research. A range of methods will be used to achieve consensus in four priority areas: pre-clinical recovery research; biomarkers of recovery; intervention development, monitoring and reporting; and measurement in clinical trials. We hope to foster a global network of researchers committed to advancing this exciting field. Recovery from stroke is challenging for many survivors. They deserve effective treatments underpinned by our evolving understanding of brain recovery and human behaviour. Working together, we can develop game-changing interventions to improve recovery and quality of life in those living with stroke.
Chou JA,Kalantar-Zadeh K
Volume Balance and Intradialytic Ultrafiltration Rate in the Hemodialysis Patient.
Curr Heart Fail Rep. 2017 Aug 12;
Volume management in hemodialysis patients is often challenging. Assessing volume status and deciding how much fluid to remove during hemodialysis, the so-called ultrafiltration rate (UFR), has remained a conundrum.
Hoffman P,Sajjadi SA,Patterson K,Nestor PJ
Data-driven classification of patients with primary progressive aphasia.
Brain Lang. 2017 Aug 10;174:86-93
Current diagnostic criteria classify primary progressive aphasia into three variants-semantic (sv), nonfluent (nfv) and logopenic (lv) PPA-though the adequacy of this scheme is debated. This study took a data-driven approach, applying k-means clustering to data from 43 PPA patients. The algorithm grouped patients based on similarities in language, semantic and non-linguistic cognitive scores. The optimum solution consisted of three groups. One group, almost exclusively those diagnosed as svPPA, displayed a selective semantic impairment. A second cluster, with impairments to speech production, repetition and syntactic processing, contained a majority of patients with nfvPPA but also some lvPPA patients. The final group exhibited more severe deficits to speech, repetition and syntax as well as semantic and other cognitive deficits. These results suggest that, amongst cases of non-semantic PPA, differentiation mainly reflects overall degree of language/cognitive impairment. The observed patterns were scarcely affected by inclusion/exclusion of non-linguistic cognitive scores.
Residual Risk After Treatment of Patients With Atherosclerotic Cardiovascular Disease With Proprotein Convertase Subtilisin-Kexin Type 9 Monoclonal Antibody Therapy (from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk Trial).
Am J Cardiol. 2017 Jul 17;
Solanas G,Peixoto FO,Perdiguero E,Jardí M,Ruiz-Bonilla V,Datta D,Symeonidi A,Castellanos A,Welz PS,Caballero JM,Sassone-Corsi P,Muñoz-Cánoves P,Benitah SA
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress.
Cell. 2017 Aug 10;170(4):678-692.e20
Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.
Sato S,Solanas G,Peixoto FO,Bee L,Symeonidi A,Schmidt MS,Brenner C,Masri S,Benitah SA,Sassone-Corsi P
Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging.
Cell. 2017 Aug 10;170(4):664-677.e11
The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD(+)-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.
Fruman DA,Chiu H,Hopkins BD,Bagrodia S,Cantley LC,Abraham RT
The PI3K Pathway in Human Disease.
Cell. 2017 Aug 10;170(4):605-635
Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.
Ziadeh C,Ziogas A,Anton-Culver H
Cancer risk in different generations of Middle Eastern Immigrants to California, 1988-2013.
Int J Cancer. 2017 Aug 12;
The objective of this study is to compare cancer risk among different generations of Middle Eastern (ME) immigrants and Non-Hispanic Whites (NHW) in California between 1988 and 2013. We used data from the California Cancer Registry to identify invasive primary incident cancer cases in three population groups: a) first generation ME immigrants, b) second or subsequent generations ME immigrants, and c) NHW. Proportional Incidence Ratio (PIR) was used to compare cancer risk of the 15 selected most common cancers in the 3 population groups taking into consideration time since immigration for first generation ME immigrants. First generation ME immigrants were more likely to be at increased risk of stomach (PIR= 3.13) and hepatobiliary (PIR=2.27) cancers in females and thyroid (PIR=2.19) and stomach (PIR=2.13) cancers in males in comparison with NHW. Second or subsequent generations ME immigrants were at increased risk of thyroid cancer (PIR=1.43 in females and 2.00 in males) in comparison with NHW, and malignant melanoma cancer (PIR=4.53 in females and 4.61 in males) in comparison with first generation ME immigrants. The risk levels of breast, thyroid, and bladder cancers in ME first generation were significantly higher compared to NHW regardless of time spent in the United States suggesting the role of genetic predisposition, and/or cultural characteristics associated with these cancers. The results suggest that differences in cancer risk between ME first generation immigrants and NHW change in second or subsequent generations, approaching the risk level of NHW and indicating the impact of acculturation in this immigrant population. This article is protected by copyright. All rights reserved.
Mei L,Xue G,Lu ZL,Chen C,Wei M,He Q,Dong Q
Corrigendum to "Long-term experience with Chinese language shapes the fusiform asymmetry of English reading" [NeuroImage 110 (2015) 3-10].
Neuroimage. 2017 Aug 08;
Mei L,Xue G,Lu ZL,He Q,Wei M,Zhang M,Dong Q,Chen C
Corrigendum to "Native language experience shapes neural basis of addressed and assembled phonologies" [Neuroimage 114 (2015) 38-48].
Neuroimage. 2017 Aug 08;
Tognini P,Thaiss CA,Elinav E,Sassone-Corsi P
Circadian Coordination of Antimicrobial Responses.
Cell Host Microbe. 2017 Aug 09;22(2):185-192
Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses. We summarize the molecular strategies employed by the circadian system against specific pathogens, the core-clock proteins as well as cells in which they are expressed that mediate host defense, and the consequences of circadian variations on immune function. Furthermore, we highlight the possible implications of such circadian gating in immune reactions against pathogenic infections for the chronopharmacology of antibacterial and antiviral therapies.
Jabbari B,Vaziri ND
The nature, consequences, and management of neurological disorders in chronic kidney disease.
Hemodial Int. 2017 Aug 11;
Perhaps no other organ in the body is affected as often and in as many ways as the brain is in patients with chronic kidney disease (CKD). Several factors contribute to the neurological disorders in CKD including accumulation of uremic toxins, metabolic and hemodynamic disorders, oxidative stress, inflammation, and impaired blood brain barrier among others. The neurological disorders in CKD involve both peripheral and central nervous system. The peripheral neurological symptoms of CKD are due to somatic and cranial peripheral neuropathies as well as a myopathy. The central neurological symptoms of CKD are due to the cortical predominantly cortical, or subcortical lesions. Cognitive decline, encephalopathy, cortical myoclonus, asterixis and epileptic seizures are distinct features of the cortical disorders of CKD. Diffuse white matter disease due to ischemia and hypoxia may be an important cause of subcortical encephalopathy. A special and more benign form of subcortical disorder caused by brain edema in CKD is termed posterior reversible encephalopathy. Subcortical pathology especially when it affects the basal ganglia causes a number of movement disorders including Parkinsonism, chorea and dystonia. A stimulus-sensitive reflex myoclonus is believed to originate from the medullary structures. Sleep disorder and restless leg syndrome are common in CKD and have both central and peripheral origin. This article provides an overview of the available data on the nature, prevalence, pathophysiology, consequences and treatment of neurological complications of CKD.
Agrawal A,Agrawal S,Gupta S
Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly.
Front Immunol. 2017;8:896
Dendritic cells (DCs) play an important role in advancing age-associated progressive decline in adaptive immune responses, loss of tolerance, and development of chronic inflammation. In aged humans, DCs secrete increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory and immune-regulatory cytokines. This may contribute to both chronic inflammation and loss of tolerance in aging. Aged DCs also display increased immune response against self-antigens contributing further to both inflammation and loss of tolerance. The secretion of innate protective cytokines such as type I and III interferons is decreased, and the function of DCs in airway remodeling and inflammation in aged is also compromised. Furthermore, the capacity of DCs to prime T cell responses also seems to be affected. Collectively, these changes in DC functions contribute to the immune dysfunction and inflammation in the elderly. This review only focuses on age-associated changes in DC function in humans.
Kim A,Popovici J,Vantaux A,Samreth R,Bin S,Kim S,Roesch C,Liang L,Davies H,Felgner P,Herrera S,Arévalo-Herrera M,Ménard D,Serre D
Characterization of P. vivax blood stage transcriptomes from field isolates reveals similarities among infections and complex gene isoforms.
Sci Rep. 2017 Aug 10;7(1):7761
Our understanding of the structure and regulation of Plasmodium vivax genes is limited by our inability to grow the parasites in long-term in vitro cultures. Most P. vivax studies must therefore rely on patient samples, which typically display a low proportion of parasites and asynchronous parasites. Here, we present stranded RNA-seq data generated directly from a small volume of blood from three Cambodian vivax malaria patients collected before treatment. Our analyses show surprising similarities of the parasite gene expression patterns across infections, despite extensive variations in parasite stage proportion. These similarities contrast with the unique gene expression patterns observed in sporozoites isolated from salivary glands of infected Colombian mosquitoes. Our analyses also indicate that more than 10% of P. vivax genes encode multiple, often undescribed, protein-coding sequences, potentially increasing the diversity of proteins synthesized by blood stage parasites. These data also greatly improve the annotations of P. vivax gene untranslated regions, providing an important resource for future studies of specific genes.
Stokes WA,Amini A,Jackson MW,Plimpton SR,Kounalakis N,Kabos P,Rabinovitch RA,Rusthoven CG,Fisher CM
Patterns of Fractionation and Boost Usage in Adjuvant External Beam Radiotherapy for Ductal Carcinoma in Situ in the United States.
Clin Breast Cancer. 2017 Jun 29;
While the roles of hypofractionated (HFxn) radiotherapy and lumpectomy boost in the adjuvant management of invasive breast cancer are supported by the results of clinical trials, randomized data supporting their use for ductal carcinoma in situ (DCIS) are forthcoming. We sought to evaluate current national trends and identify factors associated with HFxn and boost usage using the National Cancer Database.
Gupta A,Lau E,Varshney R,Hulten EA,Cheezum M,Bittencourt MS,Blaha MJ,Wong ND,Blumenthal RS,Budoff MJ,Umscheid CA,Nasir K,Blankstein R
The Identification of Calcified Coronary Plaque Is Associated With Initiation and Continuation of Pharmacological and Lifestyle Preventive Therapies: A Systematic Review and Meta-Analysis.
JACC Cardiovasc Imaging. 2017 Aug;10(8):833-842
The aim of this study was to assess the odds of initiation or continuation of pharmacological and lifestyle preventive therapies in patients with nonzero versus zero coronary artery calcium (CAC) score detected on cardiac computed tomography.
Hoyt DB,Angelos P
Concurrent Surgery: What is Appropriate?
Adv Surg. 2017 Sep;51(1):113-124
Yang J,Liu H,Liu X,Gu C,Luo R,Chen HF
Synergistic Allosteric Mechanism of Fructose-1,6-bisphosphate and Serine for Pyruvate Kinase M2 via Dynamics Fluctuation Network Analysis.
J Chem Inf Model. 2016 Jun 27;56(6):1184-1192
Pyruvate kinase M2 (PKM2) plays a key role in tumor metabolism and regulates the rate-limiting final step of glycolysis. In tumor cells, there are two allosteric effectors for PKM2: fructose-1,6-bisphosphate (FBP) and serine. However, the relationship between FBP and serine for allosteric regulation of PKM2 is unknown. Here we constructed residue/residue fluctuation correlation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in bound PKM2 is distinctly different from that in the free state, FBP/PKM2, or Ser/PKM2. The community network analysis indicates that the information can freely transfer from the allosteric sites of FBP and serine to the substrate site in bound PKM2, while there exists a bottleneck for information transfer in the network of the free state. Furthermore, the binding free energy between the substrate and PKM2 for bound PKM2 is significantly lower than either of FBP/PKM2 or Ser/PKM2. Thus, a hypothesis of "synergistic allosteric mechanism" is proposed for the allosteric regulation of FBP and serine. This hypothesis was further confirmed by the perturbational and mutational analyses of community networks and binding free energies. Finally, two possible synergistic allosteric pathways of FBP-K433-T459-R461-A109-V71-R73-MG2-OXL and Ser-I47-C49-R73-MG2-OXL were identified based on the shortest path algorithm and were confirmed by the network perturbation analysis. Interestingly, no similar pathways could be found in the free state. The process targeting on the allosteric pathways can better regulate the glycolysis of PKM2 and significantly inhibit the progression of tumor.
Livne-Luzon S,Ovadia O,Weber G,Avidan Y,Migael H,Glassman SI,Bruns TD,Shemesh H
Small-scale spatial variability in the distribution of ectomycorrhizal fungi affects plant performance and fungal diversity.
Ecol Lett. 2017 Sep;20(9):1192-1202
The effects of spatial heterogeneity in negative biological interactions on individual performance and species diversity have been studied extensively. However, little is known about the respective effects involving positive biological interactions, including the symbiosis between plants and ectomycorrhizal (EM) fungi. Using a greenhouse bioassay, we explored how spatial heterogeneity of natural soil inoculum influences the performance of pine seedlings and composition of their root-associated EM fungi. When the inoculum was homogenously distributed, a single EM fungal taxon dominated the roots of most pine seedlings, reducing the diversity of EM fungi at the treatment level, while substantially improving pine seedling performance. In contrast, clumped inoculum allowed the proliferation of several different EM fungi, increasing the overall EM fungal diversity. The most dominant EM fungal taxon detected in the homogeneous treatment was also a highly beneficial mutualist, implying that the trade-off between competitive ability and mutualistic capacity does not always exist.
Elsensohn A,Mo JH,Maly TJ,Lee PK,de Feraudy S
Myoepithelioma of Soft Tissue With Both Squamous and Adipocytic Metaplasia.
Am J Dermatopathol. 2017 Aug 03;
Soft tissue, or cutaneous, myoepitheliomas are rare tumors arising solely from a myoepithelial origin. These neoplasms are typically associated with uncertain differentiation and can contain cellular morphologies that include spindle, plasmacytoid, epithelioid, or clear cell forms. Soft tissue myoepitheliomas are commonly found on the lower limbs and in the pelvic girdle but can occur throughout the body. A small minority display heterogenous differentiation, typically osseous or cartilaginous in nature. Squamous and adipocytic cell types are much rarer. We report the case of myoepithelioma of soft tissue with both squamous and adipocytic metaplasia. In the largest myoepithelioma series of 101 soft tissue myoepitheliomas, there were only 2 cases of squamous metaplasia and 1 case of adipocytic metaplasia. Our case displays the unique occurrence of 2 rare histologic findings occurring simultaneously within an already uncommon neoplasm.