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Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

Cancer Biology & Medicine 2016年第2期13卷 277-285页

作者： Wei Liao Sanjai Sharma Division of Hematology-Oncology Greater Los Angeles VA Healthcare Center UCLA School of Medicine

Objective： Chronic lymphocytic leukemia （CLL） and mantle cell lymphoma （MCL） cells over-express a guanine exchange factor （GEF）, Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods： N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor （BCR） and chemokine signaling pathways were compared in the Rasgrf-I over-expressing and a control transfected cell line. Results： Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions： This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.

关键词： B-ceU malignancies mantle cell lymphoma chronic lymphocytic leukemia (CLL) B-cell receptor guanine exchange factorRasgrf- 1 ERK pathway

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Tattoos as a window to the psyche:How talking about skin art can inform psychiatric practice

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World Journal of Psychiatry 2017年第3期7卷 148-158页

作者： Hannah Roggenkamp Andrew Nicholls Joseph M Pierre Mental Illness Research Education and Clinical CenterVA Puget Sound Healthcare System va greater los angeles healthcare system Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at UCLA

Tattooing the skin as a means of personal expression is a ritualized practice that has been around for centuries across many different ***,the symbolic meaning of tattoos has evolved over time and is highly individualized,from both the internal perspective of the wearer and the external perspective of an *** modern Western societies through the 1970 s,tattoos represented a cultural taboo,typically associated with those outside of the mainstream such as soldiers,incarcerated criminals,gang members,and others belonging to marginalized and counter-cultural *** paper aims to review the more recent epidemiology of tattoos in Western culture in order to establish that tattooing has become a mainstream *** then review psychological and psychiatric aspects of tattoos,with a goal of revising outmoded stigmas about tattooing and helping clinicians working with tattooed patients to facilitate an exploration of the personal meaning of skin art and *** suggest that as a kind of augmentation of the physical exam,looking at and talking to patients about their tattoos can provide a valuable window into the psyche,informing clinical practice.

关键词： Tattoos Military psychiatry Deviance Skin art Psychopathology Psychology

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Sex hormones in the modulation of irritable bowel syndrome

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World Journal of Gastroenterology 2014年第10期20卷 2433-2448页

作者： Agata Mulak Yvette Taché Muriel Larauche Department of Gastroenterology and Hepatology Wroclaw Medical University 50-556 Wroclaw Poland CURE:Digestive Diseases Research Center and Oppenheimer Family Center for Neurobiology of Stress Digestive Diseases Division Department of MedicineUniversity of California Los Angeles VA Greater Los Angeles Healthcare System Los Angeles CA 90073 United States

Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.

关键词： Brain-gut axis Irritable bowel syndrome Microbiota Pain modulation Sex hormones

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Stem cell treatments for oropharyngeal dysphagia:Rationale,benefits,and challenges

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World Journal of Stem Cells 2020年第9期12卷 1001-1012页

作者： Eric K Tran Kevin O Juarez Jennifer L Long David Geffen School of Medicine University of California-Los AngelesLos AngelesCA 90095United States Department of Otolaryngology Yale School of MedicineNew HavenCT 06511United States Department of Head and Neck Surgery David Geffen School of MedicineUniversity of California-Los AngelesLos AngelesCA 90095United States greater los angeles va healthcare system Los AngelesCA 90073United States

Dysphagia,defined as difficulty swallowing,is a common symptom negatively impacting millions of adults *** prevalence ranges from 14 to 33 percent in those over age 65 to over 70 percent in a nursing home *** elderly,those with neurodegenerative diseases,head and neck cancer patients,and those with autoimmune conditions such as Sjögren's syndrome are disproportionately *** dysphagia refers specifically to difficulty in initiating a swallow due to dysfunction at or above the upper esophageal sphincter,and represents a large proportion of dysphagia *** treatments are limited and are often *** cell therapy is a new and novel advancement that may fill a much-needed role in our treatment ***,we review the current literature regarding stem cell treatments for oropharyngeal *** discussed include tissue regeneration advancements as a whole and translation of these principles into research surrounding tongue dysfunction,xerostomia,cricopharyngeal dysfunction,and finally an overview of the challenges and future directions for *** this field of study remains in its early stages,initial promising results show potential for the use of stem cell-based therapies to treat oropharyngeal dysphagia and warrant further research.

关键词： Dysphagia Xerostomia Hemiglossectomy Stem cells Myoblasts Mesenchymal stem cells

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Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: Down-regulation in ulcerative colitis

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World Journal of Gastroenterology 2013年第9期19卷 1416-1423页

作者： Ekaterini Chatzaki Peter A Anton Mulugeta Million Maria Lambropoulou Theodoros Constantinidis George Kolios Yvette Taché Dimitri E Grigoriadis Neurocrine Biosciences Inc. San Diego CA 92121 United States Laboratory of Pharmacology Faculty of Medicine Democritus University of Thrace 68100 Alexandroupolis Greece Center for HIV Prevention Research Division of Digestive Diseases University of California at Los Angeles and VA Greater Los Angeles Healthcare System Los Angeles CA 90073 United States Digestive Diseases Research Center and Center for Neurobiology of Stress Division of Digestive Diseases University of California at Los Angeles and VA Greater Los Angeles Healthcare System Los Angeles CA 90073 United States Laboratory of Histology-Embryology Faculty of Medicine Democritus University of Thrace 68100 Alexandroupolis Greece Laboratory of Hygiene and Environmental Protection Faculty of Medicine Democritus University of Thrace 68100 Alexandroupolis Greece

AIM: To assess corticotropin-releasing factor receptor 2 (CRF 2 ) expression in the colon of healthy subjects and patients with ulcerative colitis (UC). METHODS: We examined CRF2 gene and protein expression in the distal/sigmoid colonic mucosal biopsies from healthy subjects and patients with UC (active or disease in remission), human immunodeficiency virus (HIV) and functional bowel disease (FBD) by reverse transcriptionpolymerase chain reaction and immunofluorescence. RESULTS: Gene expression of CRF2 was demonstrated in the normal human colonic biopsies, but not in the human colorectal adenocarcinoma cell line Caco2. Receptor protein localization showed immunoreactive CRF 2 receptors in the lamina propria and in the epithelial cells of the distal/sigmoid biopsy samples. Interestingly, CRF 2 immunoreactivity was no longer observed in epithelial cells of patients with mild-moderately active UC and disease in remission, while receptor protein expression did not change in the lamina propria. No differences in CRF 2 expression profile were observed in distal/sigmoid intestinal biopsies from HIV infection and FBD patients, showing no signs of inflammation. CONCLUSION: The down-regulation of the CRF2 receptor in the distal/sigmoid biopsies of UC patients is indicative of change in CRF 2 signalling associated with the process of inflammation.

关键词： Colonic mucosa Corticotropin-releasing factor Corticotropin-releasing factor receptor Human immunodeficiency virus Ulcerative colitis Urocortin

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Cultured circulating tumor cells and their derived xenografts for personalized oncology

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Asian Journal of Urology 2016年第4期3卷 240-253页

作者： Ruoxiang Wang Gina CYChu Stefan Mrdenovic Alagappan A.Annamalai Andrew E.Hendifar Nicholas N.Nissen James S.Tomlinson Michael Lewis Nallasivam Palanisamy Hsian-Rong Tseng Edwin M.Posadas Michael R.Freeman Stephen J.Pandol Haiyen E.Zhau Leland W.K.Chung Uro-Oncology Research Department of MedicineSamuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA Uro-Oncology Research Department of SurgerySamuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA Department of Surgery West Los Angeles VA HospitalGreater Los Angeles Veterans Affairs Healthcare SystemLos AngelesCAUSA Department of Pathology West Los Angeles VA HospitalGreater Los Angeles Veterans Affairs Healthcare SystemLos AngelesCAUSA Henry Ford Health system DetroitMIUSA Department of Molecular and Medical Pharmacology University of California Los AngelesLos AngelesCAUSA

Recent cancer research has demonstrated the existence of circulating tumor cells(CTCs)in cancer patient’s *** identified,CTC biomarkers will be invaluable tools for clinical diagnosis,prognosis and *** this review,we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample,to derive enough CTCs for accurate and reproducible characterization of the biophysical,biochemical,gene expressional and behavioral properties of the harvested *** of tumor cell heterogeneity,it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer *** analyzing critical steps and technical issues in ex vivo CTC culture,we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells,relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells.

关键词： Cancer metastasis Peripheral blood Circulating tumor cell ex vivo culture

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Design and strategy for manufacturing kidney organoids

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Bio-Design and Manufacturing 2020年第1期3卷 7-14页

作者： Masaki Nishikawa Yasuyuki Sakai Norimoto Yanagawa Department of Chemical system Engineering School of EngineeringUniversity of TokyoRm.5A01Engineering Bldg.3Hongo 7‑3‑1BunkyoTokyo 113‑8656Japan Medical and Research Services Greater Los Angeles Veterans Affairs Healthcare System at SepulvedaNorth HillsCAUSA David Geffen School of Medicine University of California at Los AngelesLos AngelesCAUSA

Despite a continuing increase in the number of patients suffering from chronic kidney disease,currently available treatments for these patients,such as dialysis and kidney transplantation,are *** kidney is also a critical target organ vulnerable to the toxicity of various new drugs,and the lack of a reliable in vitro culture model imposes a severe limitation on drug *** the development of induced pluripotent stem cells(iPSCs)revolutionized strategies in biomedical fields,the complexity of the kidney imposed additional challenge to the application of this technology in kidney ***,the recent advancement in our understanding on the developmental origin of kidney progenitor cells and the mechanisms of their reciprocal induction and self-organization has boosted research in kidney *** since then has demonstrated that kidney organoids derived from iPSCs can serve as a useful model for drug discovery and toxicity screening,as well as for disease modeling,especially in combination with gene editing ***,attempts at kidney organoid implantation in animals have suggested their potential as an alternative source of kidney *** this review,we summarize recent progress on the generation of kidney organoids,as well as the obstacles that remain.

关键词： Kidney organoid Kidney development iPSC Progenitor cell Self-organization Regenerative medicine

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Impact of sustained virologic response on chronic kidney disease progression in hepatitis C

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World Journal of Hepatology 2017年第36期9卷 1352-1360页

作者： Elizabeth S Aby Tien S Dong Jenna Kawamoto Joseph R Pisegna Jihane N Benhammou Division of Gastroenterology Hepatology and Parenteral Nutrition Department of Medicine VA Greater Los Angeles Healthcare System the vatche and Tamar Manoukian Division of Digestive Diseases UCLA Los Angeles Department of Medicine University of California David Geffen School of Medicine

AIM To determine how sustained virological response at 12 wk(SVR12) with direct acting antivirals(DAAs) for the treatment of hepatitis C virus(HCV) infection affects chronic kidney disease(CKD) progression. METHODS A retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the va greater los angeles healthcare system from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for *** Five hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate(e GFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 m L/min ± 0.75 m L/min per 1.73 m^2 compared to a decline in e GFR of 11.0 m L/min ± 2.81 m L/min per 1.73 m^2 in patients who did not achieve SVR12(P = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in e GFR in those with untreated HCV over 2 years was 2.8 m L/min ± 1.0 m L/min per 1.73 m^2, which was not significantly different from the e GFR decline noted in HCV-treated patients who achieved SVR12(P = 0.43).CONCLUSION Patients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.

关键词： Hepatitis C Direct-acting antivirals Chronic kidney disease End stage renal disease Sustained virological response

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Distinguishing normal brain aging from the development of Alzheimer＇s disease：inflammation,insulin signaling and cognition

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Neural Regeneration Research 2018年第10期13卷 1719-1730页

作者： Paul Denver Paula L.McClean greater los angeles Veterans Affairs healthcare system West Los Angeles Medical Center and Department of NeurologyUniversity of CaliforniaLos AngelesCAUSA Centre for Molecular Biosciences University of UlsterColeraine Northern Ireland UK Northern Ireland Centre for Stratified Medicine ClinicalTranslational and Research Innovation Centre (C-TRIC)University of UlsterDerry/Londonderry Northern Ireland UK

As populations age, prevalence of Alzheimer＇s disease（AD） is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

关键词： Alzheimer's disease aging inflammation cognitive function spatial learning insulin signaling synapses cytokines

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Epistaxis in end stage liver disease masquerading as severe upper gastrointestinal hemorrhage

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World Journal of Gastroenterology 2014年第38期20卷 13993-13998页

作者： Marine Camus Dennis M Jensen Jason D Matthews Gordon V Ohning Thomas O Kovacs Rome Jutabha Kevin A Ghassemi Gustavo A Machicado Gareth S Dulai CURE Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of California Division of Digestive Diseases at University of California Los AngelesRonald Reagan Medical Center Department of Gastroenterology Lariboisiere Hospital CURE Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of CaliforniaLos AngelesLos AngelesCA 90095United States Gastroenterology Division at va greater los angeles healthcare system Hunterdon Gastrointestinal Associates

AIM: To describe the prevalence, diagnosis, treatment, and outcomes of end stage liver disease (ESLD) patients with severe epistaxis thought to be severe upper gastrointestinal hemorrhage (UGIH).

关键词： Epistaxis Upper gastrointestinal bleeding End stage liver disease Cirrhosis Nasogastric tube Liver transplantation Digestive bleeding Nasal packing Coagulopathy

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