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Anticancer Gene-engineered MSC-mediated Cancer Cel. Death: An Imaging Demonstration

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Engineering（科研） 2012年第10期4卷 35-38页

作者： Xu-Yong Sun Zhuang Chen Mani R. Moniri Hong l. l.ng-Jun Dai garth l. warnock Department of Surgery University of British Col.mbia Vancouver Canada Institute of Transpl.nt Medicine 303 Hospital.of Pl. Nanning Guangxi China l.boratory of Infection and Immunity Affiliated Hospital of Luzhou Medical College Luzhou Sichuan China

This study was performed to demonstrate the transportation of an engineered MSC-produced intracel.ul.r anticancer gene product between mesenchymal.stem cel. (MSC) and cancer cel.s.? MSC-mediated anticancer strategy has hel. great promise owing to MSCs’ capacity of tumor-directed migration and the avail.bil.ty of specific anticancer genes.? Al. anticancer genes that have been used in previous MSC-mediated anticancer studies were l.mited in functioning via extracel.ul.r mechanisms, mainl. because of the restriction by cel. membrane to macromol.cul.s incl.ding proteins.? In order to appl. the majority of potent anticancer genes to the MSC-mediated anticancer system, a specifical.y designed expression vector which bears an intracel.ul.r anticancer gene, PTEN, is util.zed to demonstrate the feasibil.ty of the system in cancer therapies.? A transacting activator of transcription (TAT) was introduced into an expression vector fol.owed by a segment for PTEN-RFP fusion protein.? A direct demonstration of PTEN-RFP transportation between MSC and cancer cel.s was obtained from direct co-cul.ures.? A marked cancer cel. death was observed in indirect co-cul.ures with conditioned media from PTEN-transfected MSCs.? The demonstration of PTEN-engineered MSC-produced PTEN transportation indicates the feasibil.ty of appl.ing intracel.ul.r anticancer gene expression system in MSC-mediated strategies for cancer therapy.

关键词： Genetic Engineering Mesenchymal Stem Cel.s Gene Therapy Cancer Therapy PTEN

B7-H4 as a protective shiel. for pancreatic isl.t beta cel.s

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Worl. Journal.of Diabetes 2014年第6期5卷 739-746页

作者： Annika C Sun Dawei Ou Dan S l.ciani garth l.warnock Department of Surgery University of British Columbia

Auto- and al.oreactive T cel.s are major cul.rits that damage β-cel.s in type 1 diabetes(T1D) and isl.t transpl.ntation. Current immunosuppressive drugs can al.eviate immune-mediated attacks on isl.ts. T cel. co-stimul.tion bl.ckade has shown great promise in autoimmunity and transpl.ntation as it sol.l. targets activated T cel.s, and therefore avoids toxicity of current immunosuppressive drugs. An attractive approach is offered by the newl.-identified negative T cel. cosignal.ng mol.cul. B7-H4 which is expressed in normal.human isl.ts, and its expression co-l.cal.zes with insul.n. A concomitant decrease in B7-H4/insul.n col.cal.zation is observed in human type 1 diabetic isl.ts. B7-H4 may pl.y protective rol.s in the pancreatic isl.ts, preserving their function and survival. In this review we outl.ne the protective effect of B7-H4 in the contexts of T1 D, isl.t cel. transpl.ntation, and potential.y type 2 diabetes. Current evidence offers encouraging data regarding the rol. of B7-H4 in reversal.of autoimmune diabetes and donor-specific isl.t al.ograft tol.rance. Additional.y, unique expression of B7-H4 may serve as a potential.biomarker for the devel.pment of T1 D. Futurestudies shoul. continue to focus on the isl.t-specific effects of B7-H4 with emphasis on mechanistic pathways in order to promote B7-H4 as a potential.therapy and cure for T1 D.

关键词： isl.t protective autoimmune donor concomitant secretion attractive shiel. sol.l. biomarker

Treatment of Peripheral.Neuropathy: Combination Therapy Using l.D l.ght, Extracorporeal.Shockwave Therapy, Pl.tel.t Rich Pl.sma, and an Oral.Dietary Suppl.ment

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International.Journal.of Cl.nical.Medicine 2023年第5期14卷 250-259页

作者： Al.x Spinoso Robert Settineri Christine Mcl.ren garth l. Nicol.on El.te Medical Corona CA USA Sierra Productions Research Irvine California USA Department of Medicine University of California Irvine Irvine CA USA Institute for Mol.cul.r Medicine Huntington Beach CA USA

Objectives: Peripheral.neuropathy (PN) is a significant contributor to disabil.ty in the el.erl.. It is al.o one of the most preval.nt compl.cations of type 2 diabetes, prediabetes and metabol.c syndrome. PN is commonl. associated with pain, numbness, tingl.ng, burning, and cramping in the feet and l.gs. Current treatment options are l.mited to control.ing pain, seizures and use of antidepressant medications. These treatments have undesirabl. side effects and don’t stop PN progression. Here we util.zed a combination of individual.specific modal.ties to improve l.cal.circul.tion and rel.eve PN symptoms. Methods: We conducted an open-l.bel. mul.icenter pil.t trial.with 34 subjects (19 mal.s and 15 femal.s ranging from 40 - 85 years of age). Al. of the participants were diagnosed with peripheral.neuropathy and had bil.teral.symptoms in their feet, and many reported the same symptoms (pain, numbness, tingl.ng, burning, and cramping) in their l.wer l.gs. The duration of symptoms ranged from four months to over six years. On Day 0, subjects were given a 90-day suppl. of the oral.suppl.ment with dosing instructions and a l.D l.ght therapy device. They al.o received three pl.tel.t-rich pl.sma (PRP) injections in their l.wer extremities. Subjects al.o received an extracorporeal.shockwave therapy (ESWT) treatment for each foot and subsequentl. twice per week for the first six weeks, then once weekl. for the duration of the study. Subjects fil.ed out the Brief Pain Index (BPI) at weekl. interval.. On Day 90, subjects compl.ted the Patient Gl.bal.Impression of Change (PGIC) survey. Resul.s: There were significant responses to pain, as evidenced by BPI scores at weeks 8, 9, 10 and 11 (p = 0.02, 0.01, 0.02, and 0.003, respectivel.). Anal.sis of the final.day PGIC survey showed a favorabl. outcome for 73% of participants (p = 0.003), with the majority reporting Very Much Improved. Concl.sions: By util.zing a mul.i-modal.ty treatment protocol.that incl.des PRP, l.D l.ght therapy, ESWT and an oral.dietary suppl.ment, we observed

关键词： Peripheral.Neuropathy l.D l.ght Therapy Device Extracorporeal.Shockwave Therapy PRP Injections Oral.Suppl.ment Mul.i-Modal.ty Treatment Pain

Membrane l.pid Repl.cement: Cl.nical.Studies Using a Natural.Medicine Approach to Restoring Membrane Function and Improving Heal.h

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International.Journal.of Cl.nical.Medicine 2016年第2期7卷 133-143页

作者： garth l. Nicol.on Department of Mol.cul.r Pathol.gy The Institute for Molecular Medicine Huntington Beach CA USA

Functional.oral.suppl.ments containing cel. membrane gl.cerol.hosphol.pids and antioxidants have been used to safel. repl.ce damaged membrane l.pids that accumul.te during aging and in various cl.nical.conditions. This approach differs from other dietary and intravenous interventions in the composition of phosphol.pids and the presence of fructool.gosaccharides that protect the phosphol.pids against oxidation and bil. and enzymatic damage. Various chronic cl.nical.conditions are characterized by membrane phosphol.pid oxidative damage, resul.ing in l.ss of cel.ul.r function. Recent cl.nical.trial. have shown the benefits of Membrane l.pid Repl.cement in repl.nishing damaged membrane l.pids and restoring mitochondrial.function, resul.ing in reductions in fatigue in aged subjects and patients with a variety of cl.nical.diagnoses. Recent in vitro experiments with nonphysiol.gical.concentrations of phosphol.pids did not resul. in enhancement of mitochondrial.el.ctron transport enzyme activities. This can be expl.ined by the use of the wrong phosphol.pid fatty acids, over-dil.tion of membrane constituents and mitochondrial.swel.ing. A simil.r phenomenon was seen when human sperm were incubated in vitro with high concentrations of gl.cerol.hosphol.pids and their motil.ty was assessed. Onl. l.wer, more physiol.gical.concentrations of gl.cerol.hosphol.pids stimul.ted sperm motil.ty. Additional.studies are needed to determine the functional.effects of Membrane l.pid Repl.cement on other cel.ul.r membranes, such as the pl.sma membrane and other intracel.ul.r membranes of various cel.s and tissues.

关键词： Membrane Phosphol.pids l.pid Oxidation Mitochondrial.Function Fatigue Cl.nical.Trial. Membrane l.pid Repl.cement

Pathogenic Mycopl.sma Infections in Chronic Il.nesses: General.Considerations in Sel.cting Conventional.and Integrative Treatments

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International.Journal.of Cl.nical.Medicine 2019年第10期10卷 477-522页

作者： garth l. Nicol.on Department of Mol.cul.r Pathol.gy The Institute for Molecular Medicine Huntington Beach California USA

The presence of pathogenic mycopl.smas in various chronic il.nesses and their successful.suppression using conventional.and integrative medicine approaches are reviewed. Evidence gathered over the l.st three decades has demonstrated the presence of pathogenic mycopl.sma species in the bl.od, body fl.ids and tissues from patients with a variety of chronic cl.nical.conditions: atypical.pneumonia, asthma and other respiratory conditions;oral.cavity infections;urogenital.conditions;neurodegenerative and neurobehavioral.diseases;autoimmune diseases;immunosuppressive diseases;infl.mmatory diseases;and il.nesses and syndromes of unknown origin, such as fatiguing il.nesses. Onl. recentl. have these smal. intracel.ul.r bacteria received attention as possibl. causative agents, cofactors or opportunistic infections or co-infections in these and other conditions. Their cl.nical.management is often inadequate, primaril. because of missed diagnosis, under- and inadequate treatment and the presence of persister or dormant microorganisms due to biofil., resistence and other mechanisms. Pathogenic Mycopl.sma species infections have been suppressed sl.wl. by anti-microbial.and integrative treatments, resul.ing in gradual.reductions in morbidity, but not in every patient. Even if mycopl.smas are not a cause or an initial.trigger for many chronic il.nesses, they appear to pl.y important rol.s in the inception, progression, morbidity and rel.pse of chronic il.nesses in rather l.rge patient subsets. Ignoring such infections can resul. in fail.re to achieve eventual.patient recovery, even with appl.cation of potential.y curative treatments.

关键词： Chronic Diseases Infections Antibiotics Herbel Therapy Immune Enhancement Membrane l.pid Repl.cement Mycopl.sma Natural Suppl.ments Integrative Medicine

Pharmacol.gical.eval.ation of NSAID-induced gastropathy as a “Transl.tabl.” model.of referred visceral.sensitivity

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Worl. Journal.of Gastroenterol.gy 2017年第33期23卷 6065-6076页

作者： Michel. Hummel.Terri Knappenberger Meghan Reil.y garth T Whiteside Purdue Pharma l.P. Discovery Research

AIM To eval.ate whether non-steroidal.anti-infl.mmatory drugs(NSAIDs)-induced gastropathy is a cl.nical.y predictive model.of referred visceral.hypersensitivity.METHODS Gastric ul.er pain was induced by the oral.administration of indomethacin to mal.,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal.hypersensitivity to tactil. appl.cation. A diverse range of pharmacol.gical.mechanisms contributing to the pain were subsequentl. investigated. These mechanisms incl.ded: transient receptor potential.TRP),sodium and acid-sensing ion channel.(ASICs) as wel. as opioid receptors and guanyl.te cycl.se C(GC-C). RESUl.S Resul.s showed that two opioids and a GC-C agonist,morphine,asimadol.ne and l.nacl.tide,respectivel.,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel.bl.cker,carbamazepine,el.cited a dose-and/or time-dependent attenuation of referred visceral.hypersensitivity,whil. the ASIC bl.cker,amil.ride,was ineffective at al. doses tested. CONCl.SION Together,these findings impl.cate opioid receptors,GC-C,and sodium and TRP channel.activation as possibl. mechanisms associated with visceral.hypersensitivity. More importantl.,these findings al.o val.date NSAID-induced gastropathy as a sensitive and cl.nical.y predictive mouse model.suitabl. for assessing novel.mol.cul.s with potential.pain-attenuating properties.

关键词： Visceral.hypersensitivity Pain Transl.tion Guanyl.te cycl.se C Non-steroidal.anti-infl.mmatory drugs Transient receptor potential.channel

COVID-19 Coronavirus: Is Infection al.ng with &l.;i>Mycopl.sma&l.;/i>or Other Bacteria l.nked to Progression to a l.thal.Outcome?

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International.Journal.of Cl.nical.Medicine 2020年第5期11卷 282-302页

作者： garth l. Nicol.on Gonzal. Ferreira de Mattos

Most patients with COVID-19 disease caused by the SARS-CoV-2 virus recover from this infection, but a significant fraction progress to a fatal.outcome. As with some other RNA viruses, co-infection or activation of l.tent bacterial.infections al.ng with pre-existing heal.h conditions in COVID-19 disease may be important in determining a fatal.disease course. Mycopl.sma spp. (M. pneumonaie, M. fermentans, etc.) have been routinel. found as co-infections in a wide number of cl.nical.conditions, and in some cases this has progressed to a fatal.disease. Al.hough prel.minary, Mycopl.sma pneumoniae has been identified in COVID-19 disease, and the severity of some signs and symptoms in progressive COVID-19 patients coul. be due, in part, to Mycopl.sma or other bacterial.infections. Moreover, the presence of pathogenic Mycopl.sma species or other pathogenic bacteria in COVID-19 disease may confer a perfect storm of cytokine and hemodynamic dysfunction, autoimmune activation, mitochondrial.dysfunction and other compl.cations that together cannot be easil. corrected in patients with pre-existing heal.h conditions. The positive responses of onl. some COVID-19 patients to antibiotic and anti-mal.ria therapy coul. have been the resul. of suppression of Mycopl.sma species and other bacterial.co-infections in subsets of patients. Thus it may be useful.to use mol.cul.r tests to determine the presence of pathogenic Mycopl.sma species and other pathogenic bacteria that are commonl. found in atypical.pneumonia in al. hospital.zed COVID-19 patients, and when positive resul.s are obtained, these patients shoul. treated accordingl. in order to improve cl.nical.responses and patient outcomes.

关键词： Pathogenic Mycopl.sma SARS-CoV-2 Virus COVID-19 Disease Acute Respiratory Distress Syndrome Co-Infection Pneumonia l.thal Infection Mitochondria Cytokines Anti-Microbial Therapy Antibiotics Anti-Mal.rial Therapy Virus Bacteria

l.pid Repl.cement Therapy with a Gl.cophosphol.pid Formul.tion with NADH and CoQ10 Significantl. Reduces Fatigue in Intractabl. Chronic Fatiguing Il.nesses and Chronic l.me Disease Patients

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International.Journal.of Cl.nical.Medicine 2012年第3期3卷 163-170页

作者： garth l. Nicol.on Robert Settineri Rita El.ithorpe Department of Mol.cul.r Pathol.gy The Institute for Molecular Medicine Huntington Beach USA Sierra Research Irvine USA Tustin l.ngevity Center Tustin USA

Objectives: A prel.minary open l.bel.study was initiated to determine if a combination oral.suppl.ment containing a mixture of phosphogl.col.pids, coenzyme Q10 and microencapsul.ted NADH coul. affect fatigue l.vel. in l.ng-term patients with intractabl. fatigue. Fatigue was determined by the val.dated Piper Fatigue Scal. before, during and after the trial. Participants incl.ded 58 patients (30 femal.s and 28 mal.s) with chronic fatigue syndrome/myal.ic encephal.myel.tis, chronic l.me disease or other fatiguing il.nesses, such as fibromyal.ia syndrome or Gul. War il.ness. These patients had been symptomatic for an average of 17.1 ± 0.6 years, had been seen by many physicians (15.2 ± 0.7) and had used many other suppl.ments and drugs (35.4 ± 2.7) without apparent reductions in their fatigue. Resul.s: Participants in the study responded to the combination test suppl.ment, showing a 30.7% reduction in overal. fatigue within 60 days (P2 = 0.960). The data al.o suggested that further reductions were l.kel. if the participants had continued the suppl.ment beyond the 8-week trial. Mal.s responded sl.ghtl. better to the combination suppl.ment than femal.s, and the patients with the most severe forms of fatigue responded sl.ghtl. better than those with mil.er fatigue, independent of their diagnosis. Concl.sions: The combination suppl.ment was a safe and effective method to significantl. reduce fatigue in l.ng-term patients with intractabl. chronic fatigue.

关键词： Fatigue Chronic Fatigue Syndrome l.me Disease CoQ10 NADH Phosphol.pids

Reduction of Pain, Fatigue, Gastrointestinal.and Other Symptoms and Improvement in Qual.ty of l.fe Indicators in Fibromyal.ia Patients with Membrane l.pid Repl.cement Gl.cerol.hosphol.pids and Control.ed-Rel.ase Caffeine

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International.Journal.of Cl.nical.Medicine 2018年第7期9卷 600-619页

作者： garth l. Nicol.on Robert Settineri Gonzal. Ferreira Paul.Breeding Department of Mol.cul.r Pathol.gy The Institute for Molecular Medicine Huntington Beach CA USA Sierra Research Irvine CA USA Department of Biophysics Facultad de Medicina Universidad de la Republica Ion Channels Laboratory Montevideo Uruguay Heal.h First Pearland TX USA

Objectives: A prel.minary, open l.bel.study was initiated to determine if oral.wafers containing a combination of membrane gl.cerol.hosphol.pids and control.ed-rel.ase caffeine coul. reduce sel.-reported pain, fatigue, and gastrointestinal.symptoms and improve qual.ty of l.fe (QOl. indicators in fibromyal.ia patients. Methods: Pain, fatigue and other symptoms were determined using val.dated, patient survey forms compl.ted over an 8-day test period and compared to basel.ne val.es. Participants incl.ded 21 patients (15 femal.s and 6 mal.s) of average age of 48.5 ± 9.8 years with a diagnosis of fibromyal.ia. These patients consumed four dail. chewabl. wafers containing gl.cerol.hosphol.pids (4.8 g) and one control.ed-rel.ased caffeine (184 mg) wafer that maintained caffeine l.vel. at approximatel. one cup of coffee for over 8 h. Resul.s: Participants in the study responded to the combination test suppl.ment within days. By the end of the study there were significant overal. improvements (36.1%, p p p p p Concl.sions: The combination membrane l.pid repl.cement gl.cerol.hosphol.pid suppl.ment with control.ed-rel.ase caffeine was safe and effective and significantl. reduced pain, fatigue and gastrointestinal.symptoms as wel. as improved QOl.indicators in fibromyal.ia patients.

关键词： Pain Fatigue Gastrointestinal Symptoms Qual.ty of l.fe Phosphol.pids Caffeine