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Kinase inhibitors:look beyond the label on the bottle

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Cancer Drug Resistance 2019年第4期2卷 1032-1043页

作者： Paul Dent Andrew Poklepovic Laurence Booth john f.Hancock Department of Biochemistry and Molecular Biology1 Virginia Commonwealth UniversityRichmondVA 23298-0035USA Department of Medicine Virginia Commonwealth UniversityRichmondVA 23298-0035USA Department of Integrative Biology and Pharmacology University of Texas Health Science CenterHoustonTX 77030USA

The majority of scientists working in the field of cancer experimental therapeutics recognize that many drugs that claim to be“specific”for one target enzyme in fact regulate to varying degrees the activities of other additional protein *** of these targets are known and are recognized as being an essential component of a drug’s ***,many other targets fall into the category of“unknown unknowns”.Thus,the collective therapeutic outcome for almost all clinically relevant drugs is reliant on both the claimed primary and secondary“on”targets as well as some of the unexpected unknown“off”*** review discusses the biology of several fDA approved cancer therapeutic drugs whose initial reported targets only represented the tip-of-the-iceberg in terms of how each agent acted as an anti-tumor *** review also discusses a putative thorough pre-visualization methodology for drug-based research,prior to executing any wet *** approaches should be performed in an agnostic fashion and be based in part on the clinically safe drug’s C max and its area under the curve in a *** on tumor heterogeneity,considerations of how to approach developmental therapeutics in the age of“personalized medicine”are also discussed.

关键词： Autophagy histone deacetylase chaperone cancer

GDNf to the rescue:GDNf delivery effects on motor neurons and nerves,and muscle re-innervation after peripheral nerve injuries

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Neural Regeneration Research 2022年第4期17卷 748-753页

作者： Alberto f.Cintrón-Colón Gabriel Almeida-Alves Juliana M.VanGyseghem john M.Spitsbergen Biological Sciences Department Western Michigan UniversityKalamazooMIUSA

Peripheral nerve injuries commonly occur due to trauma,like a traffic *** nerves get severed,causing motor neuron death and potential muscle *** current golden standard to treat peripheral nerve lesions,especially lesions with large(≥3 cm)nerve gaps,is the use of a nerve autograft or reimplantation in cases where nerve root avulsions *** not tended early,degeneration of motor neurons and loss of axon regeneration can occur,leading to loss of *** surgical procedures exist,patients often do not fully recover,and quality of life *** nerves have limited regeneration,and it is usually mediated by Schwann cells and neurotrophic factors,like glial cell line-derived neurotrophic factor,as seen in Wallerian *** cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite *** cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy,sciatic nerve crush,and compression,thus creating great interest to explore this protein as a potential treatment for peripheral nerve *** glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve *** this review,we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor,the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries,delivery systems,and complementary treatments(electrical muscle stimulation and exercise).Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients'quality of life.

关键词： electrical muscle stimulation exercise glial cell line-derived neurotrophic factor glial cell line-derived neurotrophic factor delivery motor neuron nerve gap neurotrophic factor peripheral nerve injury Schwann cells skeletal muscle atrophy

Optical read-out and modulation of peripheral nerve activity

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Neural Regeneration Research 2018年第1期13卷 58-61页

作者： Arjun K.fontaine Hans E.Anderson john H.Caldwell Richard f.Weir Department of Bioengineering University of Colorado – Anschutz Medical Campus Department of Cell and Developmental Biology University of Colorado – Anschutz Medical Campus

Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine’, has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific （individual axon） communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell （axon） types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.

关键词： peripheral nerve interface optogenetics bioelectronic medicine prosthesis control adeno-associated virus GCaMP

Bioartificial liver assist devices in support of patients with liver failure

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Hepatobiliary & Pancreatic Diseases International 2002年第1期1卷 18-25页

作者： john f.PatzerⅡ Roberto C.Lopez George V.Mazariegos john J.fung from the Thomas E Starzl Transplantation Institute

Bioartificial liver assist devices (BALs) offer anopportunity for critical care physicians and transplantsurgeons to stabilize patients prior to orthotopic livertransplantation. Such devices may also act as a bridgeto transplant, providing liver support to patientsawaiting transplant, or as support for patients post liv-ing-related donor transplant. four BAL devices thatrely on hepatocytes cultured in hollow fiber membranecartridges (Circe Biomedical HepatAssist (r), VitagenELADTM, Gerlach BELS, and Excorp Medical BLSS)are currently in various stages of clinical evalua-tion. Comparison of the four devices shows that severalunique approaches based upon the same overall systemarchitecture are possible. Preliminary results of theExcorp Medical BLSS Phase I safety evaluation at theUniversity of Pittsburgh, after treating four patients(f, 41, acetominophen-induced, two support periods;M, 50, Wilson's disease, one support period; f, 53, a-cute alcoholic hepatitis, two support periods; f, 24,chemotherapy-induced, one support period) are pre-sented. All patients presented with hypoglycemia andtransient hypotension at the start of extracorporealperfusion. Hypoglycemia was treated by IV dextroseand the transient hypotension responded positively toIV fluid bolus. Heparin anticoagulation was used onlyin the second patient. No serious or adverse eventswere noted in the four patients. Moderate biochemicalresponse to support was noted in all patients. Morecomplete characterization of the safety of the BLSSrequires completion of the Phase I safety evaluation.

关键词： bioartificial liver acute liver failure hepatocytes

Influence of drying technique on chemical composition and ruminal degradability of subtropical Cajanus cajan L.

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Animal Nutrition 2019年第1期5卷 95-100页

作者： Lindokuhle S.Buthelezi john f.Mupangwa Voster Muchenje florence V.Nherera-Chokuda University of fort Hare Department of Livestock and Pasture Science Agricultural Research Council Animal Production Institute

The experiment investigated the influence of forage drying methods on the dry-matter digestibility of foliage from Cajanus cajan varieties(ICEAP 00557, ICEAP 01514 and CIMMYT100/01). These leaves were harvested at week 20 of growth and either oven-or shade-dried and analysed for chemical components and rumen degradability. Three rumen fistulated lactating Holstein cows(430 ± 18 kg live weight) were used to evaluate ruminal degradation kinetics using in vitro and in sacco procedures. Samples were incubated for 0, 4, 8, 12, 24, 30 and 48 h in vitro(Ⅳ Daisy^(Ⅱ)) procedure. In the in sacco procedure, samples were incubated for 0, 4, 8, 12, 24, 30 and 48 h in the rumen of cows. Dry matter disappearance(DMD)data for both measures were fitted to the equation Y = a + b(1 -e^(-ct)), where b is the slowly degradable fraction and c is the degradation rate constant, to approximate rumen degradability characteristics of varieties. Shade dried leaves contained higher crude protein(CP)(P f varieties. However, shade drying method gave the higher concentration of NDIN and ADIN. Drying technique had no effect(P > 0.05) on ash, neutral detergent fiber(NDf), acid detergent fiber(ADf) and acid detergent lignin(ADL) of varieties. Drying method did not affect(P > 0.05) calcium(Ca) and phosphorus(P) concentration in the forage dry matter. Drying method had no effect(P > 0.05) on b and c of all varieties during in vitro procedure. However, shade-drying method increased(P f all varieties during in sacco procedure. It was concluded that shade-drying, in contrast to oven-drying, would be the most suitable method as it improves the nutritive value of the forage for ruminants.

关键词： forages In vitro In sacco Degradation Drying methods

Time-to-enrollment in clinical trials investigating neurological recovery in chronic spinal cord injury:observations from a systematic review and Clinical *** database

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Neural Regeneration Research 2022年第5期17卷 953-958页

作者： f M Moinuddin Yagiz Ugur Yolcu Waseem Wahood Jad Zreik Sandy Goncalves Anthony john Windebank Wenchun Qu Mohamad Bydon Mayo Clinic Neuro-Informatics Laboratory Mayo ClinicRochesterMNUSA Department of Neurologic Surgery Mayo ClinicRochesterMNUSA Dr.Kiran C.Patel College of Allopathic Medicine Nova Southeastern UniversityDavieFLUSA Department of Neurology Mayo ClinicRochesterMNUSA Department of Physical Medicine&Rehabilitation Mayo ClinicRochesterMNUSA

Currently,large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury(SCI).However,for the enrollment process,there are different views on how the time period between injury and interventions should be ***,we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials.A data set comprising 957 clinical studies from clinical *** was downloaded and analyzed focusing on the eligibility criteria for post-injury *** also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to *** of the studies were assessed and compared by dividing into three groups based on time-to-enrollment(group 1≤12 months,group 2=12-23 months and group 3≥24 months).In Clinical *** registry,445 trials were identified for chronic SCI where 87%(385)were unrestricted in the maximum post-injury time for trial *** systematic literature search,nine studies and 156 patients(group 1=30,group 2=55 and group 3=71)were *** range of time-to-enrollment was 0.5 to 321 months in those *** also observed various degrees of motor and sensory improvement in between three time-to-enrollment *** results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise *** trial designs should consider appropriate postinjury time frames to evaluate therapeutic benefit.

关键词： chronic clinical trial spinal cord injury systematic review time-to-enrollment

Promises and pitfalls of targeted agents in chronic lymphocytic leukemia

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Cancer Drug Resistance 2020年第3期3卷 415-444页

作者： Thomas E.Lew Mary Ann Anderson john f.Seymour Department of Clinical Haematology The Royal Melbourne Hospital and Peter MacCallum Cancer CentreParkville 3050Australia. Blood Cells and Blood Cancer Division Walter and Eliza Hall Institute of Medical ResearchParkville 3050Australia. faculty of Medicine Dentistry and Health SciencesThe University of MelbourneParkville 3050Australia.

Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited *** classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline ***,maturing clinical data have revealed promises and pitfalls for both *** drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy ***,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and *** patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease *** these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of *** drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

关键词： Chronic lymphocytic leukemia drug resistance venetoclax B-cell lymphoma 2 ibrutinib bruton tyrosine kinase idelalisib phosphatidylinositol 3-kinase

Biological Markers on Human Pregnancy

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Biomedical and Environmental Sciences 1991年第Z1期 56-68页

作者： ROBERT E.CANfIELD,john f.O'CONNOR Departments of Medicine Pathology Columbia University College of Physicians and Surgeons New York New York 10032

This article reviews a selected set of recently described pregnancy-associated proteins which possess potential for both signaling pregnancy onset and monitoring its course. These molecules are compared and contrasted with human chorionic gonadotropin, the first pregnancy-associated protein to be discovered, and the standard biomarker of pregnancy to which all others must still be referenced. Recent advances in hCG research have focused on the structural determination and diagnostic significance of the subunits and fragments of the hCG molecule, particularly in urine. An outline of the potential utility of this approach is also presented.

关键词： Biological Markers on Human Pregnancy

Contemporary view on neuromonitoring following severe traumatic brain injury

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World Journal of Critical Care Medicine 2012年第1期1卷 15-22页

作者： john f Stover Surgical Intensive Care Medicine University Hospital Zürich R?mistrasse 100 8091 Zürich Switzerland

Evolving brain damage following traumatic brain injury(TBI) is strongly influenced by complex pathophysiologic cascades including local as well as systemic influences. To successfully prevent secondary progression of the primary damage we must actively search and identify secondary insults e.g. hypoxia, hypotension, uncontrolled hyperventilation, anemia, and hypoglycemia, which are known to aggravate existing brain damage. for this, we must rely on specific cerebral monitoring. Only then can we unmask changes which otherwise would remain hidden, and prevent adequate intensive care treatment. Apart from intracranial pressure(ICP) and calculated cerebral perfusion pressure(CPP), extended neuromonitoring(Sjv O2, pti O2, microdialysis, transcranial Doppler sonography, electrocorticography) also allows us to define individual pathologic ICP and CPP levels. This, in turn, will support our therapeutic decision-making and also allow a more individualized and flexible treatment concept for each patient. for this, however, we need to learn to integrate several dimensions with their own possible treatment options into a complete picture. The present review summarizes the current understanding of extended neuromonitoring to guide therapeutic interventions with the aim of improving intensive care treatment following severe TBI, which is the basis for ameliorated outcome.

关键词： Microdialysis Monitoring Pathophysiology Pharmacology Traumatic brain injury