94 results on '"Dobson JR"'
Search Results
2. Maximum Mass-Radius Ratio for Compact General Relativistic Objects in Schwarzschild- de Sitter Geometry
- Author
-
Mak, M. K., Dobson, Jr., Peter N., and Harko, T.
- Subjects
General Relativity and Quantum Cosmology - Abstract
Upper limits for the mass-radius ratio are derived for arbitrary general relativistic matter distributions in the presence of a cosmological constant. General restrictions for the red shift and total energy (including the gravitational contribution) for compact objects in the Schwarzschild-de Sitter geometry are also obtained in terms of the cosmological constant and of the mean density of the star., Comment: 8 pages, no figures
- Published
- 2001
- Full Text
- View/download PDF
3. We Must Use the Vaccination Infrastructure We Already Have.
- Author
-
Dobson Jr., L. Allen and Trygstad, Troy
- Subjects
- *
VACCINATION - Published
- 2021
4. How I rediscovered what it means to be a physician.
- Author
-
Dobson Jr., L. Allen
- Subjects
PHYSICIANS ,HEALERS ,MEDICAL personnel - Abstract
In the article, the author discusses the work and responsibilities of a physician by citing his own experiences. Other topics include how physicians have deviated from their priorities in the U.S. health care system over the past 10 years as per Doctor Charles Rhodes, and the lessons he learned in his practice of medicine like the importance of communicating with patients and the power of touch when ministering to patients.
- Published
- 2023
5. Expert Systems: A Primer for the Construction Manager
- Author
-
FLORIDA UNIV GAINESVILLE, Dobson, Jr, Henry V., FLORIDA UNIV GAINESVILLE, and Dobson, Jr, Henry V.
- Abstract
Construction managers are only beginning to realize the true potential of the microcomputer. Computer systems for such applications as estimating, scheduling and cost control have been popular for many years. However, these applications are primarily limited to 'number crunching' and data manipulation. Computer systems that can make decisions and choose between alternative problem solutions are the next step towards computerization of construction management. The computer field of artificial intelligence has provided the 'expert system' which simplifies the creation of decision making systems. Keywords: Decision making, Computer systems, Management.
- Published
- 1990
6. A century of health care change reinforces the importance of physicians.
- Author
-
Dobson Jr., L. Allen
- Abstract
The article offers information on Medical Economics' 100th year in print and encourages readers to explore a cover story comparing the practice of primary care 100 years ago with today. The author reflects on changes in the healthcare system, including the undervaluation of primary care physicians, the trend to replace physicians with non-physician providers, and the need for increased investment in primary care, especially in underserved areas.
- Published
- 2023
7. Myocardial adenosine A1 -receptor-mediated adenoprotection involves phospholipase C, PKC-E, and p38 MAPK, but not HSP27.
- Author
-
Fenton, Richard A., Shea, Lynne G., Doddi, Cecilia, and Dobson, Jr, James G.
- Subjects
ADENOSYLMETHIONINE ,CORONARY heart disease complications ,PHOSPHOLIPASE C ,HEART cells ,LABORATORY mice - Abstract
Fenton RA, Shea LG, Doddi C, Dobson JG, Jr. Myocardial adenosine A
1 -receptor-mediated adenoprotection involves phospholipase C, PKC-ϵ, and p38 MAPK, but not HSP27. Am J Physiol Heart Circ Physiol 298: H1671-H1678, 2010. First published April 2, 2010; doi: 10.11 52/ajpheart.0 1 028.2009.-Adenosine via an adenosine A1 receptor (A1 R) is a negative feedback inhibitor of adrenergic stimulation in the heart, protecting it from toxic effects of overstimulation. Stimulation of the A1 R results in the activation of Gi protein, release of free Gβγ-subunits, and activation/translocation of PKC-ϵ to the receptor for activated C kinase 2 protein at the Z-line of the cardiomyocyte sarcomere. Using an anti-Gβγ peptide, we investigated the role of these subunits in the A1 R stimulation of phospholipase C (PLC), with the premise that the resulting diacyiglycerol provides for the activation of PKC-ϵ. Inositol 1,4,5-triphosphate release was an index of PLC activity. Chlorocyclopentyl adenosine (CCPA), an R agonist, increased inositol I ,4,5-triphosphate production by 273% in mouse heart homogenates, an effect absent in A1 R knockout hearts and inhibited by anti-Gi 3-y peptide. In a second study, p38 MAPK and heat shock protein 27 (HSP27), found by others to be associated with the loss of myocardial contractile function, were postulated to play a role in the actions of A1 R. Isoproterenol, a 3-adrenergic receptor agonist, increased the Ca2+ transient and sarcomere shortening magnitudes by 36 and 49%, respectively. In the rat cardiomyocyte, CCPA significantly reduced these increases, an action blocked by the p38 MAPK inhibitor SB-203580. While CCPA significantly increased the phosphorylation of HSP27, this action was inhibited by isoproterenol. These data indicate that the activation of PKC-ϵ by A1 R results from the activation of PLC via free Gβγsubunits released upon A1 R-induced dissociation of Gay. Attenuation of β-adrenergic-induced contractile function by A1 R may involve the activation of p38 MAPK, but not HSP27. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
8. Adenoprotection of the heart involves phospholipase C-induced activation and translocation of PKC-ϵ to RACK2 in adult rat and mouse.
- Author
-
Fenton, Richard A., Komatsu, Satoshi, Ikebe, Mitsuo, Shea, Lynne G., and Dobson Jr., James G.
- Subjects
ADENOSINES ,SYMPATHOMIMETIC agents ,IMMUNOCYTOCHEMISTRY ,CONFOCAL microscopy ,ISOPROTERENOL ,WESTERN immunoblotting - Abstract
Adenosine protects the heart from adrenergic overstimulation. This adenoprotection includes the direct anti-adrenergic action via adenosine A receptors (A
1 R) on the adrenergic signaling pathway. An indirect A1 R-induced attenuation of adrenergic responsiveness involves the translocation of PKC-ϵ to t-tubules and Z-line of cardiomyocytes. We investigated with sarcomere imaging, immunocytochemistry imaging, and coimmunoprecipitation (co-IP) whether R activation of PKC-ϵ induces the kinase translocation to receptor for activated C kinase 2 (RACK2) in isolated rat and mouse hearts and whether phospholipase C (PLC) is involved. Rat cardiomyocytes were treated with the A1 R agonist chlorocyclopentyladenosine (CCPA) and exposed to primary PKC-ϵ and RACK2 antibodies with secondaries conjugated to Cy3 and Cy5 (indodicarbocyanine), respectively. Scanning confocal microscopy showed that CCPA caused PKC-ϵ to reversibly colocalize with RACK2 within 3 mm. Additionally, rat and mouse hearts were perfused and stimulated with CCPA or phenylisopropyladenosine to activate A1 R, or with phorbol 12-myristate 13-acetate to activate PKC. RACK2 was immunoprecipitated from heart extracts and resolved with SDS-PAGE. Western blotting showed that CCPA, phenylisopropyladenosine, and phorbol 1, 2-myristate 13-acetate in the rat heart increased the PKC-ϵ co-IP with RACK2 by 186, 49, and >1,000%, respectively. The A1 R antagonist 8-cyclopentyl-1,3-dipropylxanthine prevented the CCPA-induced co-IP with RACK2. In mouse hearts, CCPA increased the co-IP of PKC-ϵ with RACK2 by 61%. With rat cardiomyocytes, the β-adrenergic agonist isoproterenol increased sarcomere shortening by 177%. CCPA reduced this response by 47%, an action inhibited by the PLC inhibitor U-73 122 and 8-cyclopentyl-1,3-dipropylxanthine. In conclusion, A1R stimulation of the heart is associated with PLC-initiated PKC-ϵ translocation and association with RACK2. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
9. Adenosine A2A and β-adrenergic calcium transient and contractile responses in rat ventricular myocytes.
- Author
-
Dobson Jr., James G., Shea, Lynne G., and Fenton, Richard A.
- Subjects
- *
ADENOSINES , *MUSCLE cells , *SYMPATHOLYTIC agents , *ADENINE , *PHYSIOLOGY - Abstract
The adenosine A2A receptor (A2AR) enhances cardiac contractility, and the adeno- sine A1R receptor (A1R) is antiadrenergic by reducing the adrenergic ~ receptor (I3iR)-elicited increase in contractility. In this study we compared the A2AR-, A1R-, and 131R-elicited actions on isolated rat ventricular myocytes in terms of Ca transient and contractile re- sponses involving PKA and PKC. Stimulation of A2AR with 2 p~M (-.~EC50) CGS-21680 (CGS) produced a 17-28% increase in the Ca transient ratio (CTR) and maximum velocities (Vm~,,~) of transient ratio increase (+MVT) and recovery (-MVT) but no change in the time-to-50% recovery (TTR). CGS increased myocyte sarcomere shortening (MSS) and the maximum velocities of shortening (+MVS) and relaxation (-MVS) by 31-34% with no change in time-to-50% relengthening (TTL). ~1R stimulation using 2 nM (-~EC50) isopro- terenol (Iso) increased CTR, +MVT, and -MVT by 67-162% and decreased TTR by 43%. Iso increased MSS, +MVS, and -MVS by 153-174% and decreased TI'L by 31%. The A2AR and ~31R Ca transient and contractile responses were not additive. The PKA inhibitor Rp-adenosine 3' ,5 `-cyclic monophosphorothioate triethyla- monium salt prevented both the CGS- and Iso-elicited contractile responses. The PKC inhibitors chelerythrine and KJE1-l peptide (PKCe specific) prevented the antiadrenergic action of A1R but did not influence A2AR-mediated increases in contractile variables. The findings suggest that cardiac A2AR utilize cAMPIPKA like 31R, but the Ca transient and contractile responses are less in magnitude and not equally affected. Although PKC is important in the ~ R antiad- renergic action, it does not seem to play a role in A2AR-elicited Ca transient and contractile events. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
10. Community Care of North Carolina: Improving Care Through Community Health Networks.
- Author
-
Steiner, Beat D., Denham, Amy C., Ashkin, Evan, Newton, Warren P., Wroth, Thomas, and Dobson Jr., L. Allen
- Subjects
HEALTH care networks ,MEDICAID beneficiaries ,COMMUNITY health services ,MEDICAL care of poor people - Abstract
The article focuses on the Community Care program in North Carolina. It describes the experience and the lessons learned from the program during the implementation of community health networks in the care of Medicaid recipients. It stresses that the program can be adapted as an effective system designed to achieve quality, utilization and cost objectives for the care of patients with chronic illness.
- Published
- 2008
- Full Text
- View/download PDF
11. Contractile effects of adenosine A1 and A2A receptors in isolated murine hearts.
- Author
-
Tikh, Eugene I., Fenton, Richard A., and Dobson Jr., James G.
- Subjects
ADENOSINES ,ADENINE ,SYMPATHOLYTIC agents ,CARDIAC contraction ,HEART beat - Abstract
The adenosine A
1 receptor (A1 R) inhibits β-adrenergic-induced contractile effects (antiadrenergic action), and the adenosine A2A receptor (A2A R) both opposes the A1 R action and enhances contractility in the heart. This study investigated the A1 R and A2A R function in p-adrenergic-stimulated, isolated wild-type and A2A R knockout murine hearts. Constant flow and pressure perfused preparations were employed, and the maximal rate of left ventricular pressure (LVP) development (+dp/dtmax ) was used as an index of cardiac function. A1 R activation with 2-chloro-N6 -cyclopentyladenosine (CCPA) resulted in a 27% reduction in contractile response to the β-adrenergic agonist isoproterenol (ISO). Stimulation of A2A R with 2-P(2-carboxyethyl)phenethyl-amino-5' -N-ethylcarboxyamidoadenosine (CGS -21680) attenuated this antiadrenergic effect, resulting in a partial (constant flow preparation) or complete (constant pressure preparation) restoration of the ISO contractile response. These effects of A2A R were absent in knockout hearts. Up to 63% of the A2A R influence was estimated to be mediated through its inhibition of the A1 R antiadrenergic effect, with the remainder being the direct contractile effect. Further experiments examined the effects of A2A R activation and associated vasodilation with low-flow ischemia in the absence of β-adrenergic stimulation. A2A R activation reduced by 5% the depression of contractile function caused by the flow reduction and also increased contractile performance over a wide range of perfusion flows. This effect was prevented by the A2A R antagonist 4-(2-[7- amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol (ZM-241 385). It is concluded that in the murine heart, A1 R and A2A R modulate the response to β-adrenergic stimulation with A2A R, attenuating the effects of A1 R and also increasing contractility directly. In addition, A2A R supports myocardial contractility in a setting of low-flow ischemia. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
12. Protein kinase C∈ and the antiadrenergic action of adenosine in rat ventricular myocytes.
- Author
-
Miyazaki, Koji, Komatsu, Satoshi, Ikebe, Mitsuo, Fenton, Richard A., and Dobson Jr., James G.
- Subjects
PROTEIN kinase C ,SYMPATHOLYTIC agents ,MUSCLE cells ,HEART cells ,KIDNEY tubules ,GENE transfection - Abstract
Adenosine-induced antiadrenergic effects in the heart are mediated by adenosine A
1 receptors (A1 R). The role of PKC∈ in the antiadrenergic action of adenosine was explored with adult rat ventricular myocytes in which PKC∈ was overexpressed. Myocytes were transfected with a pEGFP-N1 vector in the presence or absence of a PKC∈ construct and compared with normal myocytes. The extent of myocyte shortening elicited by electrical stimulation of quiescent normal and transfected myocytes was recorded with video imaging. PKC∈ was found localized primarily in transverse tubule's. The A1 R agonist chlorocyclopentyladenosine (CCPA) at 1 µM rendered an enhanced localization of PKC∈ in the t-tubular system. The β-adrenergic agonist isoproterenol (Iso; 0.4 µM) elicited a 29-36% increase in myocyte shortening in all three groups. Although CCPA significantly reduced the Isoproduced increase in shortening in all three groups, the reduction caused by CCPA was greatest with PKC∈ overexpression. The CCPA reduction of the Iso-elicited shortening was eliminated in the presence of a PKC∈ inhibitory peptide. These results suggest that the translocation of PKC∈ to the t-tubular system plays an important role in A1 R-mediated antiadrenergic actions in the heart. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
13. β-Adrenergic and antiadrenergic modulation of cardiac adenylyl cyclase is influenced by phosphorylation.
- Author
-
Dobson Jr., James G., Shea, Lynne G., and Fenton, Richard A.
- Subjects
- *
ADENYLATE cyclase , *MYOCARDIUM , *PHOSPHORYLATION - Abstract
β-Adrenergic and antiadrenergic modulation of cardiac adenylyl cyclase is influenced by phosphorylation. Am J Physiol Heart Circ Physiol 285: H1471-H1478, 2003. First published June 12, 2003; 10.1152/ajpheart.00950. 2002.—Adenosine protects the myocardium of the heart by exerting an antiadrenergic action via the adenosine A[sub 1] receptor (A[sub 1]R). Because β[sub 1]-adrenergic receptor (B[sub 1]R) stimulation elicits myocardial protein phosphorylation, the present study investigated whether protein kinase A (PKA) catalyzed rat heart ventricular membrane phosphorylation affects the β[sub 1]R adrenergic and A[sub 1]R adenosinergic actions on adenylyl cyclase activity. Membranes were either phosphorylated with PKA in the absence/presence of a protein kinase inhibitor (PKI) or dephosphorylated with alkaline phosphatase (AP) and assayed for adenylyl cyclase activity (AC) in the presence of the β[sub 1]R agonist isoproterenol (ISO) and/or the A[sub 1]R agonist 2-chloro-N[sup 6]-cyclopentyladenosine (CCPA). [sup 32]P incorporation into the protein substrates of 140-120, 43, and 29 kDa with PKA increased both the ISO-elicited activation of AC by 51-54% and the A[sub 1]R-mediated reduction of the ISO-induced increase in AC by 29-50%, thereby yielding a total antiadrenergic effect of ∼78%. These effects of PICA were prevented by PKI. AP reduced the ISO-induced increase in AC and eliminated the antiadrenergic effect of CCPA. Immunoprecipitation of the solubilized membrane adenylyl cyclase with the use of a polyclonal adenylyl cyclase VI antibody indicated that the enzyme is phosphorylated by PKA. These results indicate that the cardioprotective effect of adenosine afforded by its antiadrenergic action is facilitated by cardiac membrane phosphorylation. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
14. Let's Use the Pandemic to Change Health Care for the Better.
- Author
-
Dobson Jr., L. Allen
- Subjects
- *
MEDICAL quality control , *HEALTH care industry , *MEDICAL care , *QUALITY assurance , *COVID-19 pandemic - Abstract
In the article, the author discusses how to exploit the lessons learned from the COVID-19 pandemic to introduce change in health care for the better. Other topics include the issues in the U.S. health care system like the high medical costs and lack of preparedness in pandemic response, as well as how the reforms implemented by the Centers for Medicare & Medicaid Services resulted in the massive consolidation in the health care industry.
- Published
- 2021
15. Myocardial adenosine A1-receptor sensitivity during juvenile and adult stages of maturation.
- Author
-
Sawmiller, Darrell R., Fenton, Richard A., and Dobson Jr., James G.
- Subjects
ADENOSINES ,MYOCARDIUM physiology - Abstract
Determines myocardial adenosine A1-receptor effectiveness during juvenile and adult stages of maturation. Augmentation of contractile and metabolic performance of the heart; Enhance expression of the antiadrenergic action of adenosine.
- Published
- 1998
- Full Text
- View/download PDF
16. The growing division within the house of medicine.
- Author
-
Dobson Jr., L. Allen
- Subjects
HOUSEKEEPING ,CORONARY care units ,STATE licensing boards ,STATE boards of nursing - Abstract
The article discusses how collaborative and professional family of medicine as nursing organizations and other nonphysician associations advocate in state legislatures across the country to be allowed to practice independently and without restriction or supervision. It further examines many aspects of the growing conflict within the house of medicine nurse practitioners (NPs) and physician assistants (PAs).
- Published
- 2022
17. A study of the operation of labour markets from an industrial relations perspective
- Author
-
Dobson, JR
- Abstract
This PhD by published works falls entirely within the field of industrial relations\ud and contributes to three distinctive areas of the subject - general industrial\ud relations, industrial relations in the steel industry and the operation of labour\ud markets in Central and Eastern Europe.\ud A vigorous debate is currently taking place about the future of industrial\ud relations and whether the subject should be narrowly defined and be about trade\ud unions and collective bargaining, or alternatively about all aspects of employment\ud relations, including the non-unionised. Concern has also been expressed that\ud most research was conducted within a very narrow definition of the subject. The\ud publications submitted for this PhD contribute to widening the field of industrial\ud relations by examining various aspects of how labour markets actually operate in\ud practice. The research was mainly empirically based and consistently advanced\ud arguments and conclusions which went against the orthodoxy of research at the\ud time. A paper on good industrial relations questioned widely held assumptions\ud underpinning public policy. A study of multi-unionism argued against the view\ud that it was a widespread problem. Industrial relations in the steel industry\ud needed to be viewed in an historical and environmental context. The loss of\ud management control implicit in the operation of seniority promotion systems was\ud found not to inhibit efficiency. Studies of the Latvian labour market found serious\ud discrimination on the basis of ethnicity and language. While the collapse of\ud communism was often assumed to have resulted in radical changes in industrial\ud relations in Poland, my research discovered substantial continuity, albeit through\ud informal systems. And finally, despite widespread concern about the level of\ud immigration from Eastern Europe, my analysis of data obtained from the worker\ud registration scheme, suggested that much of this concern was misplaced.
18. How do we care for the caregivers?
- Author
-
Dobson Jr., L. Allen
- Subjects
CAREGIVERS ,SERVICES for caregivers ,INSURANCE company personnel ,MEDICAL economics ,SOCIAL isolation - Abstract
This article presents how COVID-19 pandemic has stressed the entire health care workforce. Topics include the particular attention in press accounts has been focused on burnout among nurses, and the doctors along with other clinical personnel resulting from long work hours, inadequate staff , shortage of supplies and the emotional toll of caring for dying patients.
- Published
- 2022
19. We must use the vaccination infrastructure we already have: Our front-line providers at physician practices and pharmacies have been dramatically underallocated COVID-19 vaccinations.
- Author
-
Dobson Jr., L. Allen and Trygstad, Troy
- Subjects
COVID-19 vaccines ,PHYSICIANS ,VACCINATION ,MEDICAL personnel ,PHARMACY ,PHARMACY education - Abstract
The article offers information on how front-line providers at physician practices and pharmacies have been under allocated COVID-19 vaccinations in the U.S. It mentions the effects of the Covid-19 experience on Generation C's early development. It discusses about the Operation Warp Speed, a public–private partnership initiated by the U.S. government to facilitate and accelerate the development, manufacturing, and distribution of Covid-19 vaccines, therapeutics, and diagnostics.
- Published
- 2021
20. To solve the COVID-19 pandemic, we must empower primary care physicians and pharmacists: It is time for an all-hands-on-deck approach.
- Author
-
Dobson Jr., L. Allen
- Subjects
COVID-19 pandemic ,PRIMARY care ,PHYSICIANS ,MEDICAL personnel ,MEDICATION therapy management ,HEALTH equity ,PHARMACISTS - Abstract
The article discusses the important role of primary care physicians and pharmacists in ending the COVID-19 pandemic in the U.S. Topics covered include the impact of the pandemic on primary care practices, the COVID-19 vaccination rates needed to achieve herd immunity, and the need for a call to action from federal and state leaders to make sure primary care providers and pharmacies are involved.
- Published
- 2021
21. A physician's hopes for 2022.
- Author
-
Dobson Jr., L. Allen
- Subjects
PHYSICIANS ,MENTAL health services ,NURSING literature ,MEDICINE & politics ,MEDICAL economics ,MEDICAL students - Abstract
The article offers information about the administrative burdens faced by the physicians due to the Covid-19 pandemic, along with mentions the challenges associated with the burnout, loss of staff, and ultimately reduced revenue. It addresses the U.S. mental health needs and recognize that mental health services are key primary care services and belong integrated in our primary care system .
- Published
- 2022
22. Beware the trend of for-profit medicine.
- Author
-
Dobson Jr., L. Allen
- Abstract
The article explores over a century ago, most states passed laws prohibiting the corporate practice of medicine. The goal was to make sure medical decisions would be uninfluenced by the profit t motive and left to the physicians caring for their patients. States were also concerned that large industries would operate their own health care services or even own their own hospitals exclusively for their employees, thereby making health care less accessible to the general population.
- Published
- 2021
23. We must address the causes of burnout.
- Author
-
Dobson Jr., L. Allen
- Subjects
PSYCHOLOGICAL burnout ,MEDICAL personnel ,PHYSICIAN-patient relations ,PHYSICIANS ,MEDICAL economics - Published
- 2021
24. Social determinants of health: The COVID-19 pandemic has widened the gap.
- Author
-
Dobson Jr., L. Allen
- Published
- 2021
25. Malcolm X, Black Liberation and the Road of Workers Power.
- Author
-
Dobson, Jr., Frank E.
- Subjects
- *
NONFICTION - Abstract
Reviews the book "Malcolm X, Black Liberation and the Road of Workers Power," by Jack Barnes.
- Published
- 2011
26. METABOLIC RESPONSE TIME OF CANINE SKELETAL MUSCLE..
- Author
-
Gladden, L B., Hogan, M C., Kelley, K M., Dobson Jr, J L., and Grassi, B
- Published
- 2002
27. Disrupted Endoplasmic Reticulum Ca 2+ Handling: A Harβinger of β-Cell Failure.
- Author
-
Dobson JR and Jacobson DA
- Abstract
The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca
2+ ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.- Published
- 2024
- Full Text
- View/download PDF
28. The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults.
- Author
-
Nakhe AY, Dadi PK, Kim J, Dickerson MT, Behera S, Dobson JR, Shrestha S, Cartailler JP, Sampson L, Magnuson MA, and Jacobson DA
- Subjects
- Animals, Male, Mice, Animals, Newborn, Disease Models, Animal, Homeostasis, Insulin metabolism, Islets of Langerhans metabolism, Mutation, Potassium Channels metabolism, Potassium Channels genetics, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Glucagon metabolism, Glucose metabolism, Insulin Secretion drug effects, Insulin Secretion genetics, Mice, Inbred C57BL
- Abstract
The gain-of-function mutation in the TALK-1 K
+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes., Competing Interests: AN, PD, JK, MD, SB, JD, SS, JC, LS, MM, DJ No competing interests declared, (© 2023, Nakhe et al.)- Published
- 2024
- Full Text
- View/download PDF
29. TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet.
- Author
-
Graff SM, Nakhe AY, Dadi PK, Dickerson MT, Dobson JR, Zaborska KE, Ibsen CE, Butterworth RB, Vierra NC, and Jacobson DA
- Subjects
- Animals, Mice, Adenosine Triphosphate metabolism, Calcium metabolism, Diet, Endoplasmic Reticulum metabolism, Glucose metabolism, Homeostasis, Insulin metabolism, Insulin Secretion, Mice, Knockout, Mitochondria metabolism, Diabetes Mellitus metabolism, Insulin-Secreting Cells metabolism
- Abstract
Mitochondrial Ca
2+ ([Ca2+ ]m ) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+ ]m uptake is dependent on elevations in cytoplasmic Ca2+ ([Ca2+ ]c ) and endoplasmic reticulum Ca2+ ([Ca2+ ]ER ) release, both of which are regulated by the two-pore domain K+ channel TALK-1. Here, utilizing a novel β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca2+ ]m accumulation and ATP production. However, following exposure to a high-fat diet (HFD), ATP-linked respiration, glucose-stimulated oxygen consumption rate, and glucose-stimulated insulin secretion (GSIS) were increased in control but not TALK1-KO mice. Although β-TALK-1-KO animals showed similar GSIS before and after HFD treatment, these mice were protected from HFD-induced glucose intolerance. Collectively, these data identify that TALK-1 channel control of β-cell function reduces [Ca2+ ]m and suggest that metabolic remodeling in diabetes drives dysglycemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
30. A Cadaveric Evaluation of Hypertrophic Obstructive Cardiomyopathy.
- Author
-
Murtha CM, Dobson JR, and Olinger AB
- Abstract
Hypertrophic obstructive cardiomyopathy (HOCM) describes a pathologic state in which the subaortic region of the interventricular septum undergoes significant hypertrophy and fibrosis, resulting in septal bowing into the left ventricle. The reduced left ventricular chamber size and altered cardiac function impair diastolic filling, stroke volume, and cardiac output. This case report evaluates the cardiac tissue of a 36-year-old, formalin-embalmed cadaver affected by HOCM, with the goal of providing a comprehensive overview of the gross and pathologic findings associated with the condition. This donor's heart was found to be larger than average, weighing 510.1 g, which is 52% heavier than the predicted value of 335.6 g for a male of similar stature. The thickness of the interventricular septum, right ventricular free wall, and left ventricular free wall was comparable to other reports of HOCM. However, asymmetrical thickening of the left ventricular walls, which is characteristic of HOCM, was less prominent than expected. Histologic staining of the cadaveric tissue, with hematoxylin and eosin, trichrome, and desmin, further bolstered the diagnosis. Importantly, this also showed that histologic examination of embalmed tissue is effective and diagnostic, even 11 months after embalming. The report herein demonstrates that morphologic and histologic analysis of cadaveric cardiac tissue is sufficient to support a diagnosis of HOCM. To the researchers' knowledge, this is the first case report evaluating HOCM in a cadaver donated for medical education., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Murtha et al.)
- Published
- 2023
- Full Text
- View/download PDF
31. G i/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na + /K + ATPase activation.
- Author
-
Dickerson MT, Dadi PK, Zaborska KE, Nakhe AY, Schaub CM, Dobson JR, Wright NM, Lynch JC, Scott CF, Robinson LD, and Jacobson DA
- Subjects
- Insulin Secretion, Sodium metabolism, Receptors, G-Protein-Coupled metabolism, Somatostatin metabolism, Sodium-Potassium-Exchanging ATPase metabolism, Insulin-Secreting Cells metabolism
- Abstract
G
i/o -coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of β-cell Gi/o -GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. β-cell membrane potential hyperpolarization resulting from Gi/o -GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, β-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated β-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o -GPCR control of electrical excitability, Ca2+ handling, and insulin secretion., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
32. National Resident Matching Program Performance Among US MD and DO Seniors in the Early Single Accreditation Graduate Medical Education Era.
- Author
-
Kortz MW, Vegas A, Moore SP, McCray E, Mureb MC, Bernstein JE, May J, Bishop B, Frydenlund M, and Dobson JR
- Abstract
Introduction: As of the 2020 National Resident Matching Program (NRMP), nearly all applicants are evaluated together for graduate medical education (GME) candidacy. We set out to characterize US MD and DO Senior residency match performance in the single-accreditation GME era., Methods: A retrospective study was conducted in 2021 utilizing data collected from the 2018 and 2020 NRMP Charting Outcomes in the Match publications aggregated and subdivided into three groups based on competitiveness: low (LC), moderate (MC), and high (HC). Nonparametric analysis was performed using Chi square or Fisher exact tests if counts were less than five. Significance was determined at p < 0.05., Results: A total of 46,853 candidates were included, with 36,194 (77.3%) US MD and 10,659 (22.7%) DO Seniors. Match rates for US DO Seniors were lower than US MD Seniors across all competitiveness strata (p < 0.0001). Research item production, national licensing examination scores, and mean number of contiguous programs ranked were lower for matched US DO Seniors compared to matched US MD Seniors, with significant differences depending on competitiveness group., Conclusions: With recent changes to GME and its application process, understanding how various groups compare will be increasingly important. US DO Seniors have lower first-rank match rates for all specialty competitiveness levels. This may be due to lower research output or nuanced specialty selection. This study could aid GME stakeholders to more effectively allocate resources and better prepare residency candidates., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kortz et al.)
- Published
- 2021
- Full Text
- View/download PDF
33. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.
- Author
-
Rodon J, Argilés G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, Giannakis M, Smith DC, Dobson JR, McLaughlin ME, Seroutou A, Ji Y, Morawiak J, Moody SE, and Janku F
- Subjects
- Administration, Oral, Adult, Aged, Enzyme Inhibitors pharmacokinetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Middle Aged, Neoplasms genetics, Pyrazines pharmacokinetics, Pyridines pharmacokinetics, Treatment Outcome, Wnt Signaling Pathway drug effects, Axin Protein genetics, Enzyme Inhibitors administration & dosage, Neoplasms drug therapy, Pyrazines administration & dosage, Pyridines administration & dosage
- Abstract
Background: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours., Methods: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules., Results: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8)., Conclusions: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity., Clinical Trial Registration: NCT01351103.
- Published
- 2021
- Full Text
- View/download PDF
34. CXCR4 signaling at the fetal-maternal interface may drive inflammation and syncytia formation during ovine pregnancy†.
- Author
-
McIntosh SZ, Maestas MM, Dobson JR, Quinn KE, Runyan CL, and Ashley RL
- Subjects
- Animals, Cells, Cultured, Endometrium metabolism, Female, Inflammation metabolism, Placentation physiology, Pregnancy, Receptors, CXCR4 genetics, Signal Transduction physiology, Inflammation veterinary, Maternal-Fetal Exchange physiology, Pregnancy, Animal physiology, Receptors, CXCR4 metabolism, Sheep physiology
- Abstract
Early pregnancy features complex signaling between fetal trophoblast cells and maternal endometrium directing major peri-implantation events including localized inflammation and remodeling to establish proper placental development. Proinflammatory mediators are important for conceptus attachment, but a more precise understanding of molecular pathways regulating this process is needed to understand how the endometrium becomes receptive to implantation. Both chemokine ligand 12 (CXCL12) and its receptor CXCR4 are expressed by fetal and maternal tissues. We identified this pair as a critical driver of placental angiogenesis, but their additional importance to inflammation and trophoblast cell survival, proliferation, and invasion imply a role in syncytia formation at the fetal-maternal microenvironment. We hypothesized that CXCL12 encourages both endometrial inflammation and conceptus attachment during implantation. We employed separate ovine studies to (1) characterize endometrial inflammation during early gestation in the ewe, and (2) establish functional implications of CXCL12 at the fetal-maternal interface through targeted intrauterine infusion of the CXCR4 inhibitor AMD3100. Endometrial tissues were evaluated for inflammatory mediators, intracellular signaling events, endometrial modifications, and trophoblast syncytialization using western blotting and immunohistochemistry. Endometrial tissue from ewes receiving CXCR4 inhibitor demonstrated dysregulated inflammation and reduced AKT and NFKB, paired with elevated autophagic activity compared to control. Immunohistochemical observation revealed an impairment in endometrial surface remodeling and diminished trophoblast syncytialization following localized CXCR4 inhibition. These data suggest CXCL12-CXCR4 regulates endometrial inflammation and remodeling for embryonic implantation, and provide insight regarding mechanisms that, when dysregulated, lead to pregnancy pathologies such as intrauterine growth restriction and preeclampsia., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
35. Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes.
- Author
-
Zhang L, MacIsaac KD, Zhou T, Huang PY, Xin C, Dobson JR, Yu K, Chiang DY, Fan Y, Pelletier M, Wang Y, Jaeger S, Krishnamurthy Radhakrishnan V, JeBailey L, Skewes-Cox P, Zhang J, Fang W, Huang Y, Zhao H, Zhao Y, Li E, Peng B, Huang A, Dranoff G, Hammerman PS, Engelman J, Bitter H, Zeng YX, and Yao Y
- Subjects
- Adult, Aged, Carcinoma pathology, Carcinoma virology, Cell Proliferation genetics, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p18 genetics, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Genomics, Herpesvirus 4, Human genetics, Herpesvirus 4, Human pathogenicity, Humans, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Mutation, NF-kappa B genetics, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms pathology, Nasopharyngeal Neoplasms virology, Transforming Growth Factor beta genetics, Wnt Signaling Pathway genetics, Carcinoma genetics, Genome, Human genetics, Nasopharyngeal Neoplasms genetics, Prognosis, Tumor Microenvironment genetics
- Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 ( CDKN2A ) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature. Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722-32. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
36. A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors.
- Author
-
Geoerger B, Bourdeaut F, DuBois SG, Fischer M, Geller JI, Gottardo NG, Marabelle A, Pearson ADJ, Modak S, Cash T, Robinson GW, Motta M, Matano A, Bhansali SG, Dobson JR, Parasuraman S, and Chi SN
- Subjects
- Adolescent, Adult, Aminopyridines adverse effects, Aminopyridines pharmacokinetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Child, Child, Preschool, Disease-Free Survival, Dose-Response Relationship, Drug, Drug-Related Side Effects and Adverse Reactions classification, Drug-Related Side Effects and Adverse Reactions pathology, Female, Humans, Infant, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Male, Maximum Tolerated Dose, Neuroblastoma genetics, Neuroblastoma pathology, Purines adverse effects, Purines pharmacokinetics, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology, Young Adult, Aminopyridines administration & dosage, Brain Neoplasms drug therapy, Cyclin-Dependent Kinase 4 genetics, Kidney Neoplasms drug therapy, Neuroblastoma drug therapy, Purines administration & dosage, Rhabdoid Tumor drug therapy
- Abstract
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors. Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK. Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m
2 Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m2 ; n = 1) or grade 4 thrombocytopenia (470 mg/m2 ; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m2 [equivalent to 600 (RP2D)-900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively. Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m2 ) and RP2D (350 mg/m2 ) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
- Full Text
- View/download PDF
37. Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition.
- Author
-
Hong D, Messier TL, Tye CE, Dobson JR, Fritz AJ, Sikora KR, Browne G, Stein JL, Lian JB, and Stein GS
- Subjects
- Blotting, Western, Breast Neoplasms metabolism, Cell Line, Tumor, Chromatin Immunoprecipitation, Epithelial Cells metabolism, Female, Fluorescent Antibody Technique, Gene Expression Profiling, Gene Knockdown Techniques, Humans, Phenotype, Polymerase Chain Reaction, Tissue Array Analysis, Transcriptome, Breast Neoplasms pathology, Core Binding Factor Alpha 2 Subunit metabolism, Epithelial Cells pathology, Epithelial-Mesenchymal Transition physiology, Gene Expression Regulation, Neoplastic physiology
- Abstract
Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFβ signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFβ and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression.
- Published
- 2017
- Full Text
- View/download PDF
38. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas.
- Author
-
Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, and Shapiro GI
- Subjects
- Adult, Aged, Aged, 80 and over, Bayes Theorem, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Female, Humans, Lymphoma metabolism, Male, Middle Aged, Neoplasms metabolism, Young Adult, Aminopyridines therapeutic use, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Lymphoma drug therapy, Neoplasms drug therapy, Purines therapeutic use
- Abstract
Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb
+ ). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas., Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle., Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months., Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2016
- Full Text
- View/download PDF
39. Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation.
- Author
-
Kuzu G, Kaye EG, Chery J, Siggers T, Yang L, Dobson JR, Boor S, Bliss J, Liu W, Jogl G, Rohs R, Singh ND, Bulyk ML, Tolstorukov MY, and Larschan E
- Subjects
- Amino Acid Motifs, Animals, Binding Sites, Biological Evolution, DNA chemistry, Female, Gene Dosage, Genes, X-Linked, Genetic Linkage, Genome, Insect, Male, Oligonucleotide Array Sequence Analysis, Sequence Analysis, DNA, DNA-Binding Proteins genetics, Dinucleotide Repeats, Dosage Compensation, Genetic, Drosophila Proteins genetics, Drosophila melanogaster genetics, X Chromosome genetics
- Abstract
Dosage compensation is an essential process that equalizes transcript levels of X-linked genes between sexes by forming a domain of coordinated gene expression. Throughout the evolution of Diptera, many different X-chromosomes acquired the ability to be dosage compensated. Once each newly evolved X-chromosome is targeted for dosage compensation in XY males, its active genes are upregulated two-fold to equalize gene expression with XX females. In Drosophila melanogaster, the CLAMP zinc finger protein links the dosage compensation complex to the X-chromosome. However, the mechanism for X-chromosome identification has remained unknown. Here, we combine biochemical, genomic and evolutionary approaches to reveal that expansion of GA-dinucleotide repeats likely accumulated on the X-chromosome over evolutionary time to increase the density of CLAMP binding sites, thereby driving the evolution of dosage compensation. Overall, we present new insight into how subtle changes in genomic architecture, such as expansions of a simple sequence repeat, promote the evolution of coordinated gene expression.
- Published
- 2016
- Full Text
- View/download PDF
40. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.
- Author
-
Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, Antonakos B, Chen CH, Chen Z, Cooke VG, Dobson JR, Deng Z, Fei F, Firestone B, Fodor M, Fridrich C, Gao H, Grunenfelder D, Hao HX, Jacob J, Ho S, Hsiao K, Kang ZB, Karki R, Kato M, Larrow J, La Bonte LR, Lenoir F, Liu G, Liu S, Majumdar D, Meyer MJ, Palermo M, Perez L, Pu M, Price E, Quinn C, Shakya S, Shultz MD, Slisz J, Venkatesan K, Wang P, Warmuth M, Williams S, Yang G, Yuan J, Zhang JH, Zhu P, Ramsey T, Keen NJ, Sellers WR, Stams T, and Fortin PD
- Subjects
- Allosteric Regulation drug effects, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Humans, Inhibitory Concentration 50, MAP Kinase Signaling System drug effects, Mice, Mice, Nude, Models, Molecular, Neoplasms pathology, Oncogene Protein p21(ras) metabolism, Piperidines chemistry, Piperidines therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Stability drug effects, Protein Structure, Tertiary drug effects, Protein Tyrosine Phosphatase, Non-Receptor Type 11 chemistry, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Pyrimidines chemistry, Pyrimidines therapeutic use, Reproducibility of Results, Xenograft Model Antitumor Assays, Neoplasms drug therapy, Neoplasms enzymology, Piperidines pharmacology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors, Pyrimidines pharmacology, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
- Published
- 2016
- Full Text
- View/download PDF
41. The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.
- Author
-
Wu Q, Madany P, Dobson JR, Schnabl JM, Sharma S, Smith TC, van Wijnen AJ, Stein JL, Lian JB, Stein GS, Muthuswami R, Imbalzano AN, and Nickerson JA
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation physiology, DNA Helicases genetics, Female, Gene Knockdown Techniques, Humans, Lipids biosynthesis, Lipogenesis, Nuclear Proteins genetics, Transcription Factors genetics, Breast Neoplasms enzymology, Chromatin metabolism, DNA Helicases metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer., Competing Interests: The authors declare that they have no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
42. hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3.
- Author
-
Dobson JR, Taipaleenmäki H, Hu YJ, Hong D, van Wijnen AJ, Stein JL, Stein GS, Lian JB, and Pratap J
- Abstract
Background: For treatment and prevention of metastatic disease, one of the premier challenges is the identification of pathways and proteins to target for clinical intervention. Micro RNAs (miRNAs) are short, non-coding RNAs, which regulate cellular activities by either mRNA degradation or translational inhibition. Our studies focused on the invasive properties of hsa-mir30c based on its high expression in MDA-MB-231 metastatic cells and our bioinformatic analysis of the Cancer Genome Atlas that identified aberrant hsa-mir-30c to be associated with poor survival., Methods: Contributions of hsa-mir-30c to breast cancer cell invasion were examined by Matrigel invasion transwell assays following modulation of hsa-mir-30c or hsa-mir-30c* levels in MDA-MB-231 cells. hsa-mir-30c in silico predicted targets linked to cell invasion were screened for targeting by hsa-mir-30c in metastatic breast cancer cells by RT-qPCR. The contribution to invasion by a target of hsa-mir-30c, Nephroblastoma overexpressed (NOV), was characterized by siRNA and invasion assays. Significant effects were determined using Student's T-tests with Welch's correction for unequal variance., Results: MCF-7 and MDA-MB-231 cells were used as models of poorly invasive and late-stage metastatic disease, respectively. By modulating the levels of hsa-mir-30c in these cells, we observed concomitant changes in breast cancer cell invasiveness. From predicted targets of hsa-mir-30c that were related to cellular migration and invasion, NOV/CCN3 was identified as a novel target of hsa-mir-30c. Depleting NOV by siRNA caused a significant increase in the invasiveness of MDA-MB-231 cells is a regulatory protein associated with the extracellular matrix., Conclusions: NOV/CCN3 expression, which protects cells from invasion, is known in patient tumors to inversely correlate with advanced breast cancer and metastasis. This study has identified a novel target of hsa-mir-30c, NOV, which is an inhibitor of the invasiveness of metastatic breast cancer cells. Thus, hsa-mir-30c-mediated inhibition of NOV levels promotes the invasive phenotype of MDA-MB-231 cells and significantly, the miR-30/NOV pathways is independent of RUNX2, a known target of hsa-mir-30c that promotes osteolytic disease in metastatic breast cancer cells. Our findings allow for mechanistic insight into the clinical observation of poor survival of patients with elevated hsa-mir-30c levels, which can be considered for miRNA-based translational studies.
- Published
- 2014
- Full Text
- View/download PDF
43. Genomic occupancy of Runx2 with global expression profiling identifies a novel dimension to control of osteoblastogenesis.
- Author
-
Wu H, Whitfield TW, Gordon JA, Dobson JR, Tai PW, van Wijnen AJ, Stein JL, Stein GS, and Lian JB
- Subjects
- Animals, Cell Line, Core Binding Factor Alpha 1 Subunit genetics, Gene Regulatory Networks, Mice, Osteoblasts cytology, Promoter Regions, Genetic, Protein Binding, Core Binding Factor Alpha 1 Subunit metabolism, Gene Expression Regulation, Developmental, Genome, Osteoblasts metabolism, Osteogenesis, Transcription, Genetic
- Abstract
Background: Osteogenesis is a highly regulated developmental process and continues during the turnover and repair of mature bone. Runx2, the master regulator of osteoblastogenesis, directs a transcriptional program essential for bone formation through genetic and epigenetic mechanisms. While individual Runx2 gene targets have been identified, further insights into the broad spectrum of Runx2 functions required for osteogenesis are needed., Results: By performing genome-wide characterization of Runx2 binding at the three major stages of osteoblast differentiation--proliferation, matrix deposition and mineralization--we identify Runx2-dependent regulatory networks driving bone formation. Using chromatin immunoprecipitation followed by high-throughput sequencing over the course of these stages, we identify approximately 80,000 significantly enriched regions of Runx2 binding throughout the mouse genome. These binding events exhibit distinct patterns during osteogenesis, and are associated with proximal promoters and also non-promoter regions: upstream, introns, exons, transcription termination site regions, and intergenic regions. These peaks were partitioned into clusters that are associated with genes in complex biological processes that support bone formation. Using Affymetrix expression profiling of differentiating osteoblasts depleted of Runx2, we identify novel Runx2 targets including Ezh2, a critical epigenetic regulator; Crabp2, a retinoic acid signaling component; Adamts4 and Tnfrsf19, two remodelers of the extracellular matrix. We demonstrate by luciferase assays that these novel biological targets are regulated by Runx2 occupancy at non-promoter regions., Conclusions: Our data establish that Runx2 interactions with chromatin across the genome reveal novel genes, pathways and transcriptional mechanisms that contribute to the regulation of osteoblastogenesis.
- Published
- 2014
- Full Text
- View/download PDF
44. Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine.
- Author
-
Raphael BJ, Dobson JR, Oesper L, and Vandin F
- Abstract
High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein sequence or structure. Finally, we review techniques to identify recurrent combinations of somatic mutations, including approaches that examine mutations in known pathways or protein-interaction networks, as well as de novo approaches that identify combinations of mutations according to statistical patterns of mutual exclusivity. These techniques, coupled with advances in high-throughput DNA sequencing, are enabling precision medicine approaches to the diagnosis and treatment of cancer.
- Published
- 2014
- Full Text
- View/download PDF
45. The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter.
- Author
-
Barutcu AR, Tai PW, Wu H, Gordon JA, Whitfield TW, Dobson JR, Imbalzano AN, Lian JB, van Wijnen AJ, Stein JL, and Stein GS
- Subjects
- Animals, Cell Differentiation, Cell Line, Humans, Mice, Osteoblasts cytology, Osteoblasts metabolism, Synteny, Transcription Factors metabolism, Chromatin chemistry, Core Binding Factor Alpha 1 Subunit genetics, Promoter Regions, Genetic, Transcription Factors genetics
- Abstract
Three-dimensional organization of chromatin is fundamental for transcriptional regulation. Tissue-specific transcriptional programs are orchestrated by transcription factors and epigenetic regulators. The RUNX2 transcription factor is required for differentiation of precursor cells into mature osteoblasts. Although organization and control of the bone-specific Runx2-P1 promoter have been studied extensively, long-range regulation has not been explored. In this study, we investigated higher-order organization of the Runx2-P1 promoter during osteoblast differentiation. Mining the ENCODE database revealed interactions between Runx2-P1 and Supt3h promoters in several non-mesenchymal human cell lines. Supt3h is a ubiquitously expressed gene located within the first intron of Runx2. These two genes show shared synteny across species from humans to sponges. Chromosome conformation capture analysis in the murine pre-osteoblastic MC3T3-E1 cell line revealed increased contact frequency between Runx2-P1 and Supt3h promoters during differentiation. This increase was accompanied by enhanced DNaseI hypersensitivity along with RUNX2 and CTCF binding at the Supt3h promoter. Furthermore, interplasmid-3C and luciferase reporter assays showed that the Supt3h promoter can modulate Runx2-P1 activity via direct association. Taken together, our data demonstrate physical proximity between Runx2-P1 and Supt3h promoters, consistent with their syntenic nature. Importantly, we identify the Supt3h promoter as a potential regulator of the bone-specific Runx2-P1 promoter., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2014
- Full Text
- View/download PDF
46. Module 5: what's next?
- Author
-
Dobson LA Jr, James MG, O'Kane ME, Salgo P, and Weissberg J
- Subjects
- Humans, Patient-Centered Care, Quality Assurance, Health Care legislation & jurisprudence, United States, Value-Based Purchasing, Advisory Committees, Patient Protection and Affordable Care Act legislation & jurisprudence
- Published
- 2013
47. Module 4: the quality enterprise and VBP principles--case studies.
- Author
-
Berthiaume JT, Dobson LA Jr, Heuser GK, Salgo P, and Weissberg J
- Subjects
- Centers for Medicare and Medicaid Services, U.S., Health Facilities economics, Patient Protection and Affordable Care Act, Quality Improvement economics, Reimbursement, Incentive organization & administration, State Government, United States, Value-Based Purchasing legislation & jurisprudence, Health Facilities standards, Value-Based Purchasing organization & administration
- Published
- 2013
48. Module 3: measuring quality in the quality enterprise.
- Author
-
Dobson LA Jr, James MG, O'Kane ME, Salgo P, and Weissberg J
- Subjects
- Insurance, Health, Reimbursement, Outcome Assessment, Health Care, Patient Protection and Affordable Care Act, Patient-Centered Care, Total Quality Management organization & administration, United States, Health Facilities standards, Quality Assurance, Health Care methods, Quality Indicators, Health Care
- Published
- 2013
49. Questioning the widely publicized savings.
- Author
-
Cosway R and Dobson A Jr
- Subjects
- Cost Savings, Medicaid economics
- Published
- 2013
50. A RUNX2-HDAC1 co-repressor complex regulates rRNA gene expression by modulating UBF acetylation.
- Author
-
Ali SA, Dobson JR, Lian JB, Stein JL, van Wijnen AJ, Zaidi SK, and Stein GS
- Subjects
- Acetylation, Cell Line, Cell Nucleolus metabolism, Cell Proliferation, Chromatin metabolism, Core Binding Factor Alpha 1 Subunit chemistry, DNA, Ribosomal metabolism, Gene Knockdown Techniques, Genetic Loci genetics, Histones metabolism, Humans, Interphase, Protein Binding, Protein Biosynthesis, Protein Transport, RNA, Ribosomal metabolism, RNA, Small Interfering metabolism, Transcription, Genetic, Co-Repressor Proteins metabolism, Core Binding Factor Alpha 1 Subunit metabolism, Gene Expression Regulation, Histone Deacetylase 1 metabolism, Pol1 Transcription Initiation Complex Proteins metabolism, RNA, Ribosomal genetics
- Abstract
The osteogenic and oncogenic transcription factor RUNX2 downregulates the RNA polymerase I (RNA Pol I)-mediated transcription of rRNAs and changes histone modifications associated with the rDNA repeat. However, the mechanisms by which RUNX2 suppresses rRNA transcription are not well understood. RUNX2 cofactors such as histone deacetylases (HDACs) play a key role in chromatin remodeling and regulation of gene transcription. Here, we show that RUNX2 recruits HDAC1 to the rDNA repeats in osseous cells. This recruitment alters the histone modifications associated with active rRNA-encoding genes and causes deacetylation of the protein upstream binding factor (UBF, also known as UBTF). Downregulation of RUNX2 expression reduces the localization of HDAC1 to the nucleolar periphery and also decreases the association between HDAC1 and UBF. Functionally, depletion of HDAC1 relieves the RUNX2-mediated repression of rRNA-encoding genes and concomitantly increases cell proliferation and global protein synthesis in osseous cells. Our findings collectively identify a RUNX2-HDAC1-dependent mechanism for the regulation of rRNA-encoding genes and suggest that there is plasticity to RUNX2-mediated epigenetic control, which is mediated through selective mitotic exclusion of co-regulatory factors.
- Published
- 2012
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.