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Article ; Online: Increased lifespan, decreased mortality, and delayed cognitive decline in osteoarthritis.

Mayburd, Anatoly L / Baranova, Ancha

2019 Volume 9, Issue 1, Page(s) 18639

Abstract: In absence of therapies targeting symptomatic dementia, better understanding of the biology underlying a cognitive decline is warranted. Here we present the results of a meta-analysis of the impact of osteoarthritis (OA) on cognitive decline and overall ... ...

Abstract	In absence of therapies targeting symptomatic dementia, better understanding of the biology underlying a cognitive decline is warranted. Here we present the results of a meta-analysis of the impact of osteoarthritis (OA) on cognitive decline and overall mortality. Across 7 independent datasets obtained in studies of populations in the USA, EU and Australia (NBER, NSHAP, TILDA, NACC, Kaiser Permanente, GRIM BOOKS, OAI, with a total of >7 × 10
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/complications ; Alzheimer Disease/epidemiology ; Alzheimer Disease/physiopathology ; Australia/epidemiology ; Cognition/physiology ; Cognitive Dysfunction/complications ; Cognitive Dysfunction/mortality ; Cognitive Dysfunction/physiopathology ; Dementia/complications ; Dementia/mortality ; Dementia/physiopathology ; Female ; Humans ; Immune System/metabolism ; Longevity ; Male ; Middle Aged ; Osteoarthritis, Knee/complications ; Osteoarthritis, Knee/mortality ; Osteoarthritis, Knee/physiopathology
Language	English
Publishing date	2019-12-09
Publishing country	England
Document type	Journal Article ; Meta-Analysis
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-54867-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Increased lifespan, decreased mortality, and delayed cognitive decline in osteoarthritis

Anatoly L. Mayburd / Ancha Baranova

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 15

Abstract: Abstract In absence of therapies targeting symptomatic dementia, better understanding of the biology underlying a cognitive decline is warranted. Here we present the results of a meta-analysis of the impact of osteoarthritis (OA) on cognitive decline and ...

Abstract	Abstract In absence of therapies targeting symptomatic dementia, better understanding of the biology underlying a cognitive decline is warranted. Here we present the results of a meta-analysis of the impact of osteoarthritis (OA) on cognitive decline and overall mortality. Across 7 independent datasets obtained in studies of populations in the USA, EU and Australia (NBER, NSHAP, TILDA, NACC, Kaiser Permanente, GRIM BOOKS, OAI, with a total of >7 × 107 profiles), OA cohorts demonstrated higher cognitive scores, later dementia onset as well as longer lifespan and lower age-specific all-cause mortality. Moreover, generalized OA with multiple localizations is associated with more significant reduction of mortality and dementia than a singly localized OA or no arthritis. In OA patients with younger ages, all-cause mortality was disproportionally reduced as compared to that in controls, while exponential term of Gompert’z hazard function was increased, accelerating mortality accrual at later ages. Up to 8–10% of poly-osteoarthritic patients are predicted and observed to reach centenarian lifespan, while in matched non-OA population the same benchmark is reached by less than 1% of patients. These results point at a possibility of life-extending and cognition preserving impacts of OA-conditioned immune system.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy.

Mayburd, Anatoly L / Koivogui, Mathilda / Baranova, Ancha

PloS one

2019 Volume 14, Issue 11, Page(s) e0224315

Abstract: Preventive treatments for dementia are warranted. Here we show that utilization of certain combinations of prescription medications and supplements correlates with reduced rates of cognitive decline. More than 1,900 FDA-approved agents and supplements ... ...

Abstract	Preventive treatments for dementia are warranted. Here we show that utilization of certain combinations of prescription medications and supplements correlates with reduced rates of cognitive decline. More than 1,900 FDA-approved agents and supplements were collapsed into 53 mechanism-based groups and traced in electronic medical records (EMRs) for >50,000 patients. These mechanistic groups were aligned with the data presented in more than 300 clinical trials, then regression model was built to fit the signals from EMRs to clinical trial performance. While EMR signals of each single agents correlated with clinical performance relatively weakly, the signals produced by combinations of active compounds were highly correlated with the clinical trial performance (R = 0.93, p = 3.8 x10^-8). Higher ranking pharmacological modalities were traced in patient profiles as their combinations, producing protective complexity estimates reflecting degrees of exposure to beneficial polypharmacy. For each age strata, the higher was the protective complexity score, the lower was the prevalence of dementia, with maximized life-long effects for the highest regression score /diversity compositions. The connection was less strong in individuals already diagnosed with cognitive impairment. Confounder analysis confirmed an independent effect of protective complexity in multivariate context. A sub-cohort with lifelong odds of dementia decreased > 5-folds was identified; this sub-cohort should be studied in further details, including controlled clinical trials. In short, our study systematically explored combinatorial preventive treatment regimens for age-associated multi-morbidity, with an emphasis on neurodegeneration, and provided extensive evidence for their feasibility.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/physiology ; Cognition/drug effects ; Cognition/physiology ; Cognitive Dysfunction/epidemiology ; Cognitive Dysfunction/physiopathology ; Cognitive Dysfunction/prevention & control ; Confounding Factors, Epidemiologic ; Databases, Factual/statistics & numerical data ; Dementia/epidemiology ; Dementia/physiopathology ; Dementia/prevention & control ; Dietary Supplements ; Disease Progression ; Electronic Health Records/statistics & numerical data ; Feasibility Studies ; Female ; Follow-Up Studies ; Humans ; Incidence ; Male ; Middle Aged ; Polypharmacy ; Prescription Drugs/administration & dosage ; Treatment Outcome
Chemical Substances	Prescription Drugs
Language	English
Publishing date	2019-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0224315
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Article ; Online: Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy.

Anatoly L Mayburd / Mathilda Koivogui / Ancha Baranova

PLoS ONE, Vol 14, Iss 11, p e

2019 Volume 0224315

Abstract	Preventive treatments for dementia are warranted. Here we show that utilization of certain combinations of prescription medications and supplements correlates with reduced rates of cognitive decline. More than 1,900 FDA-approved agents and supplements were collapsed into 53 mechanism-based groups and traced in electronic medical records (EMRs) for >50,000 patients. These mechanistic groups were aligned with the data presented in more than 300 clinical trials, then regression model was built to fit the signals from EMRs to clinical trial performance. While EMR signals of each single agents correlated with clinical performance relatively weakly, the signals produced by combinations of active compounds were highly correlated with the clinical trial performance (R = 0.93, p = 3.8 x10^-8). Higher ranking pharmacological modalities were traced in patient profiles as their combinations, producing protective complexity estimates reflecting degrees of exposure to beneficial polypharmacy. For each age strata, the higher was the protective complexity score, the lower was the prevalence of dementia, with maximized life-long effects for the highest regression score /diversity compositions. The connection was less strong in individuals already diagnosed with cognitive impairment. Confounder analysis confirmed an independent effect of protective complexity in multivariate context. A sub-cohort with lifelong odds of dementia decreased > 5-folds was identified; this sub-cohort should be studied in further details, including controlled clinical trials. In short, our study systematically explored combinatorial preventive treatment regimens for age-associated multi-morbidity, with an emphasis on neurodegeneration, and provided extensive evidence for their feasibility.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Expression variation: its relevance to emergence of chronic disease and to therapy.

Mayburd, Anatoly L

PloS one

2009 Volume 4, Issue 6, Page(s) e5921

Abstract: Background: Stochastic fluctuations in the protein turnover underlie the random emergence of neural precursor cells from initially homogenous cell population. If stochastic alteration of the levels in signal transduction networks is sufficient to ... ...

Abstract	Background: Stochastic fluctuations in the protein turnover underlie the random emergence of neural precursor cells from initially homogenous cell population. If stochastic alteration of the levels in signal transduction networks is sufficient to spontaneously alter a phenotype, can it cause a sporadic chronic disease as well -- including cancer? Methods: Expression in >80 disease-free tissue environments was measured using Affymetrix microarray platform comprising 54675 probe-sets. Steps were taken to suppress the technical noise inherent to microarray experiment. Next, the integrated expression and expression variability data were aligned with the mechanistic data covering major human chronic diseases. Results: Measured as class average, variability of expression of disease associated genes measured in health was higher than variability of random genes for all chronic pathologies. Anti-cancer FDA approved targets were displaying much higher variability as a class compared to random genes. Same held for magnitude of gene expression. The genes known to participate in multiple chronic disorders demonstrated the highest variability. Disease-related gene categories displayed on average more intricate regulation of biological function vs random reference, were enriched in adaptive and transient functions as well as positive feedback relationships. Conclusions: A possible causative link can be suggested between normal (healthy) state gene expression variation and inception of major human pathologies, including cancer. Study of variability profiles may lead to novel diagnostic methods, therapies and better drug target prioritization. The results of the study suggest the need to advance personalized therapy development.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Chronic Disease/therapy ; Computational Biology/methods ; Escherichia coli/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Genome ; Humans ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Signal Transduction ; Stochastic Processes ; Treatment Outcome
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2009-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0005921
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Influenza antiviral therapeutics.

Mayburd, Anatoly L

Recent patents on anti-infective drug discovery

2008 Volume 5, Issue 1, Page(s) 64–75

Abstract: In this review we conducted a landscaping study of the therapeutic anti-influenza agents, limiting the scope by exclusion of vaccines. The resulting 2800 patent publications were classified into 23 distinct technological sectors. The mechanism of action, ...

Abstract	In this review we conducted a landscaping study of the therapeutic anti-influenza agents, limiting the scope by exclusion of vaccines. The resulting 2800 patent publications were classified into 23 distinct technological sectors. The mechanism of action, the promise and drawbacks of the corresponding technological sectors were explored on comparative basis. A set of quantitative parameters was defined based on landscaping procedure that appears to correlate with the practical success of a given class of therapeutics. Thus, the sectors not considered promising from the mechanistic side were also displaying low value of the classifying parameters. The parameters were combined into a probabilistic Marketing Prediction Score, assessing a likelihood of a given sector to produce a marketable product. The proposed analytical methodology may be useful for automatic search and assessment of technologies for the goals of acquisition, investment and competitive bidding. While not being a substitute for an expert evaluation, it provides an initial assessment suitable for implementation with large-scale automated landscaping.
MeSH term(s)	Animals ; Antiviral Agents/adverse effects ; Antiviral Agents/chemistry ; Antiviral Agents/therapeutic use ; Drug Discovery ; Humans ; Influenza, Human/drug therapy ; Influenza, Human/virology ; Models, Statistical ; Molecular Structure ; Patents as Topic ; Structure-Activity Relationship ; Treatment Outcome
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2008-02-02
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2261296-8
ISSN	2212-4071 ; 1574-891X
ISSN (online)	2212-4071
ISSN	1574-891X
DOI	10.2174/157489110790112527
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Article ; Online: Expression variation

Anatoly L Mayburd

PLoS ONE, Vol 4, Iss 6, p e

its relevance to emergence of chronic disease and to therapy.

2009 Volume 5921

Abstract: BACKGROUND:Stochastic fluctuations in the protein turnover underlie the random emergence of neural precursor cells from initially homogenous cell population. If stochastic alteration of the levels in signal transduction networks is sufficient to ... ...

Abstract	BACKGROUND:Stochastic fluctuations in the protein turnover underlie the random emergence of neural precursor cells from initially homogenous cell population. If stochastic alteration of the levels in signal transduction networks is sufficient to spontaneously alter a phenotype, can it cause a sporadic chronic disease as well -- including cancer? METHODS:Expression in >80 disease-free tissue environments was measured using Affymetrix microarray platform comprising 54675 probe-sets. Steps were taken to suppress the technical noise inherent to microarray experiment. Next, the integrated expression and expression variability data were aligned with the mechanistic data covering major human chronic diseases. RESULTS:Measured as class average, variability of expression of disease associated genes measured in health was higher than variability of random genes for all chronic pathologies. Anti-cancer FDA approved targets were displaying much higher variability as a class compared to random genes. Same held for magnitude of gene expression. The genes known to participate in multiple chronic disorders demonstrated the highest variability. Disease-related gene categories displayed on average more intricate regulation of biological function vs random reference, were enriched in adaptive and transient functions as well as positive feedback relationships. CONCLUSIONS:A possible causative link can be suggested between normal (healthy) state gene expression variation and inception of major human pathologies, including cancer. Study of variability profiles may lead to novel diagnostic methods, therapies and better drug target prioritization. The results of the study suggest the need to advance personalized therapy development.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2009-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Successful anti-cancer drug targets able to pass FDA review demonstrate the identifiable signature distinct from the signatures of random genes and initially proposed targets.

Mayburd, Anatoly L / Golovchikova, Inna / Mulshine, James L

Bioinformatics (Oxford, England)

2008 Volume 24, Issue 3, Page(s) 389–395

Abstract: Motivation: New efforts to guide and prioritize the selection of cancer drug targets are urgently needed, as is evident by the slow development of novel anti-cancer agents and the narrow therapeutic index of existing drugs. Given these limitations, the ... ...

Abstract	Motivation: New efforts to guide and prioritize the selection of cancer drug targets are urgently needed, as is evident by the slow development of novel anti-cancer agents and the narrow therapeutic index of existing drugs. Given these limitations, the current study was conducted to explore the classification features defining the therapeutic success that can result from targeting a particular gene. Results: Classification was based on extracting features specific to known successful anti-cancer targets and combining them in a linear classifier, resulting in calculation of an enrichment score for each gene. Extended description, the search tool used in this study, enriched existing drug target candidates by up to 10-fold at an approximately 50% recall rate, covering approximately 24 000 genes or approximately 80% of genome. More importantly, the target category with high attrition rate was classified from target category with low attrition rate, allowing to refine the drug development portfolios. Biological relevance of the parameters comprising the enrichment score was explored. Enrichment in cancer-specific effects was independently demonstrated by literature analysis. Imposing these enrichment scores on existing structural, pathway and phenotype-based procedures for prospective target selection may enhance the efficiency and accuracy of target identification and accelerate drug design. Availability: The software used in this work is available upon request.
MeSH term(s)	Algorithms ; Antineoplastic Agents/administration & dosage ; Drug Approval/methods ; Drug Delivery Systems/methods ; Drug Design ; Drug Therapy, Computer-Assisted/methods ; Gene Expression Profiling/methods ; Gene Targeting/methods ; Humans ; Neoplasm Proteins/drug effects ; Neoplasm Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Oligonucleotide Array Sequence Analysis/methods ; United States ; United States Food and Drug Administration
Chemical Substances	Antineoplastic Agents ; Neoplasm Proteins
Language	English
Publishing date	2008-02-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btm447
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Article ; Online: Patent landscape of countermeasures against smallpox and estimation of grant attraction capability through patent landscape data.

Mayburd, Anatoly L / Kedia, Govind / Evans, Haydn W / Kaslival, Pritesh C

Recent patents on anti-infective drug discovery

2010 Volume 5, Issue 3, Page(s) 240–254

Abstract: The study was concerned with countermeasures against a possible smallpox outbreak. In the process of assessment 18 landscaping sectors were defined and described, the advantages and drawbacks of the corresponding countermeasures being reviewed. The data ... ...

Abstract	The study was concerned with countermeasures against a possible smallpox outbreak. In the process of assessment 18 landscaping sectors were defined and described, the advantages and drawbacks of the corresponding countermeasures being reviewed. The data of the previously published influenza landscape were revisited. The current economic climate of deficit cutting (austerity) also puts emphasis on the optimization of capital investment. We used the materials of the landscape to define and analyze metrics of capital placement optimization. Value score was obtained by fitting patent landscape internals to the sale price of individual patents. Success score was obtained as a product of a-priori parameters that measure likelihood of emergence of a marketable product in a technological sector. Both scores were combined in a qualitative metric. Our methodology defined weight as a product of the sector size by the success score. We hypothesized - based on the material of two landscapes- that a life cycle of a technology begins in IP space with a high patent quality low volume "bud" of low weight, reaches maximum weight and then weight falls again when the technology becomes outdated. The weight and the annual dynamic of weight can serve a measure of investment risk and return. In this report we modeled investment by issue of government grants or purchase of patents by government. In the smallpox landscape the number of patents purchased by government agencies was the highest in the sectors with the highest weight and the trend was confirmed by the count of NIH grants issued in support of the technological sectors. In the influenza landscape only grant issue count was statistically meaningful and the trend was also confirmed. To better fit the grant support levels, the weight expression was optimized by using training coefficients. We propose to use value scores for evaluation of individual patent publications/company portfolios and to use weights for assessment of technological sectors. Such a combination of automated analytical tools may lead to optimized allocation of capital and is intended to support the decisions taken by human experts.
MeSH term(s)	Animals ; Disease Outbreaks/legislation & jurisprudence ; Disease Outbreaks/prevention & control ; Humans ; Patents as Topic/legislation & jurisprudence ; Peer Review, Research/legislation & jurisprudence ; Smallpox/drug therapy ; Smallpox/epidemiology ; Smallpox/prevention & control ; Smallpox Vaccine/therapeutic use
Chemical Substances	Smallpox Vaccine
Language	English
Publishing date	2010-08-24
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2261296-8
ISSN	2212-4071 ; 1574-891X
ISSN (online)	2212-4071
ISSN	1574-891X
DOI	10.2174/157489110793348758
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Article: Mechanism and biological role of nitric oxide binding to cytochrome c'.

Mayburd, Anatoly L / Kassner, Richard J

Biochemistry

2002 Volume 41, Issue 39, Page(s) 11582–11591

Abstract: The binding of nitric oxide to ferric and ferrous Chromatium vinosum cytochrome c' was studied. The extinction coefficients for the ferric and ferrous nitric oxide complexes were measured. A binding model that included both a conformational change and ... ...

Abstract	The binding of nitric oxide to ferric and ferrous Chromatium vinosum cytochrome c' was studied. The extinction coefficients for the ferric and ferrous nitric oxide complexes were measured. A binding model that included both a conformational change and dissociation of the dimer into subunits provided the best fit for the ferric cytochrome c' data. The NO (nitric oxide) binding affinity of the WT ferric form was found to be comparable to the affinities displayed by the ferric myoglobins and hemoglobins. Using an improved fitting model, positive cooperativity was found for the binding of NO to the WT ferric and ferrous forms, while anticooperativity was the case for the Y16F mutant. Structural explanations accounting for the binding are proposed. The NO affinity of ferrous cytochrome c' was found to be much lower than the affinities of myoglobins, hemoglobins, and pentacoordinate heme models. Structural factors accounting for the difference in affinities were analyzed. The NO affinity of ferrous cytochrome c' was found to be in the range typical of receptors and carriers. In addition, cytochrome c' was found to react with cytosolic light-irradiated membranes in the presence of succinate and carbon monoxide. With these results, a biochemical model of cytochrome c' functioning as a nitric oxide carrier was proposed.
MeSH term(s)	Amino Acid Substitution/genetics ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/physiology ; Binding Sites/genetics ; Chromatium/enzymology ; Chromatium/genetics ; Crystallography ; Cytochrome c Group/chemistry ; Cytochrome c Group/genetics ; Cytochrome c Group/physiology ; Dimerization ; Ferric Compounds/chemistry ; Ferrous Compounds/chemistry ; Models, Chemical ; Nitric Oxide/chemistry ; Nitric Oxide/genetics ; Nitric Oxide/physiology ; Nitric Oxide Donors/chemistry ; Spectrophotometry ; Structure-Activity Relationship
Chemical Substances	Bacterial Proteins ; Cytochrome c Group ; Ferric Compounds ; Ferrous Compounds ; Nitric Oxide Donors ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2002-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi020058l
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