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Article ; Online: Progression from Prodromal Alzheimer's Disease to Mild Alzheimer's Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions.

Voss, Tiffini / Kost, James / Mercer, Swati Pal / Furtek, Christine / Randolph, Christopher / Lines, Christopher / Egan, Michael F / Cummings, Jeffrey L

Journal of Alzheimer's disease : JAD

2023 Volume 92, Issue 1, Page(s) 341–348

Abstract: Background: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized.: Objective: ...

Abstract	Background: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Dementia/drug therapy ; Cyclic S-Oxides/therapeutic use ; Thiadiazines/therapeutic use ; Disease Progression
Chemical Substances	verubecestat (J1I0P6WT7T) ; Cyclic S-Oxides ; Thiadiazines
Language	English
Publishing date	2023-02-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220836
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Article ; Online: Rational design and experimental evaluation of peptide ligands for the purification of adeno-associated viruses via affinity chromatography.

Shastry, Shriarjun / Chu, Wenning / Barbieri, Eduardo / Greback-Clarke, Paul / Smith, William K / Cummings, Christopher / Minzoni, Arianna / Pancorbo, Jennifer / Gilleskie, Gary / Ritola, Kimberly / Daniele, Michael A / Johnson, Thomas F / Menegatti, Stefano

Biotechnology journal

2023 Volume 19, Issue 1, Page(s) e2300230

Abstract: Adeno-associated viruses (AAVs) have acquired a central role in modern medicine as delivery agents for gene therapies targeting rare diseases. While new AAVs with improved tissue targeting, potency, and safety are being introduced, their biomanufacturing ...

Abstract	Adeno-associated viruses (AAVs) have acquired a central role in modern medicine as delivery agents for gene therapies targeting rare diseases. While new AAVs with improved tissue targeting, potency, and safety are being introduced, their biomanufacturing technology is lagging. In particular, the AAV purification pipeline hinges on protein ligands for the affinity-based capture step. While featuring excellent AAV binding capacity and selectivity, these ligands require strong acid (pH <3) elution conditions, which can compromise the product's activity and stability. Additionally, their high cost and limited lifetime has a significant impact on the price tag of AAV-based therapies. Seeking to introduce a more robust and affordable affinity technology, this study introduces a cohort of peptide ligands that (i) mimic the biorecognition activity of the AAV receptor (AAVR) and anti-AAV antibody A20, (ii) enable product elution under near-physiological conditions (pH 6.0), and (iii) grant extended reusability by withstanding multiple regenerations. A20-mimetic CYIHFSGYTNYNPSLKSC and AAVR-mimetic CVIDGSQSTDDDKIC demonstrated excellent capture of serotypes belonging to distinct clones/clades - namely, AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. This corroborates the in silico models documenting their ability to target regions of the viral capsid that are conserved across all serotypes. CVIDGSQSTDDDKIC-Toyopearl resin features binding capacity (≈10
MeSH term(s)	Humans ; Dependovirus/genetics ; Capsid/chemistry ; HEK293 Cells ; Transduction, Genetic ; Peptides/metabolism ; Ligands ; Chromatography, Affinity ; Genetic Vectors/genetics
Chemical Substances	Peptides ; Ligands
Language	English
Publishing date	2023-09-28
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2221885-3
ISSN	1860-7314 ; 1860-6768
ISSN (online)	1860-7314
ISSN	1860-6768
DOI	10.1002/biot.202300230
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Article: Clinical Characteristics of the 2019 Eastern Equine Encephalitis Outbreak in Michigan.

Ladzinski, Adam T / Tai, Aisha / Rumschlag, Matthew T / Smith, Christopher S / Mehta, Aditya / Boapimp, Pimpawan / Edewaard, Eric J / Douce, Richard W / Morgan, Larry F / Wang, Michael S / Fisher-Hubbard, Amanda O / Cummings, Matthew J / Jagger, Brett W

Open forum infectious diseases

2023 Volume 10, Issue 5, Page(s) ofad206

Abstract: Background: Eastern equine encephalitis virus is a mosquito-borne alphavirus responsible for unpredictable outbreaks of severe neurologic disease in animals and humans. While most human infections are asymptomatic or clinically nonspecific, a minority ... ...

Abstract	Background: Eastern equine encephalitis virus is a mosquito-borne alphavirus responsible for unpredictable outbreaks of severe neurologic disease in animals and humans. While most human infections are asymptomatic or clinically nonspecific, a minority of patients develops encephalitic disease, a devastating illness with a mortality rate of ≥30%. No treatments are known to be effective. Eastern equine encephalitis virus infection is rare in the United States, with an annual average nationwide incidence of 7 cases between 2009 and 2018. However, in 2019, 38 cases were confirmed nationwide, including 10 in Michigan. Methods: Data from 8 cases identified by a regional network of physicians in southwest Michigan were abstracted from clinical records. Clinical imaging and histopathology were aggregated and reviewed. Results: Patients were predominantly older adults (median age, 64 years), and all were male. Results of initial arboviral cerebrospinal fluid serology were frequently negative, and diagnosis was not made until a median of 24.5 days (range, 13-38 days) after presentation, despite prompt lumbar punctures in all patients. Imaging findings were dynamic and heterogeneous, with abnormalities of the thalamus and/or basal ganglia, and prominent pons and midbrain abnormalities were displayed in 1 patient. Six patients died, 1 survived the acute illness with severe neurologic sequelae, and 1 recovered with mild sequelae. A limited postmortem examination revealed diffuse meningoencephalitis, neuronophagia, and focal vascular necrosis. Conclusions: Eastern equine encephalitis is a frequently fatal condition whose diagnosis is often delayed, and for which no effective treatments are known. Improved diagnostics are needed to facilitate patient care and encourage the development of treatments.
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofad206
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Article ; Online: Lens capsule as a model to study type IV collagen.

Cummings, Christopher F / Hudson, Billy G

Connective tissue research

2014 Volume 55, Issue 1, Page(s) 8–12

Abstract: The study of collagen IV has benefited greatly from the seminal work conducted by Arthur Veis and colleagues over three decades ago. Through a series of electron microscopy studies focused on lens basement membrane, an appreciation was gained for the ... ...

Abstract	The study of collagen IV has benefited greatly from the seminal work conducted by Arthur Veis and colleagues over three decades ago. Through a series of electron microscopy studies focused on lens basement membrane, an appreciation was gained for the distinct network-forming properties of collagen IV. Veis correctly suggested that network assembly is a phenomenon of the non-collagenous termini of the molecule. This review seeks to document how the field advanced following these seminal conclusions, including recent discoveries regarding the molecular reinforcement of networks that support Veis' conclusions.
MeSH term(s)	Animals ; Basement Membrane/metabolism ; Cells/metabolism ; Collagen Type IV/chemistry ; Collagen Type IV/metabolism ; Humans ; Lens Capsule, Crystalline/metabolism ; Models, Biological
Chemical Substances	Collagen Type IV
Language	English
Publishing date	2014-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	185551-7
ISSN	1607-8438 ; 0091-1690 ; 0300-8207
ISSN (online)	1607-8438
ISSN	0091-1690 ; 0300-8207
DOI	10.3109/03008207.2013.867337
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Zs.A 1093: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 44: Show issues

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Article: Key role of dysregulated airway epithelium in response to respiratory viral infections in asthma.

Moheimani, Fatemeh / Shahdab, Nafeesa / Cummings, Stephen / Hansbro, Philip M / Ward, Christopher

ERJ open research

2022 Volume 8, Issue 3

Abstract: A differentiated air-liquid interface model shows that the airway epithelium plays a key role in response to respiratory viral infections in people with ... ...

Abstract	A differentiated air-liquid interface model shows that the airway epithelium plays a key role in response to respiratory viral infections in people with asthma
Language	English
Publishing date	2022-09-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2827830-6
ISSN	2312-0541
ISSN	2312-0541
DOI	10.1183/23120541.00314-2022
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Article ; Online: Building collagen IV smart scaffolds on the outside of cells.

Brown, Kyle L / Cummings, Christopher F / Vanacore, Roberto M / Hudson, Billy G

Protein science : a publication of the Protein Society

2017 Volume 26, Issue 11, Page(s) 2151–2161

Abstract: Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After ...

Abstract	Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Oxidoreductases/genetics ; Amino Acid Oxidoreductases/metabolism ; Animals ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Basement Membrane/metabolism ; Basement Membrane/ultrastructure ; Collagen Type IV/chemistry ; Collagen Type IV/genetics ; Collagen Type IV/metabolism ; Eukaryotic Cells/metabolism ; Eukaryotic Cells/ultrastructure ; Extracellular Matrix/metabolism ; Extracellular Matrix/ultrastructure ; Gene Expression Regulation ; Humans ; Peroxidases ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Structure, Secondary ; Protein Subunits/chemistry ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Receptors, Interleukin-1/genetics ; Receptors, Interleukin-1/metabolism
Chemical Substances	Antigens, Neoplasm ; Collagen Type IV ; Protein Subunits ; Receptors, Interleukin-1 ; PXDN protein, human (EC 1.11.1.-) ; Peroxidases (EC 1.11.1.-) ; Amino Acid Oxidoreductases (EC 1.4.-) ; LOXL2 protein, human (EC 1.4.3.-)
Language	English
Publishing date	2017-08-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.3283
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 1: Show issues

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Article: Chemical Vapor Deposited Mixed Metal Halide Perovskite Thin Films.

Magubane, Siphesihle Siphamandla / Arendse, Christopher Joseph / Ngqoloda, Siphelo / Cummings, Franscious / Mtshali, Christopher / Bolokang, Amogelang Sylvester

Materials (Basel, Switzerland)

2021 Volume 14, Issue 13

Abstract: In this article, we used a two-step chemical vapor deposition (CVD) method to synthesize methylammonium lead-tin triiodide perovskite films, ... ...

Abstract	In this article, we used a two-step chemical vapor deposition (CVD) method to synthesize methylammonium lead-tin triiodide perovskite films, MAPb
Language	English
Publishing date	2021-06-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2487261-1
ISSN	1996-1944
ISSN	1996-1944
DOI	10.3390/ma14133526
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Article ; Online: Demonstrating the consequences of learning missingness patterns in early warning systems for preventative health care: A novel simulation and solution.

Gillies, Christopher E / Taylor, Daniel F / Cummings, Brandon C / Ansari, Sardar / Islim, Fadi / Kronick, Steven L / Medlin, Richard P / Ward, Kevin R

Journal of biomedical informatics

2020 Volume 110, Page(s) 103528

Abstract: When using tree-based methods to develop predictive analytics and early warning systems for preventive healthcare, it is important to use an appropriate imputation method to prevent learning the missingness pattern. To demonstrate this, we developed a ... ...

Abstract	When using tree-based methods to develop predictive analytics and early warning systems for preventive healthcare, it is important to use an appropriate imputation method to prevent learning the missingness pattern. To demonstrate this, we developed a novel simulation that generated synthetic electronic health record data using a variational autoencoder with a custom loss function, which took into account the high missing rate of electronic health data. We showed that when tree-based methods learn missingness patterns (correlated with adverse events) in electronic health record data, this leads to decreased performance if the system is used in a new setting that has different missingness patterns. Performance is worst in this scenario when the missing rate between those with and without an adverse event is the greatest. We found that randomized and Bayesian regression imputation methods mitigate the issue of learning the missingness pattern for tree-based methods. We used this information to build a novel early warning system for predicting patient deterioration in general wards and telemetry units: PICTURE (Predicting Intensive Care Transfers and other UnfoReseen Events). To develop, tune, and test PICTURE, we used labs and vital signs from electronic health records of adult patients over four years (n = 133,089 encounters). We analyzed primary outcomes of unplanned intensive care unit transfer, emergency vasoactive medication administration, cardiac arrest, and death. We compared PICTURE with existing early warning systems and logistic regression at multiple levels of granularity. When analyzing PICTURE on the testing set using all observations within a hospital encounter (event rate = 3.4%), PICTURE had an area under the receiver operating characteristic curve (AUROC) of 0.83 and an adjusted (event rate = 4%) area under the precision-recall curve (AUPR) of 0.27, while the next best tested method-regularized logistic regression-had an AUROC of 0.80 and an adjusted AUPR of 0.22. To ensure system interpretability, we applied a state-of-the-art prediction explainer that provided a ranked list of features contributing most to the prediction. Though it is currently difficult to compare machine learning-based early warning systems, a rudimentary comparison with published scores demonstrated that PICTURE is on par with state-of-the-art machine learning systems. To facilitate more robust comparisons and development of early warning systems in the future, we have released our variational autoencoder's code and weights so researchers can (a) test their models on data similar to our institution and (b) make their own synthetic datasets.
MeSH term(s)	Adult ; Bayes Theorem ; Delivery of Health Care ; Humans ; Intensive Care Units ; ROC Curve ; Retrospective Studies ; Vital Signs
Language	English
Publishing date	2020-08-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2057141-0
ISSN	1532-0480 ; 1532-0464
ISSN (online)	1532-0480
ISSN	1532-0464
DOI	10.1016/j.jbi.2020.103528
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Article ; Online: Increases in regional brain volume across two native South American male populations.

Chaudhari, Nikhil N / Imms, Phoebe E / Chowdhury, Nahian F / Gatz, Margaret / Trumble, Benjamin C / Mack, Wendy J / Law, E Meng / Sutherland, M Linda / Sutherland, James D / Rowan, Christopher J / Wann, L Samuel / Allam, Adel H / Thompson, Randall C / Michalik, David E / Miyamoto, Michael / Lombardi, Guido / Cummings, Daniel K / Seabright, Edmond / Alami, Sarah /

Garcia, Angela R / Rodriguez, Daniel E / Gutierrez, Raul Quispe / Copajira, Adrian J / Hooper, Paul L / Buetow, Kenneth H / Stieglitz, Jonathan / Gurven, Michael D / Thomas, Gregory S / Kaplan, Hillard S / Finch, Caleb E / Irimia, Andrei

GeroScience

2024

Abstract: Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between ... ...

Abstract	Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.
Language	English
Publishing date	2024-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-024-01168-2
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Zs.A 1502: Show issues

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Article ; Online: Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma.

Bezverbnaya, Ksenia / Moogk, Duane / Cummings, Derek / Baker, Christopher L / Aarts, Craig / Denisova, Galina / Sun, Michael / McNicol, Jamie D / Turner, Rebecca C / Rullo, Anthony F / Foley, S Ronan / Bramson, Jonathan L

Cytotherapy

2021 Volume 23, Issue 9, Page(s) 820–832

Abstract: Background aims: T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which ...

Abstract	Background aims: T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which co-opts the endogenous T-cell receptor (TCR) and activates engineered T cells in an HLA-independent manner. Here the authors describe the evolution of a next-generation TAC receptor with a focus on developing a TAC-engineered T cell for multiple myeloma. Methods: To optimize the TAC scaffold, the authors employed a bona fide antigen-binding domain derived from the B-cell maturation antigen-specific monoclonal antibody C11D5.3, which has been used successfully in the clinic. The authors first tested humanized versions of the UCHT1 domain, which is used by the TAC to co-opt the TCR. The authors further discovered that the signal peptide affected surface expression of the TAC receptor. Higher density of the TAC receptor enhanced target binding in vitro, which translated into higher levels of Lck at the immunological synapse and stronger proliferation when only receptor-ligand interactions were present. Results: The authors observed that the humanized UCHT1 improved surface expression and in vivo efficacy. Using TAC T cells derived from both healthy donors and multiple myeloma patients, the authors determined that despite the influence of receptor density on early activation events and effector function, receptor density did not impact late effector functions in vitro, nor did the receptor density affect in vivo efficacy. Conclusions: The modifications to the TAC scaffold described herein represent an important step in the evolution of this technology, which tolerates a range of expression levels without impacting therapeutic efficacy.
MeSH term(s)	B-Cell Maturation Antigen ; Humans ; Immunotherapy, Adoptive ; Multiple Myeloma/therapy ; Neoplasm Recurrence, Local ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes
Chemical Substances	B-Cell Maturation Antigen ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2021.05.007
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