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  1. Article ; Online: Ryanodine receptor dysfunction in human disorders.

    Kushnir, Alexander / Wajsberg, Benjamin / Marks, Andrew R

    Biochimica et biophysica acta. Molecular cell research

    2018  Volume 1865, Issue 11 Pt B, Page(s) 1687–1697

    Abstract: Regulation of intracellular calcium ( ... ...

    Abstract Regulation of intracellular calcium (Ca
    MeSH term(s) Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Calmodulin/metabolism ; Carrier Proteins/metabolism ; Disease Susceptibility ; Endoplasmic Reticulum/metabolism ; Humans ; Ion Channel Gating/drug effects ; Ligands ; Phosphorylation ; Protein Binding ; Ryanodine Receptor Calcium Release Channel/chemistry ; Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism
    Chemical Substances Calmodulin ; Carrier Proteins ; Ligands ; Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2018-07-21
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2018.07.011
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  2. Article ; Online: Accessible Hepatitis C Care for People Who Inject Drugs: A Randomized Clinical Trial.

    Eckhardt, Benjamin / Mateu-Gelabert, Pedro / Aponte-Melendez, Yesenia / Fong, Chunki / Kapadia, Shashi / Smith, Melinda / Edlin, Brian R / Marks, Kristen M

    JAMA internal medicine

    2022  Volume 182, Issue 5, Page(s) 494–502

    Abstract: Importance: To achieve hepatitis C elimination, treatment programs need to engage, treat, and cure people who inject drugs.: Objective: To compare a low-threshold, nonstigmatizing hepatitis C treatment program that was colocated at a syringe service ... ...

    Abstract Importance: To achieve hepatitis C elimination, treatment programs need to engage, treat, and cure people who inject drugs.
    Objective: To compare a low-threshold, nonstigmatizing hepatitis C treatment program that was colocated at a syringe service program (accessible care) with facilitated referral to local clinicians through a patient navigation program (usual care).
    Design, setting, and participants: This single-site randomized clinical trial was conducted at the Lower East Side Harm Reduction Center, a syringe service program in New York, New York, and included 167 participants who were hepatitis C virus RNA-positive and had injected drugs during the prior 90 days. Participants enrolled between July 2017 and March 2020. Data were analyzed after all patients completed 1 year of follow-up (after March 2021).
    Interventions: Participants were randomized 1:1 to the accessible care or usual care arm.
    Main outcomes and measures: The primary end point was achieving sustained virologic response within 12 months of enrollment.
    Results: Among the 572 participants screened, 167 (mean [SD] age, 42.0 [10.6] years; 128 (77.6%) male, 36 (21.8%) female, and 1 (0.6) transgender individuals; 8 (4.8%) Black, 97 (58.5%) Hispanic, and 53 (32.1%) White individuals) met eligibility criteria and were enrolled, with 2 excluded postrandomization (n = 165). Baseline characteristics were similar between the 2 arms. In the intention-to-treat analysis, 55 of 82 participants (67.1%) in the accessible care arm and 19 of 83 participants (22.9%) in the usual care arm achieved a sustained virologic response (P < .001). Loss to follow-up (12.2% [accessible care] and 16.9% [usual care]; P = .51) was similar in the 2 arms. Of the participants who received therapy, 55 of 64 (85.9%) and 19 of 22 (86.3%) achieved a sustained virologic response in the accessible care and usual care arms, respectively (P = .96). Significantly more participants in the accessible care arm achieved all steps in the care cascade, with the greatest attrition in the usual care arm seen in referral to hepatitis C virus clinician and attending clinical visit.
    Conclusions and relevance: In this randomized clinical trial, among people who inject drugs with hepatitis C infection, significantly higher rates of cure were achieved using the accessible care model that focused on low-threshold, colocated, destigmatized, and flexible hepatitis C care compared with facilitated referral. To achieve hepatitis C elimination, expansion of treatment programs that are specifically geared toward engaging people who inject drugs is paramount.
    Trial registration: ClinicalTrials.gov Identifier: NCT03214679.
    MeSH term(s) Adult ; Drug Users ; Female ; Hepacivirus ; Hepatitis C/drug therapy ; Humans ; Male ; Sustained Virologic Response ; White People
    Language English
    Publishing date 2022-03-12
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
    ZDB-ID 2699338-7
    ISSN 2168-6114 ; 2168-6106
    ISSN (online) 2168-6114
    ISSN 2168-6106
    DOI 10.1001/jamainternmed.2022.0170
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  3. Article ; Online: Estimated Clinical Outcomes and Cost-effectiveness Associated With Provision of Addiction Treatment in US Primary Care Clinics.

    Jawa, Raagini / Tin, Yjuliana / Nall, Samantha / Calcaterra, Susan L / Savinkina, Alexandra / Marks, Laura R / Kimmel, Simeon D / Linas, Benjamin P / Barocas, Joshua A

    JAMA network open

    2023  Volume 6, Issue 4, Page(s) e237888

    Abstract: Importance: US primary care practitioners (PCPs) are the largest clinical workforce, but few provide addiction care. Primary care is a practical place to expand addiction services, including buprenorphine and harm reduction kits, yet the clinical ... ...

    Abstract Importance: US primary care practitioners (PCPs) are the largest clinical workforce, but few provide addiction care. Primary care is a practical place to expand addiction services, including buprenorphine and harm reduction kits, yet the clinical outcomes and health care sector costs are unknown.
    Objective: To estimate the long-term clinical outcomes, costs, and cost-effectiveness of integrated buprenorphine and harm reduction kits in primary care for people who inject opioids.
    Design, setting, and participants: In this modeling study, the Reducing Infections Related to Drug Use Cost-Effectiveness (REDUCE) microsimulation model, which tracks serious injection-related infections, overdose, hospitalization, and death, was used to examine the following treatment strategies: (1) PCP services with external referral to addiction care (status quo), (2) PCP services plus onsite buprenorphine prescribing with referral to offsite harm reduction kits (BUP), and (3) PCP services plus onsite buprenorphine prescribing and harm reduction kits (BUP plus HR). Model inputs were derived from clinical trials and observational cohorts, and costs were discounted annually at 3%. The cost-effectiveness was evaluated over a lifetime from the modified health care sector perspective, and sensitivity analyses were performed to address uncertainty. Model simulation began January 1, 2021, and ran for the entire lifetime of the cohort.
    Main outcomes and measures: Life-years (LYs), hospitalizations, mortality from sequelae (overdose, severe skin and soft tissue infections, and endocarditis), costs, and incremental cost-effectiveness ratios (ICERs).
    Results: The simulated cohort included 2.25 million people and reflected the age and gender of US persons who inject opioids. Status quo resulted in 6.56 discounted LYs at a discounted cost of $203 500 per person (95% credible interval, $203 000-$222 000). Each strategy extended discounted life expectancy: BUP by 0.16 years and BUP plus HR by 0.17 years. Compared with status quo, BUP plus HR reduced sequelae-related mortality by 33%. The mean discounted lifetime cost per person of BUP and BUP plus HR were more than that of the status quo strategy. The dominating strategy was BUP plus HR. Compared with status quo, BUP plus HR was cost-effective (ICER, $34 400 per LY). During a 5-year time horizon, BUP plus HR cost an individual PCP practice approximately $13 000.
    Conclusions and relevance: This modeling study of integrated addiction service in primary care found improved clinical outcomes and modestly increased costs. The integration of addiction service into primary care practices should be a health care system priority.
    MeSH term(s) Humans ; Cost-Benefit Analysis ; Analgesics, Opioid/therapeutic use ; Buprenorphine/therapeutic use ; Life Expectancy ; Primary Health Care
    Chemical Substances Analgesics, Opioid ; Buprenorphine (40D3SCR4GZ)
    Language English
    Publishing date 2023-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2023.7888
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  4. Article ; Online: The national utilization of nonoperative management for small renal masses over 10 years.

    Filipas, Dejan K / Beatrici, Edoardo / Nolazco, Jose I / Qian, Zhiyu / Marks, Phillip / Labban, Muhieddine / Stone, Benjamin V / Pierorazio, Phillip M / Lipsitz, Stuart R / Trinh, Quoc-Dien / Chang, Steven L / Cole, Alexander P

    JNCI cancer spectrum

    2023  Volume 7, Issue 6

    Abstract: Background: Management of small renal masses often involves a nonoperative approach, but there is a paucity of information about the use and associated predictors of such approaches. This study aimed to determine the trends in and predictors of use of ... ...

    Abstract Background: Management of small renal masses often involves a nonoperative approach, but there is a paucity of information about the use and associated predictors of such approaches. This study aimed to determine the trends in and predictors of use of nonoperative management of small renal masses.
    Methods: Using data from the National Cancer Database for localized small renal masses (N0/M0, cT1a) diagnosed between 2010 and 2020, we conducted a cross-sectional study. Nonoperative management was defined as expectant management (active surveillance or watchful waiting) or focal ablation. Adjusted odds ratios (AORs) were calculated using multivariable logistic regression models.
    Results: Of the 156 734 patients included, 10.5% underwent expectant management, and 13.9% underwent focal ablation. Later year of diagnosis was associated with a higher likelihood of nonoperative management. In 2020, the odds of receiving expectant management and focal ablation were 90% (AOR = 1.90, 95% confidence interval [CI] = 1.71 to 2.11) and 44% (AOR = 1.44, 95% CI = 1.31 to 1.57) higher, respectively, than in 2010. Black patients had increased odds of expectant management (AOR = 1.47, 95% CI = 1.39 to 1.55) but decreased odds of focal ablation (AOR = 0.93, 95% CI = 0.88 to 0.99).
    Conclusion: Over the decade, the use nonoperative management of small renal masses increased, with expectant management more frequently used than focal ablation among Black patients. Possible explanations include race-based differences in physicians' risk assessments and resource allocation. Adjusting for Black race in calculations for glomerular filtration rate could influence the differential uptake of these techniques through deflated glomerular filtration rate calculations. These findings highlight the need for research and policies to ensure equitable use of less invasive treatments in small renal masses.
    MeSH term(s) Humans ; Cross-Sectional Studies ; Kidney Neoplasms/therapy ; Risk Assessment ; Black or African American ; Ablation Techniques ; Watchful Waiting
    Language English
    Publishing date 2023-08-27
    Publishing country England
    Document type Journal Article
    ISSN 2515-5091
    ISSN (online) 2515-5091
    DOI 10.1093/jncics/pkad084
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  5. Article: Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

    Fram, Benjamin / Truebridge, Ian / Su, Yang / Riesselman, Adam J / Ingraham, John B / Passera, Alessandro / Napier, Eve / Thadani, Nicole N / Lim, Samuel / Roberts, Kristen / Kaur, Gurleen / Stiffler, Michael / Marks, Debora S / Bahl, Christopher D / Khan, Amir R / Sander, Chris / Gauthier, Nicholas P

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Designing optimized proteins is important for a range of practical applications. Protein design is a rapidly developing field that would benefit from approaches that enable many changes in the amino acid primary sequence, rather than a small number of ... ...

    Abstract Designing optimized proteins is important for a range of practical applications. Protein design is a rapidly developing field that would benefit from approaches that enable many changes in the amino acid primary sequence, rather than a small number of mutations, while maintaining structure and enhancing function. Homologous protein sequences contain extensive information about various protein properties and activities that have emerged over billions of years of evolution. Evolutionary models of sequence co-variation, derived from a set of homologous sequences, have proven effective in a range of applications including structure determination and mutation effect prediction. In this work we apply one of these models (EVcouplings) to computationally design highly divergent variants of the model protein TEM-1 β-lactamase, and characterize these designs experimentally using multiple biochemical and biophysical assays. Nearly all designed variants were functional, including one with 84 mutations from the nearest natural homolog. Surprisingly, all functional designs had large increases in thermostability and most had a broadening of available substrates. These property enhancements occurred while maintaining a nearly identical structure to the wild type enzyme. Collectively, this work demonstrates that evolutionary models of sequence co-variation (1) are able to capture complex epistatic interactions that successfully guide large sequence departures from natural contexts, and (2) can be applied to generate functional diversity useful for many applications in protein design.
    Language English
    Publishing date 2023-05-09
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.09.539914
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  6. Article ; Online: Humoral and cellular immune responses in persons with rheumatoid arthritis after a third dose of mRNA COVID-19 vaccine.

    Tedeschi, Sara K / Solomon, Daniel H / Chen, Yuezhou / Ellrodt, Jack / Whelan, Mary Grace / Stratton, Jacklyn / Hayashi, Keigo / Whiteman, Noah Benjamin / Chen, Lin / Adejoorin, Ifeoluwakiisi / Marks, Kathryne E / Gomez-Rivas, Emma / Rao, Deepak A / Jonsson, A Helena / Wesemann, Duane R

    Seminars in arthritis and rheumatism

    2023  Volume 59, Page(s) 152177

    Abstract: Objective: Disease-modifying anti-rheumatic drugs (DMARDs) that treat rheumatoid arthritis (RA) may reduce immune responses to COVID-19 vaccination. We compared humoral and cell-mediated immunity before and after a 3rd dose of mRNA COVID vaccine in RA ... ...

    Abstract Objective: Disease-modifying anti-rheumatic drugs (DMARDs) that treat rheumatoid arthritis (RA) may reduce immune responses to COVID-19 vaccination. We compared humoral and cell-mediated immunity before and after a 3rd dose of mRNA COVID vaccine in RA subjects.
    Methods: RA patients that received 2 doses of mRNA vaccine enrolled in an observational study in 2021 before receiving a 3rd dose. Subjects self-reported holding or continuing DMARDs. Blood samples were collected pre- and 4 weeks after the 3rd dose. 50 healthy controls provided blood samples. Humoral response was measured with in-house ELISA assays for anti-Spike IgG (anti-S) and anti-receptor binding domain IgG (anti-RBD). T cell activation was measured after stimulation with SARS-CoV-2 peptide. Spearman's correlations assessed the relationship between anti-S, anti-RBD, and frequencies of activated T cells.
    Results: Among 60 subjects, mean age was 63 years and 88% were female. 57% of subjects held at least 1 DMARD around the 3rd dose. 43% (anti-S) and 62% (anti-RBD) had a normal humoral response at week 4, defined as ELISA within 1 standard deviation of the healthy control mean. No differences in antibody levels were observed based on holding DMARDs. Median frequency of activated CD4 T cells was significantly greater post- vs. pre-3rd dose. Changes in antibody levels did not correlate with change in frequency of activated CD4 T cells.
    Conclusion: Virus-specific IgG levels significantly increased in RA subjects using DMARDs after completing the primary vaccine series, though fewer than two-thirds achieved a humoral response like healthy controls. Humoral and cellular changes were not correlated.
    MeSH term(s) Humans ; Female ; Middle Aged ; Male ; COVID-19 Vaccines ; COVID-19 ; SARS-CoV-2 ; Immunity, Cellular ; Antirheumatic Agents ; Arthritis, Rheumatoid ; RNA, Messenger ; Immunoglobulin G
    Chemical Substances COVID-19 Vaccines ; Antirheumatic Agents ; RNA, Messenger ; Immunoglobulin G
    Language English
    Publishing date 2023-02-10
    Publishing country United States
    Document type Observational Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120247-9
    ISSN 1532-866X ; 0049-0172
    ISSN (online) 1532-866X
    ISSN 0049-0172
    DOI 10.1016/j.semarthrit.2023.152177
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    Zs.A 790: Show issues Location:
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  7. Article ; Online: Cost of providing co-located hepatitis C treatment at a syringe service program exceeds potential reimbursement: Results from a clinical trial.

    Kapadia, Shashi N / Eckhardt, Benjamin J / Leff, Jared A / Fong, Chunki / Mateu-Gelabert, Pedro / Marks, Kristen M / Aponte-Melendez, Yesenia / Schackman, Bruce R

    Drug and alcohol dependence reports

    2022  Volume 5

    Abstract: Background: Co-located hepatitis C treatment at syringe service programs (SSP) is an emerging model of care for people who inject drugs (PWID). Implementation of these models can be informed by understanding the program costs.: Methods: We conducted ... ...

    Abstract Background: Co-located hepatitis C treatment at syringe service programs (SSP) is an emerging model of care for people who inject drugs (PWID). Implementation of these models can be informed by understanding the program costs.
    Methods: We conducted an economic evaluation of a hepatitis C treatment intervention at an SSP in New York City implemented as one arm of a randomized trial from 2017 to 2021. Start-up and operating costs were determined from the treatment program's perspective using micro-costing and were compared to potential Medicaid reimbursement. We applied nationally representative unit costs and wage rates. Results are reported in 2020 USD.
    Results: The treatment program was staffed by one physician and one care coordinator. Participants were offered hepatitis C clinical evaluation and treatment, a 45-min reinfection prevention education session, and additional care coordination as needed. The trial enrolled 84 PWID with hepatitis C in the intervention arm; 64 initiated treatment and 55 achieved sustained virological response. Start-up costs including training and equipment totaled $4677. Overhead costs including rent, utilities and software totaled $2229 per month. Clinical and care coordination totaled $4867 per participant, of which $3722 was care coordination. The total cost excluding startup was $6035 per enrolled participant and $7921 per treated participant; estimated potential reimbursement was $628 per enrolled participant.
    Conclusion: Our results provide insight to US-based SSPs seeking to provide co-located hepatitis C care and highlight the intensive care coordination services provided. Successful implementation likely requires funding sources beyond health insurers or substantial changes to insurance reimbursement for care coordination.
    Language English
    Publishing date 2022-10-07
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2772-7246
    ISSN (online) 2772-7246
    DOI 10.1016/j.dadr.2022.100109
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  8. Article: Hepatitis C Treatment Outcomes for People Who Inject Drugs Treated in an Accessible Care Program Located at a Syringe Service Program.

    Eckhardt, Benjamin J / Scherer, Matthew / Winkelstein, Emily / Marks, Kristen / Edlin, Brian R

    Open forum infectious diseases

    2018  Volume 5, Issue 4, Page(s) ofy048

    Abstract: Hepatitis C virus (HCV) is a significant public health problem that disproportionately afflicts people who inject drugs. We describe outcomes of HCV treatment co-located within a syringe services program (SSP). Fifty-three participants started therapy, ... ...

    Abstract Hepatitis C virus (HCV) is a significant public health problem that disproportionately afflicts people who inject drugs. We describe outcomes of HCV treatment co-located within a syringe services program (SSP). Fifty-three participants started therapy, and 91% achieved sustained virologic response. SSPs provide an effective venue for HCV treatment.
    Language English
    Publishing date 2018-03-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2757767-3
    ISSN 2328-8957
    ISSN 2328-8957
    DOI 10.1093/ofid/ofy048
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  9. Article ; Online: Simulated Cost-effectiveness and Long-term Clinical Outcomes of Addiction Care and Antibiotic Therapy Strategies for Patients With Injection Drug Use-Associated Infective Endocarditis.

    Adams, Joëlla W / Savinkina, Alexandra / Hudspeth, James C / Gai, Mam Jarra / Jawa, Raagini / Marks, Laura R / Linas, Benjamin P / Hill, Alison / Flood, Jason / Kimmel, Simeon / Barocas, Joshua A

    JAMA network open

    2022  Volume 5, Issue 2, Page(s) e220541

    Abstract: Importance: Emerging evidence supports the use of outpatient parenteral antimicrobial therapy (OPAT) and, in many cases, partial oral antibiotic therapy for the treatment of injection drug use-associated infective endocarditis (IDU-IE); however, long- ... ...

    Abstract Importance: Emerging evidence supports the use of outpatient parenteral antimicrobial therapy (OPAT) and, in many cases, partial oral antibiotic therapy for the treatment of injection drug use-associated infective endocarditis (IDU-IE); however, long-term outcomes and cost-effectiveness remain unknown.
    Objective: To compare the added value of inpatient addiction care services and the cost-effectiveness and clinical outcomes of alternative antibiotic treatment strategies for patients with IDU-IE.
    Design, setting, and participants: This decision analytical modeling study used a validated microsimulation model to compare antibiotic treatment strategies for patients with IDU-IE. Model inputs were derived from clinical trials and observational cohort studies. The model included all patients with injection opioid drug use (N = 5 million) in the US who were eligible to receive OPAT either in the home or at a postacute care facility. Costs were annually discounted at 3%. Cost-effectiveness was evaluated from a health care sector perspective over a lifetime starting in 2020. Probabilistic sensitivity, scenario, and threshold analyses were performed to address uncertainty.
    Interventions: The model simulated 4 treatment strategies: (1) 4 to 6 weeks of inpatient intravenous (IV) antibiotic therapy along with opioid detoxification (usual care strategy), (2) 4 to 6 weeks of inpatient IV antibiotic therapy along with inpatient addiction care services that offered medication for opioid use disorder (usual care/addiction care strategy), (3) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by OPAT (OPAT strategy), and (4) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by partial oral antibiotic therapy (partial oral antibiotic strategy).
    Main outcomes and measures: Mean percentage of patients completing treatment for IDU-IE, deaths associated with IDU-IE, life expectancy (measured in life-years [LYs]), mean cost per person, and incremental cost-effectiveness ratios (ICERs).
    Results: All modeled scenarios were initialized with 5 million individuals (mean age, 42 years; range, 18-64 years; 70% male) who had a history of injection opioid drug use. The usual care strategy resulted in 18.63 LYs at a cost of $416 570 per person, with 77.6% of hospitalized patients completing treatment. Life expectancy was extended by each alternative strategy. The partial oral antibiotic strategy yielded the highest treatment completion rate (80.3%) compared with the OPAT strategy (78.8%) and the usual care/addiction care strategy (77.6%). The OPAT strategy was the least expensive at $412 150 per person. Compared with the OPAT strategy, the partial oral antibiotic strategy had an ICER of $163 370 per LY. Increasing IDU-IE treatment uptake and decreasing treatment discontinuation made the partial oral antibiotic strategy more cost-effective compared with the OPAT strategy. When assuming that all patients with IDU-IE were eligible to receive partial oral antibiotic therapy, the strategy was cost-saving and resulted in 0.0247 additional discounted LYs. When treatment discontinuation was decreased from 3.30% to 2.65% per week, the partial oral antibiotic strategy was cost-effective compared with OPAT at the $100 000 per LY threshold.
    Conclusions and relevance: In this decision analytical modeling study, incorporation of OPAT or partial oral antibiotic approaches along with addiction care services for the treatment of patients with IDU-IE was associated with increases in the number of people completing treatment, decreases in mortality, and savings in cost compared with the usual care strategy of providing inpatient IV antibiotic therapy alone.
    MeSH term(s) Adult ; Analgesics, Opioid/therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Anti-Infective Agents/therapeutic use ; Cost-Benefit Analysis ; Endocarditis/drug therapy ; Endocarditis, Bacterial/drug therapy ; Female ; Humans ; Male
    Chemical Substances Analgesics, Opioid ; Anti-Bacterial Agents ; Anti-Infective Agents
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2022.0541
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  10. Article ; Online: Perturbation biology links temporal protein changes to drug responses in a melanoma cell line.

    Nyman, Elin / Stein, Richard R / Jing, Xiaohong / Wang, Weiqing / Marks, Benjamin / Zervantonakis, Ioannis K / Korkut, Anil / Gauthier, Nicholas P / Sander, Chris

    PLoS computational biology

    2020  Volume 16, Issue 7, Page(s) e1007909

    Abstract: Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. Cancer drugs targeting these alterations often work initially, but ... ...

    Abstract Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. Cancer drugs targeting these alterations often work initially, but resistance is common. Combinations of targeted drugs may overcome or prevent resistance, but their selection requires context-specific knowledge of signaling pathways including complex interactions such as feedback loops and crosstalk. To infer quantitative pathway models, we collected a rich dataset on a melanoma cell line: Following perturbation with 54 drug combinations, we measured 124 (phospho-)protein levels and phenotypic response (cell growth, apoptosis) in a time series from 10 minutes to 67 hours. From these data, we trained time-resolved mathematical models that capture molecular interactions and the coupling of molecular levels to cellular phenotype, which in turn reveal the main direct or indirect molecular responses to each drug. Systematic model simulations identified novel combinations of drugs predicted to reduce the survival of melanoma cells, with partial experimental verification. This particular application of perturbation biology demonstrates the potential impact of combining time-resolved data with modeling for the discovery of new combinations of cancer drugs.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Therapy, Combination ; Humans ; Melanoma ; Models, Biological ; Phosphoproteins/analysis ; Phosphoproteins/metabolism ; Signal Transduction/drug effects ; Systems Biology
    Chemical Substances Antineoplastic Agents ; Phosphoproteins
    Language English
    Publishing date 2020-07-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1007909
    Database MEDical Literature Analysis and Retrieval System OnLINE

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