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1.
Food Chem ; 367: 130677, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343803

RESUMO

This study investigated the physicochemical properties and 3D structure of Macadamia integrifolia antimicrobial protein 2 (MiAMP2) and its interaction with palmitoleic acid (POA) or oleic acid (OA) in macadamia oil. The 3D structure of MiAMP2 was constructed for the first time by ab initio modelling using the TrRosetta server. The results showed that MiAMP2 was highly hydrophilic and had seven disulfide bonds and higher α-helix and ß-sheet/turn contents. Molecular simulation showed that the hydrophobic pocket of MiAMP2 created a favourable environment for the binding of POA and OA. Free energy landscape and independent gradient model (IGM) analyses revealed that hydrogen bonds and van der Waals forces were the major driving forces stabilizing complexes formed by MiAMP2 and POA or OA. The present study provides a theoretical basis and new insight for the future development and utilization of macadamia nut protein in the food industry.

2.
Protein Expr Purif ; 188: 105974, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520839

RESUMO

Human growth hormone (hGH) plays an important role in growth control, growth promotion, cell development, and regulation of numerous metabolic pathways in the human body and has been approved by the U.S. FDA for the treatment of several human dysfunctions. Over-expression of recombinant hGH (rhGH) affords a misfolded form in cytoplasm of Escherichia coli, and the refolding step required to obtain active rhGH greatly affects its production costs. Herein, the cleavable self-aggregating tag (cSAT) scheme was used for the expression and purification of rhGH in E. coli. Four aggregating tags (L6KD/α3-peptide/EFK8/ELK16) successfully drove rhGH into active protein aggregates. After the Mxe GyrA intein-mediated cleavage, 2.8-21.4 µg rhGH/mg wet cell weight was obtained at laboratory scale, of which the L6KD fusion achieved the highest rhGH yield. The further refined rhGH maintained 92% of the bioactivity compared to commercial rhGH. The self-assembling of the aggregating tag might physically separate the hGH polypeptide chains, which in turn was beneficial to its folding into the active form. This study provided a simple and cost-effective approach for active rhGH production, and suggested an opportunity for improve folding of recombinant proteins in E. coli.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34465137

RESUMO

Yunnan is the first place where HIV-1 became prevalent in China, and it is also the place with the most complicated HIV-1 genetic diversity in China. On October 23, 2019, a patient newly diagnosed with acquired immunodeficiency syndrome from a hospital in Baosan, Yunnan, was recruited for genetic analysis. Near full-length genome of HIV-1 was amplified from the plasma sample. Phylogenetic analysis revealed that this sequence (BS6F24) has a close relationship with CRF86_BC and a unique recombinant form (KY406739), which was formed by recombination of subtypes B and C. Bootscan analysis confirmed that the first part (HXB2:1022-5832) and last part (HXB2:5833-9120) genomes of BS6F24 had the same recombinant structures as KY406739 and CRF86_BC, respectively. A second-generation recombinant form that originated from CRF86_BC and a unique recombinant form were reported for the first time. This indicates the need for continuous monitoring of the genetic diversity of HIV-1 in Yunnan, China.

4.
J Hazard Mater ; 416: 126120, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492915

RESUMO

Evidence is limited regarding the acute effects of personal fine particulate matter (PM2.5) exposure and its respiratory tract depositions on the alteration of children's blood pressure (BP). We conducted 2 longitudinal panel studies in 2 cities to evaluate the relations of 72-h real-time personal PM2.5 exposure and its depositions in 3 respiratory tract regions over different lag times with BP and the risk of prehypertension and hypertension among 286 children aged 4-12 years. We found the strongest effects of PM2.5 exposure on increased BP and risk of prehypertension and hypertension at lag 2 day, in dose-response manner, even when PM2.5 below Chinese Ambient Air Quality Standard (CAAQS) Grade II. Moreover, compared to PM2.5, tracheobronchial and alveolar depositions displayed more evident effects on BP outcomes. Interestingly, all above relationships were stronger among children in Guangzhou with lower PM2.5 and its deposited doses than those in Weinan. Additionally, boys and those with daily extra-school activity ≥ 1 h were more susceptible to PM2.5-induced BP effects with significant interactions. Our results highlighted that short-term PM2.5 exposure and its respiratory tract depositions were dose-responsive related to higher BP, prevalence of prehypertension and hypertension among children, even when PM2.5 below CAAQS II.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Pressão Sanguínea , Criança , China/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Humanos , Masculino , Material Particulado/análise , Material Particulado/toxicidade , Sistema Respiratório
5.
J Hazard Mater ; 416: 126251, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492994

RESUMO

Due to the nonbiodegradability and accumulation of mercury ion, even in extremely small amount, it will cause varying degrees of harm to environment and human health. Although researchers have developed many strategies to detect and monitor trace Hg2+, only a few provide sensitivities of less than 1.0 pM. Surface Enhanced Raman Spectroscopy (SERS) is a common method to detect mercury ion due to its high sensitivity, rapid detection and easy operation. In this work, we report a new SERS aptasensor based on dual recycling amplification for the detection of trace mercury ion, which combines SERS with nucleic acid signal amplification through functional aptamer and elaborately designed hairpin DNA. Under the optimal experimental conditions, this SERS aptasensor exhibits excellent selectivity and high sensitivity. A linear range (0.2-125 fM) and a low detection limit (0.11 fM) are obtained. By using specific aptamers, the strategy will provide a new idea for the trace detection of toxic contaminants in water environment.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Mercúrio , DNA , Ouro , Humanos , Limite de Detecção , Análise Espectral Raman , Água
6.
BMC Cancer ; 21(1): 1039, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530774

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. METHODS: We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients' tissue samples. The drug relations of S100As were analyzed by using the Drugbank database. RESULTS: The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. CONCLUSIONS: Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

7.
Clin Lab ; 67(9)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34542963

RESUMO

BACKGROUND: COVID-19 caused by SARS-CoV-2 has been inducing an ongoing global health and economic emergency. Although viral pneumonia is the most striking presentation for COVID-19 patients, it has been noticed that some patients may also be accompanied with an abnormal liver function. METHODS: CT was performed in both lungs, and routine bloodwork and the blood metabolic panel were measured. RESULTS: Here, we report on a young male patient without any history of live diseases who suffered simultaneously both SARS-CoV-2 caused pneumonia and hepatitis as evidenced by increased serum bilirubin together with increased serum transaminases. CONCLUSIONS: Studies on mechanisms whereby SARS-CoV-2 causing liver damages might provide more information about the pathogenesis of COVID-19 and help management of this global health emergency.

8.
Am J Surg Pathol ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469333

RESUMO

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

10.
Talanta ; 235: 122747, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517615

RESUMO

Microchip capillary electrophoresis (MCE) is a powerful technique for rapid separation; however, its acceptance in routine laboratories is still limited. Compromises caused by the efforts for solving different problems, such as reducing its cost of fabrication and ensuring high separation efficiency, undermine the competitiveness of this technology compared to other separation techniques. Contrary to the conventional pursuit of narrow microchannels, this study investigated the suitability of microchips with channels at the sub-millimeter level, targeting the simplification of the overall operation, cost reduction, and robustness improvement. To this effect, we considered the influence of pressurized flow and Joule heating on the separation. The suppression of pressurized flow with viscous solutions was confirmed through a combination of simulations and experimental results, indicating that the buffer viscosity was enough for successful separation. We fabricated channels of 200 µm × 230 µm using computer numerical controlled (CNC) machining and obtained theoretical plate numbers of 4.8 × 105 m-1 and 5.3 × 105 m-1 for fluorescein isothiocyanate (FITC) labeled small molecules and DNA fragments, respectively, with a buffer viscosity of 168 mPa s (0.5 % hydroxypropyl methylcellulose, HPMC). These values are comparable with that of narrow-bore microchips. Furthermore, we did not observe any deleterious effects with low-conductivity buffers. We investigated the rapid and highly sensitive detection of mycoplasma contamination and the real samples of circulating cell-free DNA (cfDNA), which gave a limit of detection (LOD) as low as 2.3 ng mL-1. Owing to the significant reduction in cost, ease of operation, and fast separation capabilities demonstrated in this work, MCE can be a viable alternative to the usual slab gel electrophoresis running in most biological laboratories.


Assuntos
Eletroforese em Microchip , DNA , Eletroforese Capilar , Derivados da Hipromelose , Limite de Detecção
11.
Langmuir ; 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370465

RESUMO

Photosurfactants have shown considerable promise for enabling stimuli-responsive control of the properties and motion of fluid interfaces. Recently, a number of photoswitch chemistries have emerged to tailor the photoresponsive properties of photosurfactants. However, systematic studies investigating how photoresponsive surfactant behavior depends on the photochemical and photophysical properties of the switch remain scarce. In this work, we develop synthetic schemes and surfactant designs to produce a well-controlled library of photosurfactants to comparatively assess the behavior of photoswitch chemistry on interfacial behavior. We employ photoinduced spreading of droplets at fluid interfaces as a model for such studies. We show that although photosurfactant response is largely guided by expected trends with changes in polarity of the photoswitch, interfacial behavior also depends nontrivially and sometimes counter-intuitively on the kinetics and mechanisms of photoswitching, particularly at the interface of two solvents, as well as on complex interactions with other surfactants. Understanding these complexities enables the design of new photosurfactant systems and their optimization toward responsive functions including triggered spreading, dewetting, and destabilization of droplets on solid and fluid surfaces.

12.
Psychiatry Investig ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34380296

RESUMO

OBJECTIVE: The connectivity alterations in the putamen were found in revealing the neural correlates of attention-deficit/hyperactivity disorder (ADHD), but whether the effective connectivity of the putamen is atypical in ADHD remains unclear. Investigating this abnormality contributes to describing the neural circuit of ADHD at the level of macrostructural organization. METHODS: Data were acquired from thirty-two boys with ADHD and fifty-two matched typically developing controls (TDC) from Peking University (Peking) dataset deposited at the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) platform. We examined the effective connectivity of the putamen using Granger causality analysis (GCA) and then determined whether these connections could differentiate ADHD from TDC. RESULTS: Compared with TDC, the ADHD group showed decreased effective connectivity from the left ventral rostral putamen (VRP) to left calcarine (CAL), right medial part of the superior frontal gyrus, left orbital part of superior frontal gyrus and left middle occipital gyrus (MOG). Increased effective connectivity from the left inferior occipital gyrus and right lingual gyrus to left VRP was also found in ADHD. The result of the classification accuracy showed that 72.3% of participants were correctly classified using support vector machine. Moreover, GCA values from the left VRP to left CAL and left MOG were significantly correlated with hyper/impulsive scores of patients with ADHD. CONCLUSION: The findings may help extend our understanding of the ADHD-related neural loops.

13.
Adv Mater ; : e2102529, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34418177

RESUMO

Metal halide perovskites are emerging scintillator materials in X-ray detection and imaging. However, the vulnerable structure of perovskites triggers unreliable performance when they are utilized in X-ray detectors under cumulative dose irradiation. Herein, a self-limited growth strategy is proposed to construct CsPbBr3 nanocrystals that are embedded in a transparent amorphous network structure, featuring X-imaging with excellent resolution (≈16.8 lp mm-1 ), and fast decay time (τ = 27 ns). Interestingly, it is found that the performance degradation of the scintillator, caused by the damage from high-dose X-ray irradiation, can be fully recovered after a facile thermal treatment process. This indicates a superior recycling behavior of the explored perovskites scintillator for practical applications. The recoverability of the as-explored scintillator is attributed to the low atom-migration rate in the amorphous network with high-viscosity (1 × 1014  cP). This result highlights the practical settlement of the promising perovskites for long-term, cost-effective scintillator devices.

14.
BMC Cardiovasc Disord ; 21(1): 390, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384364

RESUMO

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in patients with hypertension. ELABELA, which has cardioprotective effects, is decreased in the plasma of patients with hypertension and might be associated with AF in the hypertensive population. This study aims to measure the ELABELA plasma levels in hypertension patients with and without AF and to analyse the related factors. METHODS: A total of 162 hypertension patients with or without AF were recruited for our monocentric observational study. Subjects were excluded if they had a history of valvular heart disease, rheumatic heart disease, cardiomyopathy, thyroid diseases, or heart failure. The patients' histories were recorded, and laboratory examinations were conducted. Plasma ELABELA was detected by immunoassay. Echocardiographs were performed, and parameters were collected by two experienced doctors. Binary logistic regression analysis was used to identify the association between ELABELA plasma level and AF in patients with hypertension. RESULTS: Plasma ELABELA levels were lower in hypertension patients with AF than in those without AF (2.0 [1.5, 2.8] vs. 4.0 [3.4, 5.0] ng/ml, P < 0.001). ELABELA levels were correlated with age, heart rate, BNP levels and left atrial dimension. In addition to the left atrial dimension, ELABELA plasma levels were associated with AF in patients with hypertension (OR 0.081, 95% CI 0.029-0.224, P < 0.001). ELABELA levels were further decreased in the persistent AF subgroup compared with the paroxysmal AF subgroup (1.8 [1.4, 2.5] vs. 2.2 [1.8, 3.0] ng/ml, P = 0.012) and correlated with HR, BNP and ESR levels. CONCLUSIONS: ELALABELA levels were decreased in hypertension patients with AF and further lowered in the persistent AF subgroup. Decreased ELABELA plasma levels were associated with AF in hypertension patients and may be an underlying risk factor.

15.
Psychosom Med ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34419998

RESUMO

OBJECTIVE: Comorbid depression is common in schizophrenia, and sex differences are prominent in many aspects of schizophrenia. However, few studies have investigated sex difference in comorbid depression in schizophrenia. This large sample study aimed to investigate sex differences in first-episode drug-naive (FEDN) patients with schizophrenia comorbid major depressive episode (MDE) (SZ-MDE). METHODS: A total of 996 FEDN patients with schizophrenia (472 males/524 females) were recruited. The 17-item Hamilton Depression Rating Scale (HAMD-17) and Positive and Negative Syndrome Scale (PANSS) were applied. RESULTS: There was no difference in the prevalence of comorbid MDE between male and female patients with schizophrenia. Among SZ-MDE patients, men had more severe psychotic symptoms (scores of PANSS total scale, negative scale, and general psychopathology scale), more severe depressive symptoms and higher proportion of severe depression than women (all p < 0.001). The early onset age of schizophrenia, smoking and PANSS positive score were the risk factors for comorbid MDE only in female patients with schizophrenia (all p < 0.05). Furthermore, in female patients with SZ-MDE, smoking was associated with the severity category of depression (p = 0.001, OR = 2.70). Multiple variable regression demonstrated HAMD17 score correlated with PANSS general psychopathology (p = 0.01) and total scores (p = 0.04) in female SZ-MDE. CONCLUSIONS: Our results indicate sex differences in proportion of severe depression, clinical symptoms, and factors of comorbid MDE in FEDN patients with schizophrenia. These sex differences have clinical implications for the treatment of depression as related to the nature and severity of psychopathological symptoms in patients with schizophrenia.

16.
J Cell Physiol ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431091

RESUMO

Periodontitis is a chronic inflammatory disease leading to the destruction of periodontal tissues associated with high prevalence and significant economic burden. As special collagen-binding tyrosine kinase receptors, the discoidin domain receptors (DDRs) can control cell migration, adhesion, proliferation, and extracellular matrix remodeling. DDRs are constitutively expressed and widely distributed in periodontal tissues which are rich in collagen. Ddr1/2 knockout mice showed significant periodontal defects including connective tissue destruction, alveolar bone loss, and even tooth loss. It has been demonstrated that bone homeostasis, inflammation, matrix metalloproteinases, and autophagy are crucial characteristics involved in the pathogenesis of periodontitis. Of note, DDRs have been reported to participate in the above pathophysiological processes, implicating the potential roles of DDRs in periodontitis. In this review article, we aim to illustrate the possible roles of DDRs in periodontitis in an attempt to explore their potential value as therapeutic targets for periodontitis.

17.
Environ Toxicol Pharmacol ; 87: 103725, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34416396

RESUMO

The objective of this study was to evaluate the toxic effects of Cr6+ on bioaccumulation, digestion, immunity, oxidative stress, apoptosis and inflammation-related genes in Channa asiatica. The fish was exposed to waterborne Cr6+ concentrations (0, 0.5, 1.0 and 2.0 mg/L) for 28 and 56 days. Our results demonstrated that the accumulation of Cr6+ in tissues increased in a concentration-dependent manner, and the content in tissue was liver > gill > gut > muscle. Meanwhile, Cr6+ exposure led to a remarkable suppression of digestion, immunity and antioxidant capacity in C. asiatica. Inversely, MDA and PC content were positively correlated with Cr6+ exposure concentration. Furthermore, the expression of genes went up with the increase of waterborne Cr6+ concentration. Among them, HSP90, NF-κB and TNF-α have a sharp increase. These results elucidate that waterborne Cr6+ exposure may induce bioaccumulation, inhibit digestion and immunity, promote oxidative stress and up-regulate the expression of apoptosis and inflammation-related genes in C. asiatica.

18.
Bioorg Med Chem Lett ; 50: 128319, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34403728

RESUMO

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

19.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3705-3711, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402295

RESUMO

To observe the effect of Xinfeng Capsules on rheumatoid arthritis (RA) B lymphocytes,inflammatory mediators,FAK/CAPN/PI3K pathway,in order to explore the mechanism of Xinfeng Capsules in improving clinical symptoms of RA.Joint and systemic symptoms of RA patients were observed,and laboratory indicators[hemoglobin (HGB),platelet count (PLT),erythrocyte sedimentation (ESR),immunoglobulin (Ig) G,Ig A,Ig M,rheumatoid factor (RF),anti-cyclic citrulline antibody (CCP-AB),C-reactive protein (CRP)]were detected.ELISA was used to detect serum interleukin (IL)-1ß,IL-10,IL-33,chemokine 5 (CCL5),and vascular endothelial growth factor (VEGF).CD3~-CD19~+B cells were measured by flow cytometry.Western blot was used to detect FAK,p-FAK,CAPN,PI3K protein.The results showed that Xinfeng Capsules could significantly alleviate RA joint and systemic symptoms and improve clinical efficacy.And Xinfeng Capsules could increase HGB,decrease PLT,CCP-AB,CRP,ESR index,upregulate IL-10 expression,and down-regulate IL-1ß,IL-33,CCL5,VEGF,CD3~-CD19~+B cells,FAK,p-FAK,CAPN,PI3K expressions (P<0.01).Based on the above results,Xinfeng Capsules may reduce the expression of CD3~-CD19~+,regulate the balance of inflammatory cytokines and chemokines,inhibit abnormal activation of FAK/CAPN/PI3K pathway,and improve clinical symptoms of RA.


Assuntos
Artrite Reumatoide , Fosfatidilinositol 3-Quinases , Artrite Reumatoide/tratamento farmacológico , Linfócitos B , Cápsulas , Medicamentos de Ervas Chinesas , Humanos , Fator A de Crescimento do Endotélio Vascular
20.
Cancers (Basel) ; 13(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34359745

RESUMO

The ATM serine/threonine kinase (HGNC: ATM) is involved in initiation of repair of DNA double-stranded breaks, and ATM inhibitors are currently being tested as anti-cancer agents in clinical trials, where pharmacodynamic (PD) assays are crucial to help guide dose and scheduling and support mechanism of action studies. To identify and quantify PD biomarkers of ATM inhibition, we developed and analytically validated a 51-plex assay (DDR-2) quantifying protein expression and DNA damage-responsive phosphorylation. The median lower limit of quantification was 1.28 fmol, the linear range was over 3 orders of magnitude, the median inter-assay variability was 11% CV, and 86% of peptides were stable for storage prior to analysis. Use of the assay was demonstrated to quantify signaling following ionizing radiation-induced DNA damage in both immortalized lymphoblast cell lines and primary human peripheral blood mononuclear cells, identifying PD biomarkers for ATM inhibition to support preclinical and clinical studies.

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