Publications by authors named "Hua Guo"

950 Publications

LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through MEK/ERK signaling pathway.

Mol Metab 2021 Apr 3:101230. Epub 2021 Apr 3.

Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. Electronic address:

Objective: Adaptive rewiring of cancer energy metabolism has received more attention. By binding with LDLs, LDLRs make most of the circulating cholesterol available for cells to utilize. However, paucity still remains regarding how LDLR works in HCC development by affecting cholesterol metabolism.

Methods: Databases analyses and immunohistochemical staining were used to identify the clinical significance of LDLR in HCC. The transcriptome analysis was used to reveal the mechanism of LDLR aberration in HCC progression. The liver orthotopic transplantation model was used to evaluate the role of LDLR in HCC progression in vivo.

Results: Downregulation of LDLR was identified as a negative prognostic factor in human HCC. Reduced expression of LDLR in HCC cell lines led to LDL uptake impairment but promoted proliferation and metastasis in vitro and in vivo. Mechanistically, increasing intracellular de novo cholesterol biosynthesis was the chief contributor to the malignant behaviors caused by LDLR inhibition, which could be rescued by simvastatin. Activation of the MEK/ERK pathway by LDLR downregulation partially contributed to intracellular cholesterol synthesis in HCC.

Conclusions: Downregulation of LDLR may elevate intracellular cholesterol synthesis to accelerate proliferation and motility via a mechanism partially attributed to stimulation of the MEK/ERK signaling pathway. Repression of intracellular cholesterol synthesis with statins may constitute a targetable liability in the context of lower LDLR expression in HCC.
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http://dx.doi.org/10.1016/j.molmet.2021.101230DOI Listing
April 2021

Deep learning-enhanced T mapping with spatial-temporal and physical constraint.

Magn Reson Med 2021 Apr 6. Epub 2021 Apr 6.

Center for Biomedical Imaging Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.

Purpose: To propose a reconstruction framework to generate accurate T maps for a fast MR T mapping sequence.

Methods: A deep learning-enhanced T mapping method with spatial-temporal and physical constraint (DAINTY) was proposed. This method explicitly imposed low-rank and sparsity constraints on the multiframe T -weighted images to exploit the spatial-temporal correlation. A deep neural network was used to efficiently perform T mapping as well as denoise and reduce undersampling artifacts. Additionally, the physical constraint was used to build a bridge between low-rank and sparsity constraint and deep learning prior, so the benefits of constrained reconstruction and deep learning can be both available. The DAINTY method was trained on simulated brain data sets, but tested on real acquired phantom, 6 healthy volunteers, and 7 atherosclerosis patients, compared with the narrow-band k-space-weighted image contrast filter conjugate-gradient SENSE (NK-CS) method, kt-sparse-SENSE (kt-SS) method, and low-rank plus sparsity (L+S) method with least-squares T fitting and direct deep learning mapping.

Results: The DAINTY method can generate more accurate T maps and higher-quality T -weighted images compared with other methods. For atherosclerosis patients, the intraplaque hemorrhage can be successfully detected. The computation speed of DAINTY was 10 times faster than traditional methods. Meanwhile, DAINTY can reconstruct images with comparable quality using only 50% of k-space data.

Conclusion: The proposed method can provide accurate T maps and good-quality T -weighted images with high efficiency.
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http://dx.doi.org/10.1002/mrm.28793DOI Listing
April 2021

MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression.

Open Life Sci 2020 22;15(1):939-950. Epub 2020 Dec 22.

Department of Cardiovascular Medicine and Dongguan Cardiovascular Institute, The Third People's Hospital of Dongguan City, No. 1, Xianglong Road, Shi Long Town, Dongguan, China.

Diabetic nephropathy (DN) is the most serious long-term microvascular complication of diabetes, which mainly causes podocyte injury. Many studies have shown that microRNAs play a vital role in the development of DN. Studies have shown that miR-203-3p is involved in mesangial cell proliferation and apoptosis of DN mice. Therefore, we speculated that miR-203-3p might be related to the development of DN, but our study does not provide any evidence. In animal experiments, diabetic mice (db/db) were transfected with iR-203-3p overexpression lentiviral vectors (LV-miR-203-3p) and their control (LV-miR-con), with normal mice (db/m) being used as the control. High glucose (HG)-induced podocytes were used to construct a DN cell model . The expression levels of miR-203-3p, Semaphorin 3A (Sema3A) and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction. Also, serum creatinine and blood urea nitrogen levels were used to evaluate the degree of renal injury in DN mice. Sema3A and apoptosis-related protein levels were assessed by the western blot analysis. Enzyme-linked immunosorbent assay was used to determine the different oxidative stress-related indicators and inflammatory cytokines. Flow cytometry and caspase-3 activity detection were used to analyze the degree of podocyte apoptosis. Our results suggested that the expression of miR-203-3p was lower in DN mice and in HG-induced podocytes. Overexpression of miR-203-3p reduced the body weight, blood glucose and renal injury of DN mice , as well as relieve the oxidative stress, inflammatory response and apoptosis of HG-induced podocytes . Functionally, Sema3A was a target of miR-203-3p, and Sema3A overexpression reversed the inhibitory effect of miR-203-3p on HG-induced podocyte injury. Our findings revealed that miR-203-3p alleviated the podocyte injury induced by HG via regulating Sema3A expression, suggesting that miR-203-3p might be a new therapeutic target to improve the progression of DN.
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http://dx.doi.org/10.1515/biol-2020-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874591PMC
December 2020

Visual detection of hepatocellular carcinoma cells with cell imprinted substrate and pH-sensitive allochroic-graphene oxide.

Mater Sci Eng C Mater Biol Appl 2021 Apr 12;123:111966. Epub 2021 Feb 12.

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. Electronic address:

Herein, we integrate cell-imprinted substrate (CIS) and allochroic-graphene oxide (AGO) for specific visualization sorting of hepatocellular carcinoma cells. The state-of-the-art-of detection method relies on the enzyme linked immunosorbent assay (ELISA)-like sandwich strategy with hierarchical recognition. The target tumor cells are first selectively captured by the CIS based on cell imprinted recognition, and then specifically labeled with AGO by boronate affinity recognition between boronic acid on AGO and cis-diols on the surface of target cells. The selectively recognition of CIS for target template cells is verified by cell function experiments. It is also worth mentioning that the AGO can specifically recognize target tumor cells under physiological pH, and then perform signal amplification and output through pH-triggered allochroism. The CIS linked AGO for cell assay (CIS-AGO-CA) is successfully used for visualization detection of human hepatocarcinoma HLE cells from hepatocyte suspension. When the hepatocyte suspension is spiked with 1.0 × 10 cells, the recoveries of CIS-AGO-CA are 80.67 ± 4.33% for target HLE cells, and only 12.00 ± 1.00% for non-target Hep3B cells. It is worth emphasizing that the CIS-AGO-CA process is antibody-free. Therefore, this novel ELISA-like sandwich strategy is high specificity, cost-efficient and easy-to-use, and exhibits great prospect in the visualization sorting of tumor subpopulation.
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http://dx.doi.org/10.1016/j.msec.2021.111966DOI Listing
April 2021

Prolonged chronic social defeat stress promotes less resilience and higher uniformity in depression-like behaviors in adult male mice.

Biochem Biophys Res Commun 2021 Mar 22;553:107-113. Epub 2021 Mar 22.

NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases & Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China. Electronic address:

Chronic social defeat stress (CSDS) is widely applied to study of depression in rodents. 10-day CSDS was a most commonly employed paradigm but with high resilience ratio (∼30%), producing potential variation in depression-like behavioral symptoms. Whether prolonged period (21 days) of CSDS would promote less resilience and reduce behavioral variability remains unknown. We applied 10-day and 21-day CSDS paradigms to induce mouse model of depression and compared their resilience ratio and behavioral phenotypes. Mice under 21-day CSDS had significantly lower resilience ratio and greater changes in behavioral indicators relative to mice under 10-day CSDS. Behavioral indicators from 21-day CSDS paradigm had higher correlations and better prediction for susceptibility which indicating higher uniformity in behavioral phenotypes. Furthermore, a subset of behavioral indicators in 21-day CSDS had high prediction efficacy and should be first applied to screen susceptibility of CSDS. Thus, our study demonstrates that 21-day CSDS is a more robust paradigm inducing reliable depression-like behaviors relative to 10-day CSDS, and should be preferentially used in rodent studies of depression.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.058DOI Listing
March 2021

Visualizing the double-gyroid twin.

Proc Natl Acad Sci U S A 2021 Mar;118(12)

Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77840;

Periodic gyroid network materials have many interesting properties (band gaps, topologically protected modes, superior charge and mass transport, and outstanding mechanical properties) due to the space-group symmetries and their multichannel triply continuous morphology. The three-dimensional structure of a twin boundary in a self-assembled polystyrene--polydimethylsiloxane (PS-PDMS) double-gyroid (DG) forming diblock copolymer is directly visualized using dual-beam scanning microscopy. The reconstruction clearly shows that the intermaterial dividing surface (IMDS) is smooth and continuous across the boundary plane as the pairs of chiral PDMS networks suddenly change their handedness. The boundary plane therefore acts as a topological mirror. The morphology of the normally chiral nodes and strut loops within the networks is altered in the twin-boundary plane with the formation of three new types of achiral nodes and the appearance of two new classes of achiral loops. The boundary region shares a very similar surface/volume ratio and distribution of the mean and Gaussian curvatures of the IMDS as the adjacent ordered DG grain regions, suggesting the twin is a low-energy boundary.
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http://dx.doi.org/10.1073/pnas.2018977118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000518PMC
March 2021

Rainbow scattering in rotationally inelastic collisions of HCl and H.

J Chem Phys 2021 Mar;154(10):104304

Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, Nevada 89154, USA.

We examine rotational transitions of HCl in collisions with H by carrying out quantum mechanical close-coupling and quasi-classical trajectory (QCT) calculations on a recently developed globally accurate full-dimensional ab initio potential energy surface for the HCl system. Signatures of rainbow scattering in rotationally inelastic collisions are found in the state resolved integral and differential cross sections as functions of the impact parameter (initial orbital angular momentum) and final rotational quantum number. We show the coexistence of distinct dynamical regimes for the HCl rotational transition driven by the short-range repulsive and long-range attractive forces whose relative importance depends on the collision energy and final rotational state, suggesting that the classification of rainbow scattering into rotational and l-type rainbows is effective for H + HCl collisions. While the QCT method satisfactorily predicts the overall behavior of the rotationally inelastic cross sections, its capability to accurately describe signatures of rainbow scattering appears to be limited for the present system.
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http://dx.doi.org/10.1063/5.0043658DOI Listing
March 2021

Neurite orientation dispersion and density imaging parameters may help for the evaluation of epileptogenic tubers in tuberous sclerosis complex patients.

Eur Radiol 2021 Mar 10. Epub 2021 Mar 10.

Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China.

Objectives: To investigate the usefulness of neurite orientation dispersion and density imaging (NODDI) in evaluating cortical tubers, especially epileptogenic tubers in tuberous sclerosis complex (TSC) patients.

Methods: High-resolution conventional MRI and multi-shell diffusion-weighted imaging were performed in 27 TSC patients. Diffusion images were fitted to NODDI and DTI models. Tubers were visually assessed on different image types and scored by two neuroradiologists. For 10 patients who underwent epilepsy surgery, the contrast ratios between lesion and background tissue were measured on different image types, and these were compared between 16 epileptogenic tubers and 92 non-epileptogenic tubers.

Results: There were significant differences in lesion conspicuity scores and lesion-background contrast ratios across different sequences (both p < 0.001). The post hoc analysis showed that both the conspicuity scores and contrast ratios of intracellular volume fraction (ICVF) derived from NODDI were higher than other image types. For the 16 epileptogenic tubers, lesion visibility on ICVF was better/equal in 4/12 tubers compared with conventional MRI and better/equal in 5/11 tubers compared with DTI. Significant differences were observed between epileptogenic and non-epileptogenic tubers on diffusion maps, especially on orientation dispersion index derived from NODDI (p < 0.0001).

Conclusions: ICVF demonstrated higher contrast than conventional MRI and DTI, which helped detection of subtle epileptogenic tubers. Moreover, NODDI parameters showed the potential to identify epileptogenicity.

Key Points: • The noninvasive localization of epileptogenic cortical tubers is essential for the preparation of epilepsy surgery for TSC patients. • ICVF derived from NODDI showed greater contrast than conventional MRI and DTI in detecting tubers, especially subtle epileptogenic ones. • Diffusion parameters, especially ODI derived from NODDI, can support the identification of epileptogenicity.
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http://dx.doi.org/10.1007/s00330-020-07626-7DOI Listing
March 2021

Enabling complete multichannel nonadiabatic dynamics: A global representation of the two-channel coupled, 1,2A and 1A states of NH using neural networks.

J Chem Phys 2021 Mar;154(9):094121

Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, USA.

Global coupled three-state two-channel potential energy and property/interaction (dipole and spin-orbit coupling) surfaces for the dissociation of NH(Ã) into NH + H and NH + H are reported. The permutational invariant polynomial-neural network approach is used to simultaneously fit and diabatize the electronic Hamiltonian by fitting the energies, energy gradients, and derivative couplings of the two coupled lowest-lying singlet states as well as fitting the energy and energy gradients of the lowest-lying triplet state. The key issue in fitting property matrix elements in the diabatic basis is that the diabatic surfaces must be smooth, that is, the diabatization must remove spikes in the original adiabatic property surfaces attributable to the switch of electronic wavefunctions at the conical intersection seam. Here, we employ the fit potential energy matrix to transform properties in the adiabatic representation to a quasi-diabatic representation and remove the discontinuity near the conical intersection seam. The property matrix elements can then be fit with smooth neural network functions. The coupled potential energy surfaces along with the dipole and spin-orbit coupling surfaces will enable more accurate and complete treatment of optical transitions, as well as nonadiabatic internal conversion and intersystem crossing.
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http://dx.doi.org/10.1063/5.0037684DOI Listing
March 2021

Immunotherapy: A Potential Approach for High-Grade Spinal Cord Astrocytomas.

Front Immunol 2020 18;11:582828. Epub 2021 Feb 18.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Spinal cord astrocytomas (SCAs) account for 6-8% of all primary spinal cord tumors. For high-grade SCAs, the prognosis is often poor with conventional therapy, thus the urgent need for novel treatments to improve patient survival. Immunotherapy is a promising therapeutic strategy and has been used to treat cancer in recent years. Several clinical trials have evaluated immunotherapy for intracranial gliomas, providing evidence for immunotherapy-mediated ability to inhibit tumor growth. Given the unique microenvironment and molecular biology of the spinal cord, this review will offer new perspectives on moving toward the application of successful immunotherapy for SCAs based on the latest studies and literature. Furthermore, we will discuss the challenges associated with immunotherapy in SCAs, propose prospects for future research, and provide a periodic summary of the current state of immunotherapy for SCAs immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2020.582828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930372PMC
February 2021

Evidence for Progressive Cognitive Deficits in Patients With Major Depressive Disorder.

Front Psychiatry 2021 16;12:627695. Epub 2021 Feb 16.

Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.

Cognitive deficits have shown progressive feature in major depressive disorder (MDD). However, it remains unknown which component of cognitive function is progressively impaired across episodes of MDD. Here we aim to identify the progressively impaired cognitive components in patients with MDD. A comprehensive neurocognitive test battery was used to assess the cognitive components (executive function, attention, processing speed, memory, working memory, inhibition, shifting, and verbal fluency) in 35 patients with first-episode MDD (FED), 60 patients with recurrent MDD (RD) and 111 matched healthy controls (HCs). After 6 months of treatment with antidepressant, 20 FED and 36 RD patients achieved clinical remission and completed their second-time neurocognitive tests. Statistical analyses were conducted to identify the impaired cognitive components in the FED and RD groups before and after treatment, and to assess the relationship between the cognitive components and the number of episodes and total illness duration in the MDD patient group. At baseline, both the FED and RD groups showed impairments in all of the cognitive components; the FED and RD groups showed no significant difference in all of the components except for shifting. After remission, only shifting in the RD group showed no significant improvement and remained in an impaired status. Furthermore, shifting was the only component negatively correlated with the number of episodes as well as the total illness duration. Shifting may serve as the progressive cognitive deficit across episodes of MDD. Registry name: HPA function and MRI study of trauma-related depression; Registration number: ChiCTR1800014591; URL: http://www.chictr.org.cn/edit.aspx?pid=24669&htm=4.
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http://dx.doi.org/10.3389/fpsyt.2021.627695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921310PMC
February 2021

Potential energy surfaces for high-energy N + O collisions.

J Chem Phys 2021 Feb;154(8):084304

Department of Chemistry, Chemical Theory Center, and Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota 55455-0431, USA.

Potential energy surfaces for high-energy collisions between an oxygen molecule and a nitrogen atom are useful for modeling chemical dynamics in shock waves. In the present work, we present doublet, quartet, and sextet potential energy surfaces that are suitable for studying collisions of O(Σ) with N(S) in the electronically adiabatic approximation. Two sets of surfaces are developed, one using neural networks (NNs) with permutationally invariant polynomials (PIPs) and one with the least-squares many-body (MB) method, where a two-body part is an accurate diatomic potential and the three-body part is expressed with connected PIPs in mixed-exponential-Gaussian bond order variables (MEGs). We find, using the same dataset for both fits, that the fitting performance of the PIP-NN method is significantly better than that of the MB-PIP-MEG method, even though the MB-PIP-MEG fit uses a higher-order PIP than those used in previous MB-PIP-MEG fits of related systems (such as N and NO). However, the evaluation of the PIP-NN fit in trajectory calculations requires about 5 times more computer time than is required for the MB-PIP-MEG fit.
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http://dx.doi.org/10.1063/5.0039771DOI Listing
February 2021

Diagnostic value of 5 serum biomarkers for hepatocellular carcinoma with different epidemiological backgrounds: A large-scale, retrospective study.

Cancer Biol Med 2021 Feb;18(1):256-270

Department of Tumor Cell Biology.

Objective: Hepatocellular carcinoma (HCC) is a lethal global disease that requires an accurate diagnosis. We assessed the potential of 5 serum biomarkers (AFP, AFU, GGT-II, GPC3, and HGF) in the diagnosis of HCC.

Methods: In this retrospective study, we measured the serum levels of each biomarker using ELISAs in 921 participants, including 298 patients with HCC, 154 patients with chronic hepatitis (CH), 122 patients with liver cirrhosis (LC), and 347 healthy controls from 3 hospitals. Patients negative for hepatitis B surface antigen and hepatitis C antibody (called "NBNC-HCC") and patients positive for the above indices (called "HBV-HCC and HCV-HCC") were enrolled. The selected diagnostic model was constructed using a training cohort ( = 468), and a validation cohort ( = 453) was used to validate our results. Receiver operating characteristic analysis was used to evaluate the diagnostic accuracy.

Results: The α-L-fucosidase (AFU)/α-fetoprotein (AFP) combination was best able to distinguish NBNC-HCC [area under the curve: 0.986 (95% confidence interval: 0.958-0.997), sensitivity: 92.6%, specificity: 98.9%] from healthy controls in the test cohort. For screening populations at risk of developing HCC (CH and LC), the AFP/AFU combination improved the diagnostic specificity for early-stage HCC [area under the curve: 0.776 (0.712-0.831), sensitivity: 52.5%, specificity: 91.6% in the test group]. In all-stage HBV-HCC and HCV-HCC, AFU was also the best candidate biomarker combined with AFP [area under the curve: 0.835 (0.784-0.877), sensitivity 69.1%, specificity: 87.4% in the test group]. All results were verified in the validation group.

Conclusions: The AFP/AFU combination could be used to identify NBNC-HCC from healthy controls and hepatitis-related HCC from at-risk patients.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877174PMC
February 2021

Associations Between Regional Environment and Cornea-Related Morphology of the Eye in Young Adults: A Large-Scale Multicenter Cross-Sectional Study.

Invest Ophthalmol Vis Sci 2021 Feb;62(2):35

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China.

Purpose: To investigate environmental factors associated with corneal morphologic changes.

Methods: A cross-sectional study was conducted, which enrolled adults of the Han ethnicity aged 18 to 44 years from 20 cities. The cornea-related morphology was measured using an ocular anterior segment analysis system. The geographic indexes of each city and meteorological indexes of daily city-level data from the past 40 years (1980-2019) were obtained. Correlation analyses at the city level and multilevel model analyses at the eye level were performed.

Results: In total, 114,067 eyes were used for analysis. In the correlation analyses at the city level, the corneal thickness was positively correlated with the mean values of precipitation (highest r [correlation coefficient]: >0.700), temperature, and relative humidity (RH), as well as the amount of annual variation in precipitation (r: 0.548 to 0.721), and negatively correlated with the mean daily difference in the temperature (DIF T), duration of sunshine, and variance in RH (r: -0.694 to 0.495). In contrast, the anterior chamber (AC) volume was negatively correlated with the mean values of precipitation, temperature, RH, and the amount of annual variation in precipitation (r: -0.672 to -0.448), and positively associated with the mean DIF T (r = 0.570) and variance in temperature (r = 0.507). In total 19,988 eyes were analyzed at the eye level. After adjusting for age, precipitation was the major explanatory factor among the environmental factors for the variability in corneal thickness and AC volume.

Conclusions: Individuals who were raised in warm and wet environments had thicker corneas and smaller AC volumes than those from cold and dry ambient environments. Our findings demonstrate the role of local environmental factors in corneal-related morphology.
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http://dx.doi.org/10.1167/iovs.62.2.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910644PMC
February 2021

Ubrogepant for the Acute Treatment of Migraine: Pooled Efficacy, Safety, and Tolerability From the ACHIEVE I and ACHIEVE II Phase 3 Randomized Trials.

Neurol Ther 2021 Feb 20. Epub 2021 Feb 20.

AbbVie, Madison, NJ, USA.

Introduction: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The efficacy and safety of ubrogepant were demonstrated in two pivotal phase 3, single-attack, randomized, placebo-controlled trials (ACHIEVE I and ACHIEVE II).

Methods: We conducted a post hoc analysis of pooled data from the ACHIEVE trials to evaluate the efficacy, safety, and tolerability of ubrogepant 50 mg (the only dose evaluated in both trials) versus placebo across a large population of participants with migraine. The coprimary efficacy outcomes were pain freedom and absence of the most bothersome migraine-associated symptom (including photophobia, phonophobia, and nausea) at 2 h post dose. Secondary outcomes included pain relief at 2 h post dose, sustained pain relief and pain freedom from 2 to 24 h, and absence of specific migraine-associated symptoms at 2 h post dose.

Results: A total of 2240 eligible participants were randomized to placebo (n = 1122) or ubrogepant 50 mg (n = 1118) in the ACHIEVE trials. Pain freedom at 2 h was reported in 13.0% of participants in the pooled placebo group and 20.5% in the pooled ubrogepant 50 mg group (odds ratio [OR] 1.72; 95% confidence interval [CI] 1.34, 2.22; P < 0.001). Absence of the most bothersome migraine-associated symptom at 2 h was reported by 27.6% in the pooled placebo group and by 38.7% in the pooled ubrogepant 50 mg group (OR 1.68; 95% CI 1.37, 2.05; P < 0.001). Adverse events (AEs) within 48 h after the initial or optional second dose were reported by 11.5 and 11.2% of participants in the pooled placebo and pooled ubrogepant 50 mg groups, respectively. The most common AE was nausea (1.8 and 1.9%, respectively). No serious AEs related to treatment or discontinuations due to AEs were reported.

Conclusion: These results further support the efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine.

Trial Registration: ClinicalTrials.gov Identifiers: ACHIEVE I: NCT02828020; ACHIEVE II: NCT02867709.
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http://dx.doi.org/10.1007/s40120-021-00234-7DOI Listing
February 2021

Insights into adsorption, diffusion, and reactions of atomic nitrogen on a highly oriented pyrolytic graphite surface.

J Chem Phys 2021 Feb;154(7):074708

Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131, USA.

To gain insight into the nitrogen-related gas-surface reaction dynamics on carbon-based thermal protection systems of hypersonic vehicles, we have investigated the adsorption, diffusion, and reactions of atomic nitrogen, N(S), on the (0001) face of graphite using periodic density functional theory with a dispersion corrected functional. The atomic nitrogen is found to bind with pristine graphite at a bridge site, with a barrier of 0.88 eV for diffusing to an adjacent bridge site. Its adsorption energy at defect sites is significantly higher, while that between graphene layers is lower. The formation of N via Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms was also investigated. In the LH pathway, the recombinative desorption of N proceeds via a transition state with a relatively low barrier (0.53 eV). In addition, there is a metastable surface species, which is capable of trapping the nascent N at low surface temperatures as a result of the large energy disposal into the N-N vibration. The desorbed N is highly excited in both of its translational and vibrational degrees of freedom. The ER reaction is direct and fast, and it also leads to translationally and internally excited N. Finally, the formation of CN from a defect site is calculated to be endoergic by 2.75 eV. These results are used to rationalize the results of recent molecular beam experiments.
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http://dx.doi.org/10.1063/5.0042298DOI Listing
February 2021

Chitooligosaccharides inhibit tumor progression and induce autophagy through the activation of the p53/mTOR pathway in osteosarcoma.

Carbohydr Polym 2021 Apr 21;258:117596. Epub 2021 Jan 21.

Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. Electronic address:

Osteosarcoma is the most common primary sarcoma of bone. The use of Chitooligosaccharide (COS) as a drug carrier is an emerging new strategy for cancer therapy. However, the application of COS in osteosarcoma has not been reported. Here, we investigated the influence of COS on osteosarcoma, and suggested the underlying mechanism. Initially, we obtained COS with a low-degree-polymerized (DP = 2-6) by enzymatic hydrolysis. Using these COS materials, in vitro assays showed that COS elicited the anti-tumor activity against osteosarcoma cells. We found that COS had significant effects on cell growth, metastasis inhibition, apoptosis and autophagy induction, and triggered pro-apoptosis autophagy through p53/mTOR signaling pathway in osteosarcoma cells. In addition, the COS also inhibited tumor growth and metastasis in an osteosarcoma xenograft model in vivo. Finally, we showed that COS could increase sensitivity to chemotherapy of cisplatin in vitro. Thus, we provide experimental evidence to demonstrate that COS has anti-tumor effect on osteosarcoma, and COS can be a new potential therapeutic candidate for the treatment of osteosarcoma.
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http://dx.doi.org/10.1016/j.carbpol.2020.117596DOI Listing
April 2021

Towards bridging the structure gap in heterogeneous catalysis: the impact of defects in dissociative chemisorption of methane on Ir surfaces.

Phys Chem Chem Phys 2021 Feb;23(7):4376-4385

Hefei National Laboratory for Physical Science at the Microscale, Department of Chemical Physics, University of Science and Technology of China, Hefei, Anhui 230026, China.

A quantitative understanding of the role played by defect sites in heterogeneous catalysis is of great importance in designing new and more effective catalysts. In this work, we report a detailed dynamic study of a key step in methane steam reforming under experimentally relevant conditions on a new high-dimensional potential energy surface determined from first principles data with the aid of machine learning, with which the interactions of CH4 with both the flat Ir(111) and stepped Ir(332) surfaces are described. In particular, we argue based on our simulations that the experimentally observed "negatively activated" dissociative chemisorption of methane on Ir surfaces could be due to a combined effect of defects and high substrate temperature, which lowers the reaction barrier relative to that on terraces. Furthermore, a model based on dynamic information of trapping and reaction channels is proposed, which allows a quantitative prediction of the initial sticking probability for different defect densities, thus helping to close the so-called structure gap in heterogeneous catalysis.
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http://dx.doi.org/10.1039/d0cp06535hDOI Listing
February 2021

Insights into the Formation of Hydroxyl Radicals with Nonthermal Vibrational Excitation in the Meinel Airglow.

J Phys Chem Lett 2021 Feb 12;12(7):1822-1828. Epub 2021 Feb 12.

Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

To understand night time airglow in the Meinel bands and heat conversion from the highly excited OH radicals in the upper atmosphere via the important atmospheric reaction H + O → OH + O, we report here a quasi-classical trajectory study of the reaction dynamics on a recently developed full-dimensional potential energy surface (PES). Our results indicate that the reaction energy of this highly exoergic reaction is almost exclusively channeled into the vibration of the OH product, underscoring an extreme departure from the statistical limit. The calculated OH vibrational distribution is highly inverted and peaks near the highest accessible vibrational state, in excellent agreement with experimental observations, validating the accuracy of the PES. More importantly, the dynamical origin of the nonthermal excitation of the OH vibrational mode is identified by its large projection onto the reaction coordinate at a small potential barrier in the entrance channel, which controls the energy flow into various degrees of freedom in the products.
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http://dx.doi.org/10.1021/acs.jpclett.1c00159DOI Listing
February 2021

Single atom catalysis poised to transition from an academic curiosity to an industrially relevant technology.

Nat Commun 2021 02 9;12(1):895. Epub 2021 Feb 9.

Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM, USA.

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http://dx.doi.org/10.1038/s41467-021-21152-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873241PMC
February 2021

The neuroprogressive nature of major depressive disorder: evidence from an intrinsic connectome analysis.

Transl Psychiatry 2021 Feb 4;11(1):102. Epub 2021 Feb 4.

Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Major depressive disorder (MDD) is a prevailing chronic mental disorder with lifetime recurring episodes. Recurrent depression (RD) has been reported to be associated with greater severity of depression, higher relapse rate and prominent functioning impairments than first-episode depression (FED), suggesting the progressive nature of depression. However, there is still little evidence regarding brain functional connectome. In this study, 95 medication-free MDD patients (35 with FED and 60 with RD) and 111 matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI) scanning. After six months of treatment with paroxetine, 56 patients achieved clinical remission and finished their second scan. Network-based statistics analysis was used to explore the changes in functional connectivity. The results revealed that, compared with HCs, patients with FED exhibited hypoconnectivity in the somatomotor, default mode and dorsal attention networks, and RD exhibited hyperconnectivity in the somatomotor, salience, executive control, default mode and dorsal attention networks, as well as within and between salience and executive control networks. Moreover, the disrupted components in patients with current MDD did not change significantly when the patients achieved remission after treatment, and sub-hyperconnectivity and sub-hypoconnectivity were still found in those with remitted RD. Additionally, the hypoconnectivity in FED and hyperconnectivity in RD were associated with the number of episodes and total illness duration. This study provides initial evidence supporting that impairment of intrinsic functional connectivity across the course of depression is a progressive process.
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http://dx.doi.org/10.1038/s41398-021-01227-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862649PMC
February 2021

Quantification of pancreatic iron overload and fat infiltration and their correlation with glucose disturbance in pediatric thalassemia major patients.

Quant Imaging Med Surg 2021 Feb;11(2):665-675

Department of Radiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Diabetes mellitus affects more than a quarter of patients with thalassemia major (TM) worldwide, and increases the risk for cardiac complications, contributing to significant morbidity. Pancreatic iron overload (IO) and fat infiltration have been correlated with this endocrinal complication in adult TM patients. It has been shown that in adult TM patients, iron accumulation and fat infiltration are found to be heterogeneous in the pancreatic head, body, and tail region. R2* and a fat fraction (FF) generated by gradient-echo imaging can be used as quantitative parameters to assess the iron and fat contents of the pancreas. This study aimed to determine the pattern of pancreatic iron accumulation and fat infiltration in pediatric TM patients with gradient-echo imaging and evaluate the association between pancreatic IO and fat infiltration and glucose disturbances.

Methods: A total of 90 children with TM (10.7±3.1 years) were included. All patients underwent pancreatic magnetic resonance imaging (MRI) using multi-echo gradient-echo sequences. IO was measured by R2* relaxometry in 90 patients, and FF values were measured using iterative decomposition of water and fat with echo asymmetry and the least-squares estimation (IDEAL) method in 40 patients. R2* and FF were assessed in the pancreatic head, body, and tail. The global R2* and global FF values were obtained by averaging the respective values from the pancreatic head, body, and tail. The correlations between global R2*, global FF, and fasting glucose were determined using Spearman's correlation analysis. The Friedman test was used to compare R2* and FF among different pancreatic regions. Receiver operating characteristic (ROC) analysis was used to determine the performance of global R2* and global FF in discriminating impaired fasting glucose from normal fasting glucose patients.

Results: The global R2* was positively correlated with the global FF in the pancreas (r=0.895, P<0.001). No significant differences were found in R2* among the 3 regions of the pancreas (χ=4.050, P=0.132), but significant differences were found in FF among the 3 pancreatic regions (χ=16.350, P<0.001). Both global pancreatic R2* (r=0.408, P<0.001) and global FF (r=0.523, P=0.001) were positively correlated with fasting glucose. ROC analysis showed that global pancreatic R2* and global FF had an area under the curve of 0.769 and 0.931 (both P<0.001), respectively, in discriminating between impaired and normal glucose function patients.

Conclusions: Pediatric TM patients can have homogeneous iron siderosis and heterogeneous fat infiltration in the pancreas as measured by gradient-echo imaging, both of which are risk factors for diabetes.
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http://dx.doi.org/10.21037/qims-20-292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779935PMC
February 2021

Isomer-specific kinetics of the C + HO reaction at the temperature of interstellar clouds.

Sci Adv 2021 Jan 6;7(2). Epub 2021 Jan 6.

Department of Physics and Astronomy, University of California, Los Angeles, Los Angeles, CA 90095, USA.

The reaction C + HO → HCO/HOC + H is one of the most important astrophysical sources of HOC ions, considered a marker for interstellar molecular clouds exposed to intense ultraviolet or x-ray radiation. Despite much study, there is no consensus on rate constants for formation of the formyl ion isomers in this reaction. This is largely due to difficulties in laboratory study of ion-molecule reactions under relevant conditions. Here, we use a novel experimental platform combining a cryogenic buffer-gas beam with an integrated, laser-cooled ion trap and high-resolution time-of-flight mass spectrometer to probe this reaction at the temperature of cold interstellar clouds. We report a reaction rate constant of = 7.7(6) × 10 cm s and a branching ratio of formation η = HOC/HCO = 2.1(4). Theoretical calculations suggest that this branching ratio is due to the predominant formation of HOC followed by isomerization of products with internal energy over the isomerization barrier.
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http://dx.doi.org/10.1126/sciadv.abe4080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787479PMC
January 2021

Macropinocytosis: mechanism and targeted therapy in cancers.

Am J Cancer Res 2021 1;11(1):14-30. Epub 2021 Jan 1.

Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University Nanchang 330006, Jiangxi, China.

Macropinocytosis is a form of endocytosis which provides an effective way for non-selective uptakes of extracellular proteins, liquids, and particles. The endocytic process is initiated by the activation of the growth factors signaling pathways. After activation of the biochemical signal, the cell starts internalizing extracellular solutes and nutrients into the irregular endocytic vesicles, known as macropinosomes that deliver them into the lysosomes for degradation. Macropinocytosis plays an important role in the nutritional supply of cancer cells. Due to the rapid expansion of cancer cells and the abnormal vascular microenvironment, cancer cells are usually deprived of oxygen and nutrients. Therefore, they must transform their metabolism to survive and grow in this harsh microenvironment. To satisfy their energy needs, cancer cells enhance the activity of macropinocytosis. Therefore, this metabolic adaptation that is used by cancer cells can be exploited to develop new targeted cancer therapies. In this review, we discuss the molecular mechanism that actuates the process of macropinocytosis in a variety of cancers, and the novel anti-cancer therapeutics in targeting macropinocytosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840718PMC
January 2021

Effects of neoadjuvant chemotherapy on the contralateral non-tumor-bearing breast assessed by diffuse optical tomography.

Breast Cancer Res 2021 Jan 31;23(1):16. Epub 2021 Jan 31.

Departments of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, NY, 11201, USA.

Background: The purpose of this study is to evaluate whether the changes in optically derived parameters acquired with a diffuse optical tomography breast imager system (DOTBIS) in the contralateral non-tumor-bearing breast in patients administered neoadjuvant chemotherapy (NAC) for breast cancer are associated with pathologic complete response (pCR).

Methods: In this retrospective evaluation of 105 patients with stage II-III breast cancer, oxy-hemoglobin (ctOHb) from the contralateral non-tumor-bearing breast was collected and analyzed at different time points during NAC. The earliest monitoring imaging time point was after 2-3 weeks receiving taxane. Longitudinal data were analyzed using linear mixed-effects modeling to evaluate the contralateral breast ctOHb changes across chemotherapy when corrected for pCR status, age, and BMI.

Results: Patients who achieved pCR to NAC had an overall decrease of 3.88 μM for ctOHb (95% CI, 1.39 to 6.37 μM), p = .004, after 2-3 weeks. On the other hand, non-pCR subjects had a non-significant mean reduction of 0.14 μM (95% CI, - 1.30 to 1.58 μM), p > .05. Mixed-effect model results indicated a statistically significant negative relationship of ctOHb levels with BMI and age.

Conclusions: This study demonstrates that the contralateral normal breast tissue assessed by DOTBIS is modifiable after NAC, with changes associated with pCR after only 2-3 weeks of chemotherapy.
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http://dx.doi.org/10.1186/s13058-021-01396-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849076PMC
January 2021

Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells.

Front Med 2021 Jan 29. Epub 2021 Jan 29.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%-18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.
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http://dx.doi.org/10.1007/s11684-021-0837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843238PMC
January 2021

Theoretical H + O rate coefficients from ring polymer molecular dynamics on an accurate global potential energy surface: assessing experimental uncertainties.

Phys Chem Chem Phys 2021 Feb;23(5):3300-3310

Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.

Thermal rate coefficients and kinetic isotope effects have been calculated for an important atmospheric reaction H/D + O3 → OH/OD + O2 based on an accurate permutation invariant polynomial-neural network potential energy surface, using ring polymer molecular dynamics (RPMD), quasi-classical trajectory (QCT) and variational transition-state theory (VTST) with multidimensional tunneling. The RPMD approach yielded results that are generally in better agreement with experimental rate coefficients than the VTST and QCT ones, especially at low temperatures, attributable to its capacity to capture quantum effects such as tunneling and zero-point energy. The theoretical results support one group of existing experiments over the other. In addition, rate coefficients for the D + O3 → OD + O2 reaction are also reported using the same methods, which will allow a stringent assessment of future experimental measurements, thus helping to reduce the uncertainty in the recommended rate coefficients of this reaction.
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http://dx.doi.org/10.1039/d0cp05771aDOI Listing
February 2021

Quasiclassical simulations based on cluster models reveal vibration-facilitated roaming in the isomerization of CO adsorbed on NaCl.

Nat Chem 2021 03 18;13(3):249-254. Epub 2021 Jan 18.

Department of Chemistry and Cherry L. Emerson Center for Scientific Computation, Emory University, Atlanta, GA, USA.

The desire to better understand the quantum nature of isomerization led to recent experimental observations of the vibrationally induced isomerization of OC-NaCl(100) to CO-NaCl(100). To investigate the mechanism of this isomerization, we performed dynamics calculations using finite (CO-NaCl) cluster models. We constructed new potential energy surfaces for CO-NaCl and CO-CO interactions using high-level ab initio data and report key properties of the bare CO-NaCl potential energy surface, which show much in common with the experiment. We investigated the isomerization dynamics using several cluster models and, in all cases, isomerization was seen for highly excited CO vibrational states, in agreement with experiments. A detailed examination of the reaction trajectories indicates that isomerization occurs when the distance between CO and NaCl is larger than the distance at the conventional isomerization saddle point, which is a strong indicator of 'roaming'.
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http://dx.doi.org/10.1038/s41557-020-00612-yDOI Listing
March 2021

Changes in Diffuse Optical Tomography Images During Early Stages of Neoadjuvant Chemotherapy Correlate with Tumor Response in Different Breast Cancer Subtypes.

Clin Cancer Res 2021 Apr 15;27(7):1949-1957. Epub 2021 Jan 15.

Departments of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, New York.

Purpose: This study's primary objective was to evaluate the changes in optically derived parameters acquired with a diffuse optical tomography breast imaging system (DOTBIS) in the tumor volume of patients with breast carcinoma receiving neoadjuvant chemotherapy (NAC).

Experimental Design: In this analysis of 105 patients with stage II-III breast cancer, normalized mean values of total hemoglobin ([Formula: see text]), oxyhemoglobin ([Formula: see text]), deoxy-hemoglobin concentration ([Formula: see text]), water, and oxygen saturation ([Formula: see text]) percentages were collected at different timepoints during NAC and compared with baseline measurements. This report compared changes in these optical biomarkers measured in patients who did not achieve a pathologic complete response (non-pCR) and those with a pCR. Differences regarding molecular subtypes were included for hormone receptor-positive and HER2-negative, HER2-positive, and triple-negative breast cancer.

Results: At baseline, [Formula: see text] was higher for pCR tumors (3.97 ± 2.29) compared with non-pCR tumors (3.00 ± 1.72; = 0.031). At the earliest imaging point after starting therapy, the mean change of [Formula: see text] compared with baseline ([Formula: see text]) was statistically significantly higher in non-pCR (1.23 ± 0.67) than in those with a pCR (0.87 ± 0.61; < 0.0005), and significantly correlated to residual cancer burden classification ( = 0.448; < 0.0005). [Formula: see text] combined with HER2 status was proposed as a two-predictor logistic model, with AUC = 0.891; < 0.0005; and 95% confidence interval, 0.812-0.969.

Conclusions: This study demonstrates that DOTBIS measured features change over time according to tumor pCR status and may predict early in the NAC treatment course whether a patient is responding to NAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1108DOI Listing
April 2021