The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. Show less
Florian, J.; Schrier, R. van der; Gershuny, V.; Davis, M.C.; Wang, C.; Han, X.M.; ... ; Strauss, D.G. 2022
Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to... Show moreImportance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -infinity to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -infinity to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -infinity to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -infinity to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -infinity to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -infinity to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Show less
Xie, F.; Zhou, X.X.; Su, P.; Li, H.Y.; Tu, Y.F.; J.J. du; ... ; Zhou, F.F. 2022
Understanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer... Show moreUnderstanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer active TGF-beta type II receptors to CD8 + T cells to render them exhausted, thus paralyzing the anti-tumor immune response.Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-beta type II receptor (T beta RII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-beta signaling in recipient cells. Up-take of extracellular vesicle-T beta RII (EV-T beta RII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-T beta RII delivered as cargo to CD8(+) T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8(+) T cell exhaustion, resulting in failure of immunotherapy. The levels of T beta RII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors. Show less
Purpose: To analyze the in vivo tibiofemoral cartilage contact patterns in knees undergoing double-bundle anterior cruciate ligament reconstruction(DB-ACLR) with or without anterolateral structure... Show morePurpose: To analyze the in vivo tibiofemoral cartilage contact patterns in knees undergoing double-bundle anterior cruciate ligament reconstruction(DB-ACLR) with or without anterolateral structure augmentation (ALSA). Methods: Twenty patients with an ACL-ruptured knee and a healthy contralateral side were included. Nine patients received an isolated DB-ACLR (DB-ACLR group), and 11 patients had a DB-ACLR with ALSA (DB+ALSA group). At 1-year follow-up, a combined computed tomography, magnetic resonance imaging, and dual fluoroscopy imaging system analysis was used to capture a single-legged lunge of both the operated and healthy contralateral side. Tibiofemoral contact points (CPs) of the medial and lateral compartments were compared. CP locations were expressed as anteroposterior (AP, +/-) and medial-lateral (ML, -/+) values according to the tibia. Results: In the DB-ACLR knees, no significant differences were found in CPs when compared with the healthy contralateral knees (P >= .31). However, in the DB+ALSA knees, the CPs in the lateral compartment had a significantly more anterior (mean AP: operative, -2.8 mm, 95% confidence interval [CI] -5.0 to-0.7 vs healthy, -5.0 mm, 95% CI -6.7 to -3.2; P = .006) and lateral (mean ML: operative, 23.2 mm, 95% CI 21.9-24.5 vs healthy, 21.8 mm, 95% CI 20.2-23.3; P = .013) location. The CPs in the medial compartment were located significantly more posterior (mean AP: operative, -3.4, 95% CI -5.0 to -1.9 vs healthy, -1.3, 95% CI -2.6 to -0.1; P = .006) and lateral (mean ML: operative, -21.3, 95% CI -22.6 to -20.0 vs healthy, -22.6, 95% CI -24.2 to -21.0; P = .021). Conclusions: DB-ACLR restored the tibiofemoral cartilage contact mechanics to near-normal values at 1-year follow-up. Adding the ALSA to the DB-ACLR resulted in significantly altered tibiofemoral cartilage contact locations in both the medial and lateral compartments. Show less
A rehabilitation program after anterior cruciate ligament reconstruction is of great importance to obtain a satisfactory prognosis after surgery. However, there is still an onging debate over... Show moreA rehabilitation program after anterior cruciate ligament reconstruction is of great importance to obtain a satisfactory prognosis after surgery. However, there is still an onging debate over whether closed kinetic chain or open kinetic chain exercises should be chosen. Our study was designed to compare the in vivo tibiofemoral kinematics during closed kinetic chain and open kinetic chain exercises. Eighteen healthy volunteers were asked to perform box squat and unloaded/10 kg-loaded seated knee extension. In vivo 3-dimensional analysis of tibiofemoral kinematics of different motions were determined using a dual fluoroscopic imaging system. The study found significantly more tibial anterior displacement during loaded seated knee extension than during unloaded seated knee extension from 25 degrees-50 degrees of knee flexion (p < 0.031). The knees exhibited significantly more internal tibial rotation and lateral tibial translation during the box squat than both seated knee extensions during mid-flexion. In addition, the knees showed less internal-external (IE) range of motion (ROM) from 20 degrees- 75 degrees of flexion (p < 0.001) and medial-lateral (ML) ROM from 75 degrees to full extension (p < 0.006) during box squat than both extensions. This knowledge may help optimize rehabilitation plans for patients post ACL reconstruction. Show less
Wang, C.; Baratchi, M.; Bäck, T.H.W.; Hoos, H.H.; Limmer, S.; Olhofer, M. 2022
DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >... Show moreDNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated. Show less
Antonio, M. di; Overkleeft, H.S.; Wang, C.; Rulka, A. 2021
We would like to take this opportunity to thank all of RSC Chemical Biology’s reviewers, and in particular highlight the Outstanding Reviewers for the journal in 2020, as selected by the editorial... Show moreWe would like to take this opportunity to thank all of RSC Chemical Biology’s reviewers, and in particular highlight the Outstanding Reviewers for the journal in 2020, as selected by the editorial team for their significant contribution to RSC Chemical Biology. We announce our Outstanding Reviewers annually and each receives a certificate to give recognition for their contribution. The reviewers have been chosen based on the number, timeliness and quality of the reports completed over the last 12 months.Dr Marco Di AntonioImperial CollegeORCID: 0000-0002-7321-1867Dr Herman OverkleeftLeiden UniversityORCID: 0000-0001-6976-7005Dr Chu WangPeking UniversityORCID: 0000-0002-6925-1268We would also like to thank the RSC Chemical Biology Editorial Board and Advisory Board and the chemical biology community for their continued support of the journal, as authors, reviewers and readers.Dr Anna Rulka, Executive Editor Show less
Zheng, X.; Zou, Y.; Lounsbury, A. W.; Wang, C.; Wang, R. 2021
The global popularity of green roofs (GRs) rises as urban runoff becomes a primary environmental concern in both developed and developing countries. Although a growing number of studies have... Show moreThe global popularity of green roofs (GRs) rises as urban runoff becomes a primary environmental concern in both developed and developing countries. Although a growing number of studies have measured the runoff retention (RR) performance of GRs and investigated the underpinning factors, a systematic and quantitative understanding is lacking. This study applies a statistical approach on a dataset of 2375 original experimental samples associated with the RR performance of GRs observed across 21 countries, consolidated from 75 internationally peer-reviewed studies published in 2005–2020. The results show that the sampled RR rates (i.e., the proportion of rainfall retained on a per-event basis) range widely (0–100%), with an average of 62%. Rainfall intensity, substrate depth, GR surface coverage, climate type, vegetation type, and season type partially explain the variances in retention performance. Moreover, the effects of some factors (e.g., rainfall intensity) are not isolated but contingent on other factors (e.g., vegetative cover). This global synthesis shows few samples emanate from Africa, Central America, and Central Asia, highlighting the need of more GR research and applications in these regions. The average GR RR rate appears lower than some specified in green building standards, which implies the need to further improve the RR performance of GRs or combine GRs with other RR measures. Contingent effects of GR RR influencing factors demonstrate the need to leverage design parameters and to account for local weather and climate characteristics in the optimization of GR performance. Show less
Integrating the social and natural sciences to effectively tackle the intertwined challenges represented by the Sustainable Development Goals (SDGs) has been advocated for years. However, the... Show moreIntegrating the social and natural sciences to effectively tackle the intertwined challenges represented by the Sustainable Development Goals (SDGs) has been advocated for years. However, the practice is challenging, especially with respect to the beliefs, morals, and practices of individuals and groups or, more succinctly put, culture, which, despite attracting growing awareness, remains understated in sustainability. Here, we examine how and to what extent cultural values are linked to the achievement of the SDGs. Synthesizing knowledge from more than 300 publications, we show that cultural traits are linked to the achievement of all 17 SDGs and 79% of SDG targets. Further, empirical understanding obtained from a panel data analysis highlights that cultural values explain as much as 26% of the variations in the SDG achievements, yet the links are strikingly divergent across cultural traits and indicators. Our findings imply the need to consider more cultural contexts and nuances in sustainability science communications and policy design and to develop new cross-disciplinary solutions to sustainability challenges. Show less
Caminada, C.L.J.; Goudswaard, K.P.; Wang, C.; Wang, J. 2020
Unfavorable clinical outcomes after medial patellofemoral ligament (MPFL) reconstruction, such as early osteoarthritis of the patellofemoral joint, were considered to be associate with tunnel... Show moreUnfavorable clinical outcomes after medial patellofemoral ligament (MPFL) reconstruction, such as early osteoarthritis of the patellofemoral joint, were considered to be associate with tunnel malpositioning. Length change studies have found that small changes in the femoral position can cause great changes in elongation trends. Further studying the MPFL kinematics may help us to understand the consequences of tunnel malpositioning and optimize the reconstruction techniques. Fifteen healthy subjects were studied with a combined computed tomography and biplane fluoroscopic imaging technique during a lunge motion. Five femoral and three patellar attachments were used to simulate different MPFL bundles. Kinematics of MPFL was defined as elongation and orientation changes (i.e., deviation angle and elevation angle). The mean deviation angle was 28.7 degrees (95% confidence interval, 28.0 degrees-29.4 degrees) at full extension and remained nearly unchanged up to 60 degrees of flexion, and increased to 56.5 degrees (54.1 degrees-58.9 degrees) at 110 degrees. The elevation angle decreased linearly from 12.6 degrees (9.3 degrees-15.9 degrees) at full extension to -86.2 degrees (-92.7-79.7 degrees) at 110 degrees of flexion. The MPFL was most stretched anteriorly and laterally relative to femur from full extension to 30 degrees of flexion and remained near isometric beyond 30 degrees. The current study found that proximal and anterior femoral attachments caused excessive lateral stretching of the MPFL at deeper flexion angles. Such abnormal MPFL kinematics may subsequently cause overconstraint and increased cartilage pressures of the medial patellofemoral joint. Show less
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a powerful tool for genome engineering in plants. The RNAguided Cas9 endonuclease is usually... Show moreClustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a powerful tool for genome engineering in plants. The RNAguided Cas9 endonuclease is usually delivered into plant cells as a DNA construct encoding Cas9 and the single guide RNA (sgRNA). However, constitutive expression of nucleases may cause off target mutations. In addition, DNA constructs can integrate into the host genome, causing mutations and complicating regulatory approval. Instead of DNA, here we deliver Cas9 through the Agrobacterium T4SS, accomplished by fusion of the VirF T4SS translocation peptide to Cas9 (NCas9F). Co-cultivation of Agrobacteria expressing NCas9F with yeast (Saccharomyces cerevisiae) harboring a sgRNA targeting CAN1 showed that NCas9F was translocated via T4SS and induced targeted mutations in the yeast genome. Infiltration of Nicotiana benthamiana leaves with Agrobacteria expressing NCas9F and sgRNA-PHYTOENE DESATURASE (PDS) resulted in targeted modifications at the PDS locus, albeit at a very low rate. In order to increase the mutation frequency NCas9F protein was co-transported with a TDNA encoding sgRNA-PDS1. Next generation sequencing confirmed that this resulted in targeted mutations at the PDS locus with a similar distribution but at a 5-fold lower frequency as the mutations obtained with a T-DNA encoding both Cas9 and sgRNA-PDS1. Similarly, infection with Tobacco rattle virus (TRV) encoding sgRNA-PDS2 combined with NCas9F protein translocation resulted in an equally high frequency of PDS mutations in N. benthamiana compared to T-DNA encoded sgRNA-PDS1 combined with NCas9F protein translocation. Our results revealed that translocation of NCas9F protein via the Agrobacterium T4SS can be used for targeted mutagenesis in host cells instead of the permanent and constitutive expression of Cas9 from a T-DNA. Show less
Objectives Coronary CT angiography (cCTA) has been used to non-invasively assess both the anatomical and hemodynamic significance of coronary stenosis. The current study investigated a new CFD... Show moreObjectives Coronary CT angiography (cCTA) has been used to non-invasively assess both the anatomical and hemodynamic significance of coronary stenosis. The current study investigated a new CFD-based method of evaluating pressure-flow curves across a stenosis to further enhance the diagnostic value of cCTA imaging. Methods Fifty-eight patients who underwent both cCTA imaging and invasive coronary angiography (ICA) with fractional flow reserve (FFR) within 2 weeks were enrolled. The pressure-flow curve-derived parameters, viscous friction (VF) and expansion loss (EL), were compared with conventional cCTA parameters including percent area stenosis (AS) and minimum lumen area (MLA) by receiver operating characteristic (ROC) curve analysis. FFR <= 0.80 was used to indicate ischemia-causing stenosis. Correlations between FFR and other measurements were calculated by Spearman's rank correlation coefficient (rho). Results Sixty-eight stenoses from 58 patients were analyzed. VF, EL, and AS were significantly larger in the group of FFR <= 0.8 while smaller MLA values were observed. The ROC-AUC of VF (0.91, 95% CI 0.81-0.96) was better than that of AS (change in AUC (Delta AUC) 0.27, p < 0.05) and MLA (Delta AUC 0.17, p < 0.05), and ROC-AUC of EL (0.90, 95%CI 0.80-0.96) was also better than that of AS (Delta AUC 0.26, p < 0.05) and MLA (Delta AUC 0.16, p < 0.05). FFR values correlated well with VF (rho = - 0.74 (95% CI - 0.83 to - 0.61, p < 0.0001) and EL (rho = - 0.74 (95% CI - 0.83 to - 0.61, p < 0.0001). Conclusion Pressure-flow curve-derived parameters enhance the diagnostic value of cCTA examination. Show less
Xiong, Y.; Zhang, Z.; Zhang, Y.; Cui, X.; Yang, Y.; Duijn, A. van; ... ; Wang, C. 2020
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are... Show moreIncreased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. Show less
