Unmet Needs and Treatment Preference of Systemic Treatments for Moderate-to-Severe Psoriasis from the Perspectives of Patients and Dermatologists in China.

INTRODUCTION: The treatment options for moderate to severe psoriasis (msPsO) in China have been greatly increased with the approvals of biologics. However, the unmet needs and treatment preferences of systemic treatments for msPsO in China remain unclarified. METHODS: Fifty dermatologists and 300 patients with msPsO (41% with severe psoriasis) were surveyed for effectiveness, safety, treatment convenience, and treatment preferences (using a choice-based conjoint questionnaire). Descriptive statistics and conjoint simulation analyses were employed to summarize survey information and assess treatment preferences. RESULTS: Both patients and dermatologists reported shorter treatment duration for oral drugs (2.7-6.2 months) than that for biologics (9.5-17.0 months). The most frequently reported treatment discontinuation reasons by the surveyed patients and dermatologists were unsatisfactory effectiveness (average 84.5%) for oral drugs and loss of efficacy over time (average 68.5%) for biologics. Commonly reported treatment inconveniences included regular lab tests for traditional oral drugs (average 71.5%) and administration assistance for biologics (average 58.0%). Injection site reactions (average 51.5%) and needle fear (average 35.5%) were frequently reported for biologics among the surveyed patients and dermatologists. Once-daily oral treatment was preferred over biweekly subcutaneous injection treatment when the two had comparable attributes (average in patients 87.1% vs. 12.9%; average in dermatologists 93.4% vs. 6.6%). CONCLUSIONS: Unmet needs of systemic treatments remain for msPsO in China. Once-daily oral treatment is preferred over biweekly subcutaneous injections to treat msPsO when other treatment attributes are comparable.

DeKinomics pulse-chases kinase functions in living cells.

Cellular context is crucial for understanding the complex and dynamic kinase functions in health and disease. Systematic dissection of kinase-mediated cellular processes requires rapid and precise stimulation ('pulse') of a kinase of interest, as well as global and in-depth characterization ('chase') of the perturbed proteome under living conditions. Here we developed an optogenetic 'pulse-chase' strategy, termed decaging kinase coupled proteomics (DeKinomics), for proteome-wide profiling of kinase-driven phosphorylation at second-timescale in living cells. We took advantage of the 'gain-of-function' feature of DeKinomics to identify direct kinase substrates and further portrayed the global phosphorylation of understudied receptor tyrosine kinases under native cellular settings. DeKinomics offered a general activation-based strategy to study kinase functions with high specificity and temporal resolution under living conditions.

Different responses of taxonomic and functional trait structure of benthic macroinvertebrate assemblages to eutrophication in a large Chinese freshwater lake.

Functional trait measures have the potential to represent local habitat conditions and are considered promising tools for biomonitoring and bioassessment programs. Macroinvertebrates are an ecologically significant group in freshwater ecosystems and possess a range of functional traits which are employed to assess ecological quality. Nevertheless, the relationships between macroinvertebrate functional structure and anthropogenic disturbances remain poorly understood. In this study, we conducted a comparison of how functional trait-based and taxonomy-based composition of macroinvertebrate assemblages responded to eutrophication in Lake Taihu, a typical large eutrophic freshwater lake in China. Specifically, we examined both the taxonomy-based and trait-based compositions of benthic macroinvertebrates varied along the eutrophication gradient. Eutrophication was associated with remarkable decreases in the abundance of gastropod taxa and increases in Oligochaeta and Chironomidae. Ten categories belonging to six traits were significantly different among three site groups. The eutrophic and transition sites showed higher abundance of Size2, burrowers, and integument-respiration organisms than macrophytic sites, whereas abundance of Size1, conical-shaped, sprawlers, scrapers, and lung-respiration were higher in macrophytic sites. Both taxonomic (36.8%) and functional compositions (39.8%) of macroinvertebrate assemblages were influenced by the same variables: CODMn and transparency. Our study showed that macroinvertebrate trait-based approaches can be considered a useful supplement to traditional taxonomic approach for biomonitoring programs in freshwater lakes.

Duty ratio drive prediction model of lifetime degradation for organic light emitting diode-on-silicon microdisplay.

A duty ratio drive prediction (DRDP) model of luminance degradation for organic light emitting diodes (OLED) microdisplay is proposed in this paper. The traditional stretched exponential decay (SED) model is not applicable for OLED driven by duty ratio. The DRDP model introduces the duty ratio as the variables affecting the lifetime of OLED. By fitting the undetermined coefficients with the measured luminance data, the quantitative relationships among the initial luminance, duty ratio, and OLED lifetime are obtained. Meanwhile, the model quantifies the phenomenon of spontaneous luminance recovery, which occurs when OLED switches from bright to dark. Finally, the DRDP model is used to compensate the luminance degradation of OLED driven by duty ratio. The experimental results show that the average prediction accuracy of DRDP model for white, red, green, and blue (W/R/G/B) OLED degradation trend is 0.9623. The average prediction accuracy of W/R/G/B OLED lifetime is 0.6119, which is greater than that of SED model. The lifetime is extended by 89.83% after compensation.

DeepRTAlign: toward accurate retention time alignment for large cohort mass spectrometry data analysis.

Retention time (RT) alignment is a crucial step in liquid chromatography-mass spectrometry (LC-MS)-based proteomic and metabolomic experiments, especially for large cohort studies. The most popular alignment tools are based on warping function method and direct matching method. However, existing tools can hardly handle monotonic and non-monotonic RT shifts simultaneously. Here, we develop a deep learning-based RT alignment tool, DeepRTAlign, for large cohort LC-MS data analysis. DeepRTAlign has been demonstrated to have improved performances by benchmarking it against current state-of-the-art approaches on multiple real-world and simulated proteomic and metabolomic datasets. The results also show that DeepRTAlign can improve identification sensitivity without compromising quantitative accuracy. Furthermore, using the MS features aligned by DeepRTAlign, we trained and validated a robust classifier to predict the early recurrence of hepatocellular carcinoma. DeepRTAlign provides an advanced solution to RT alignment in large cohort LC-MS studies, which is currently a major bottleneck in proteomics and metabolomics research.

Cost-effectiveness of obinutuzumab plus bendamustine in Chinese patients with relapse and refractory follicular lymphoma.

A decision analytic model was constructed to assess the cost-effectiveness of obinutuzumab plus bendamustine followed by obinutuzumab maintenance therapy (O-B-O) in Chinese patients with relapsed and refractory follicular lymphoma (rrFL). O-B-O was associated with a dominant or more favorable cost-effectiveness than the conventional therapies. Survival outcomes, quality of life of progression-free survival, and subsequent treatment costs for progressive disease were the main drivers of the cost-effectiveness of O-B-O. The cost-effectiveness proportions of O-B-O relative to conventional therapies under the recommended cost-effectiveness threshold ranged from 61.0% to 99.9%. Thus, O-B-O was highly cost-effective for treating patients with rrFL in China compared with conventional therapies.

Comparisons of procedural characteristics and clinical outcomes between SMARTTOUCH SURROUNDFLOW catheter and other catheters for atrial fibrillation radiofrequency catheter ablation: a systematic literature review.

BACKGROUND: SMARTTOUCH SURROUNDFLOW (STSF) catheter is the new generation of SMARTTOUCH (ST) catheter with an upgraded irrigation system for radiofrequency catheter ablation (RFCA) in patients with atrial fibrillation (AF). METHODS: This systematic literature review searched the major English and Chinese bibliographic databases from 2016 to 2022 for any original clinical studies assessing the STSF catheter for RFCA in AF patients. Meta-analysis with a random effects model was used for evidence synthesis. RESULTS: Pooled outcomes from 19 included studies indicated that STSF catheter was associated with a significantly shorter procedure time (weighted mean difference (WMD): -17.4 min, p<0.001), shorter ablation time (WMD: -6.6 min, p<0.001) and lower catheter irrigation fluid volume (WMD: -492.7 mL, p<0.001) than ST catheter. Pooled outcomes from four included studies with paroxysmal AF patients reported that using the STSF catheter for RFCA was associated with a significantly shorter ablation time (WMD: -5.7 min, p<0.001) and a lower risk of 1-year postablation arrhythmia recurrence (rate ratio: 0.504, p<0.001) than the SURROUNDFLOW (SF) catheter. Significant reductions in procedure time and ablation time associated with the STSF catheter were also reported in the other four studies using non-ST/SF catheters as the control. Overall complications of STSF catheter and control catheters were comparable. CONCLUSIONS: Using the STSF catheter was superior to using the ST catheter to conduct RFCA for AF by significantly reducing procedure time, ablation time, fluoroscopy time and irrigation fluid volume. The superiority of the STSF catheter over the SF catheter and other non-ST/SF catheters for RFCA needs further confirmation.

Oropharynx pain, discomfort, and economic impact of transesophageal echocardiography for planned radio-frequency catheter ablation in patients with atrial fibrillation: A cross-sectional survey study.

Background: To survey the unmet medical needs associated with atrium thrombus screening in Chinese patients with atrial fibrillation (AF) who underwent transesophageal echocardiography (TEE) for planned radio-frequency catheter ablation (RFCA). Methods: This cross-sectional survey study interviewed 300 patients who underwent their first TEE for planned RFCA. The surveyed information included patients' anxiety, oropharynx pain and discomfort, time expense, and patient satisfaction related to TEE examination. Patient preference for a new atrium thrombus screening technology, hospital length of stay (LOS) of RFCA, and hospital costs of RFCA in these surveyed patients were collected as well. Descriptive statistical methods were used to summarize the collected survey information. Results: Of the 300 interviewed patients, 36.3% reported anxiety before TEE examination, 58.6% reported oropharynx pain related to TEE, and 76.2% reported oropharynx discomforts, mainly including foreign body sensation (54.3%), dry heaves (33.8%), nausea (31.9%), and bleeding (22.9%). Even though 62.3% were satisfied with TEE, 84.3% preferred a new technology to replace TEE. Conducting outpatient TEE took more wait time (4.4 days vs. 0.1 days, p = 0.016) but led to significantly shorter hospital LOS (3.8 days vs. 6.4 days, p < 0.001) and significant lower hospital costs for RFCA (¥74,097 vs. ¥85,843, p < 0.001) than conducting inpatient TEE. Conclusions: Most AF patients experienced oropharynx pain and discomfort during or after TEE. Although more than half of AF patients were satisfied with TEE, most AF patients preferred a new technology to replace TEE for atrium thrombus screening. TEE was associated with economic impact on RFCA irrespective of TEE conducting settings.

Clinical effectiveness and efficiency of a new steerable sheath technology for radiofrequency ablation in Chinese patients with atrial fibrillation: a retrospective comparative cohort study.

Background: The clinical effectiveness and efficiency of a steerable sheath for radiofrequency catheter ablation (RFCA) in Chinese patients with atrial fibrillation (AF) needs to be compared with a fixed curve sheath to optimize RFCA procedure. Methods: This retrospective study included adult AF patients with their first RFCA that was conducted by the same electrophysiologist using a steerable sheath (VIZIGO, Biosense Webster, Inc.) or a fixed curve sheath (NaviEase, Synaptic Medical) in a Chinese tertiary care hospital from January to November 2021. The medical records kept at the hospital were the source of study data that included patient baseline characteristics and outcome measures for the clinical effectiveness and efficiency of RFCA procedure. Multivariate generalized linear regression analyses were performed to explore the impact of sheath type on clinical effectiveness and efficiency after adjustment. Results: Fourteen patients using steerable sheath and 34 patients using fixed curve sheath for RFCA were included in the data analysis. Most of patient baseline characteristics associated with the two study groups were comparable except that the steerable sheath group had significantly higher left atrium diameter (41.9±6.5 vs. 38.1±3.9 mm, P=0.017) and larger left atrium volume (150.4±29.5 vs. 126.8±27.5 mL, P=0.017) than the fixed curve sheath group. Using steerable sheath was associated with significantly shorter total pulmonary vein isolation (PVI) fluoroscopy time and post-surgery hospital length of stay (LOS) than using fixed curve sheath in both unadjusted comparisons (PVI fluoroscopy time: 1.3±1.5 vs. 4.0±3.9 min, P=0.004; post-surgery LOS: 2.1±0.7 vs. 2.9±1.5 days, P=0.034) and multivariate generalized regression analyses (PVI fluoroscopy time: coefficient =-0.859, P=0.014; post-surgery LOS: coefficient =-0.303, P=0.018). Conclusions: Compared to fixed curve sheath, steerable sheath used for RFAC could have the potential to shorten the PVI fluoroscopy time and reduce post-surgery LOS in a Chinese real-world hospital setting. Future real-world studies with large sample size are needed to confirm our study findings.

miR-185-5p / ATG101 axis alleviated intestinal barrier damage in intestinal ischemia reperfusion through autophagy.

Objective: Intestinal ischemia-reperfusion (II/R) is a common pathological injury in clinic, and the systemic inflammatory response it causes will lead to multiple organ damage and functional failure. miR-185-5p has been reported to be a regulator of inflammatory response and autophagy, but whether it participates in the regulation of autophagy in II/R is still unclear. Therefore, we aimed to explore the mechanism of miR-185-5p regulating intestinal barrier injury in (II/R). Methods: Caco-2 cells was induced by oxygen-glucose deprivation/reoxygenation (OGD/R) to establish II/R model. The superior mesenteric artery of C57BL/6 mice was clamped for 45 min and then subjected to reperfusion for 4 h for the establishment of II/R mice model. miR-185-5p mimic, miR-185-5p inhibitor, pcDNA-autophagy-related 101 (ATG101) were respectively transfected into Caco-2 cells. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to assess miR-185-5p expression. Western blot detected the level of ATG101 and tight junction-associated proteins ZO1, Occludin, E-cadherin, ß-catenin, as well as autophagy markers ATG5, ATG12, LC3Ⅰ/Ⅱ, Beclin1 and SQSTM1. Transepithelial electrical resistance (TEER) values was detected by a resistance meter. FITC-Dextran was performed to measure cell permeability. 5-ethynyl-2'-deoxyuridine (EDU) staining measured cell proliferation. Transmission electron microscope was conducted to observe autophagosomes. Hematoxylin & eosin (H&E) staining observed the damage of mice intestinal. Immunohistochemistry (IHC) measured the percentage of ki67 positive cells. TdT-mediated dUTP nick-end labeling (TUNEL) assay assessed cell apoptosis in intestinal tissues of II/R. Dual-luciferase assay verified the targeting relationship between miR-185-5p and ATG101.Results miR-185-5p was overexpressed in OGD/R-induced Caco-2 cells and intestinal tissues of II/R mice. Knocking down miR-185-5p markedly promoted autophagy and TEER values, reduced cell permeability, and alleviated intestinal barrier damage. ATG101 was a target of miR-185-5p, and overexpression of ATG101 promoted autophagy and dampened OGD/R-induced intestinal barrier damage. Overexpression of miR-185-5p reversed the effect of overexpressed ATG101 on OGD/R-induced Caco-2 cells. Conclusion: Knockdown of miR-185-5p enhanced autophagy and alleviated II/R intestinal barrier damage by targeting ATG101.

Sustainable response strategy for COVID-19: Pandemic zoning with urban multimodal transport data.

In the post-COVID-19 era, the pandemic response is increasingly difficult and entails a high cost to society. Existing pandemic control methods, such as lockdowns, greatly affect residents' normal lives. This paper proposes a pandemic control method, consisting of the scientific delineation of urban areas based on multimodal transportation data. An improved Leiden method based on the gravity model is used to construct a preliminary zoning scheme, which is then modified by spatial constraints. The modularity index demonstrates the suitability of this method for community detection. This method can minimize cut-off traffic flows between pandemic control areas. The results show that only 24.8% of travel links are disrupted using our method, which could reduce both the impact of pandemic control on the daily life of residents and its cost. These findings can help develop sustainable strategies and proposals for effective pandemic response.

MicroRNA-31 regulates TNF-α and IL-17A co-induced-endothelial cell apoptosis by repressing E2F6.

Vascular endothelial cell (VEC) apoptosis is the fundamental cause of pulmonary arterial hypertension. MicroRNA-31 (MiR-31) is a novel target for hypertension treatment. However, the role and mechanism of miR-31 in the apoptosis of VECs remain unclear. The purpose of this study is to determine whether miR-31 plays an important role in VEC apoptosis as well as the detailed mechanisms involved. We found that pro-inflammatory cytokines IL-17A and TNF-α were highly expressed in serum and aorta, and the expression of miR-31 was significantly increased in aortic intimal tissue from Angiotensin II (AngII)- induced hypertensive mice (WT-AngII) compared with control mice (WT-NC). In vitro, co-stimulation of VECs with IL-17A and TNF-α resulted in increased expression of miR-31 and VEC apoptosis. MiR-31 inhibition strikingly decreased TNF-α and IL-17A co-induced VEC apoptosis. Mechanistically, in IL-17A and TNF-α co-stimulated VECs (co-induced VECs), we found that the activation of the NF-κB signal effectively increased the expression of miR-31. Dual-luciferase reporter gene assay revealed that miR-31 directly targeted and inhibited the expression of the E2F transcription factor 6 (E2F6). The expression of E2F6 was decreased in Co-induced VECs. MiR-31 inhibition significantly alleviated the decreased expression of E2F6 in co-induced VECs. Consistent with the co-stimulated effect of IL-17A and TNF-α on VECs, transfection of siRNA E2F6 induced cell apoptosis without the stimulation of the above cytokines. In conclusion, TNF-α and IL-17A generated in the aortic vascular tissue and serum from Ang II-induced hypertensive mice could trigger VECs apoptosis by the miR-31/E2F6 axis. To sum up, our study suggests that the key factor between cytokine co-stimulation effect and VEC apoptosis was miR-31/E2F6 axis, which was mainly regulated by NF-қB signaling pathway. This gives us a new sight to treat hypertension-associated VR.

The impact of cognitive impairment on disease burden in Chinese patients with multiple sclerosis: A model simulation study.

BACKGROUND: Cognitive impairment (CI) is prevalent in Chinese patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A decision analytic model was constructed to simulate Chinese patients with newly diagnosed RRMS and their matched control cohort without MS for the risks of developing CI, developing secondary progressive MS (SPMS), and mortality. Both English and Chinese bibliographic databases were searched for evidence to estimate model inputs. Base case analysis and sensitivity analysis were conducted for the point estimations and uncertainty of the measured burden outcomes. RESULTS: Model simulations estimated that the lifetime cumulative risk of CI in newly diagnosed RRMS patients was 85.2%. Relative to the matched control cohort, newly diagnosed RRMS patients were associated with a lower life expectancy (33.2 years vs. 41.7 years, difference: -8.5 years), lower quality-adjusted life years (QALY) (18.4 QALY vs. 38.4 QALY, difference: -19.9 QALY), and higher lifetime medical costs (¥613,883 vs. ¥202,726, difference: ¥411,157) and indirect costs (¥1,099,021 vs. ¥94,612, difference: ¥1,004,410). Patients who developed CI accounted for at least half of the measured burden. The disease burden outcomes were mainly driven by the risk of developing CI, progression risk from RRMS to SPMS, hazard ratios of mortality associated with CI relative to no CI, utility of patients with RRMS, annual relapse risk, and annual costs of personal care. CONCLUSION: Most Chinese patients with newly diagnosed RRMS are likely to develop CI in their lifetime, and such patients that develop CI could significantly contribute to the disease burden of RRMS.

Comparative Investigation on the Phytochemicals and Biological Activities of Jackfruit (Artocarpus heterophyllus Lam.) pulp from Five Cultivars.

Jackfruit is one of the major tropical fruits, but information on the phytochemicals and biological benefits of its pulp is limited. In this study, the phytochemicals and biological activities including antioxidant, antitumor and anti-inflammatory activities of five jackfruit pulp cultivars (M1, M2, M3, M7 and T5) were comparatively investigated. A total of 11 compounds were identified in all cultivars of jackfruit pulp, among which 4-hydroxybenzoic acid, caffeic acid, ferulic acid and tryptophan N-glucoside were reported for the first time in jackfruit. T5 exhibited the highest total phenolic content (7.69 ± 0.73 mg GAE/g DW), antioxidant capacity (109.8, 96.7 and 207 mg VCE/g DW for DPPH, ABTS and FRAP, respectively), antitumor activity (80.31%) and anti-inflammatory activity (78.44%) among five cultivars. These results can provide a reference for growers to choose jackfruit cultivar and offer an insight into the industrial application of jackfruit pulp derived-products.

Morphological specificity analysis of an image-based 3D model of airway filling in a difficult airway.

BACKGROUND: The purpose of this study was to analyze position-specific morphological changes of the upper airway and to further assess the impact of these changes in difficult airway during intubation. METHODS: This observational comparative study included two groups (n = 20 patients/group): Group A had normal airway and Group B had difficult airway. Data obtained from two-dimensional magnetic resonance imaging were imported to Mimics V20.0 software for processing. We then reconstructed three-dimensional models of upper airway filling in patients in the supine and maximum extension position based on the imaging data. Those models were projected on coronal, sagittal, and horizontal planes to investigate multiple morphological features. We measured the surface area, radial length, and corner angle of the projected areas. RESULTS: Group A had larger upper airway filling volumes compared to Group B The volumes for the supine position were 6,323.83 ± 156.06 mm3 for Group A and 5,336.22 ± 316.13 mm3 for Group B (p = 0.003). The volumes the maximum extension position were 9,186.58 ± 512.61 mm3 for Group A and 6,735.46 ± 794.63 mm3 for Group B (p = 0.003). Airway volume increased in the upper airway filling model as the body position varied from the supine to maximum extension position (Group A: volume increase 2,953.75 ± 524.6 mm3, rate of change 31%; Group B: volume increase 1,632.89 ± 662.66 mm3, rate of change 25%; p = 0.052). CONCLUSION: The three-dimensional reconstruction model developed in this study was used to digitally quantify morphological features of a difficult airway and could be used as a novel airway management assessment tool.

Integrated and High-Throughput Approach for Sensitive Analysis of Tyrosine Phosphoproteome.

Tyrosine phosphorylation (pTyr) regulates various signaling pathways under normal and cancerous states. Due to their low abundance and transient and dynamic natures, systematic profiling of pTyr sites is challenging. Antibody and engineered binding domain-based approaches have been well applied to pTyr peptide enrichment. However, traditional methods have the disadvantage of a long sample preparation process, which makes them unsuitable for processing limited amount of samples, especially in a high-throughput manner. In this study we developed a 96-well microplate-based approach to integrate all the sample preparation steps starting from cell culture to MS-compatible pTyr peptide enrichment in three consecutive 96-well microplates. By assembling an engineered SH2 domain onto a microplate, nonspecific adsorption of phosphopeptides is greatly reduced, which allows us to remove the Ti-IMAC purification and three C18 desalting steps (after digestion, pTyr enrichment, and Ti-IMAC purification) and, therefore, greatly simplifies the entire pTyr peptide enrichment workflow, especially when processing a large number of samples. Starting with 96-well microplate-cultured, pervanadate-stimulated cells, our approach could enrich 21% more pTyr sites than the traditional serial pTyr enrichment approach and showed good sensitivity and reproducibility in the range of 200 ng to 200 µg peptides. Importantly, we applied this approach to profile tyrosine kinase inhibitor-mediated EGFR signaling pathway and could well differentiate the distinct response of different pTyr sites. Collectively, the integrated 96-well microplate-based approach is valuable for profiling pTyr sites from limited biological samples and in a high-throughput manner.

Application of the BP Neural Network Model in the Coordinated Development of Tourism Economic Networks in the Guangdong-Hong Kong-Macao Greater Bay Area.

In the present era, people are facing enough challenges, either personally or technically, and some people do suffer from having to keep up with the current technological improvements. The Guangdong-Hong Kong-Macao Greater Bay Area (GHKMGBA) is one of the areas that has been highly managed for tourism with economic networks in it. Here, the exploitation results in underground spacing management automate the alleviation process using various methods. Apart from the characterization, it is one such mandatory consideration to create a master plan with the rise of utilization and urban underground spacing planned to be placed among large cities for tourism is considered. This paper focuses on the strategy to understand the concepts and popularisation of urban underground spacing. This matter is followed by a complementary approach with a supportive technical system. This research focuses on economic development in the cities of GHKMGBA, and the analysis is carried out with the implementation of the backpropagation neural network (BPNN).

Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry.

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a critical regulator of cellular processes. We took a chemical biology approach to gain further insights into its function. We developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by several co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC50 and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. These studies collectively further expand our understanding of DYRK2 and provide a valuable tool to pinpoint its biological function.

Burden of tyrosine kinase inhibitor failure in Chinese chronic myeloid leukemia patients: a systematic literature review.

Aim: To conduct a systematic literature review of real-world evidence on the burden of tyrosine kinase inhibitor (TKI) failure in Chinese patients with chronic myeloid leukemia (CML). Methods: We identified 155 references in Chinese- and English-language journals from 2001 to 2021. Results: The age-adjusted mortality rate in Chinese CML patients was decreasing. Imatinib treatment had a higher annual treatment failure risk than nilotinib (0.199 vs 0.041). Patients with TKI treatment failure tended to be young (median: 38.6 years), have progressive disease (44.3%) and harbor BCR-ABL1 mutations (51.6%). The disease burden of TKI treatment failure included reduced health outcomes and increased health resource utilization and costs. Conclusion: CML relapse cases could continuously rise in China due to increasing TKI treatment failure over extended survival.