A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

HNetGO: protein function prediction via heterogeneous network transformer.

Protein function annotation is one of the most important research topics for revealing the essence of life at molecular level in the post-genome era. Current research shows that integrating multisource data can effectively improve the performance of protein function prediction models. However, the heavy reliance on complex feature engineering and model integration methods limits the development of existing methods. Besides, models based on deep learning only use labeled data in a certain dataset to extract sequence features, thus ignoring a large amount of existing unlabeled sequence data. Here, we propose an end-to-end protein function annotation model named HNetGO, which innovatively uses heterogeneous network to integrate protein sequence similarity and protein-protein interaction network information and combines the pretraining model to extract the semantic features of the protein sequence. In addition, we design an attention-based graph neural network model, which can effectively extract node-level features from heterogeneous networks and predict protein function by measuring the similarity between protein nodes and gene ontology term nodes. Comparative experiments on the human dataset show that HNetGO achieves state-of-the-art performance on cellular component and molecular function branches.

FoxO induces pupal diapause by decreasing TGFß signaling.

Diapause is a form of dormancy used widely by insects to survive adverse seasons. Previous studies have demonstrated that forkhead box O (FoxO) is activated during pupal diapause initiation in the moth Helicoverpa armigera. However, it is unclear how FoxO induces diapause. Here, we show that knockout of FoxO causes H. armigera diapause-destined pupae to channel into nondiapause, indicating that FoxO is a master regulator that induces insect diapause. FoxO activates the ubiquitin-proteasome system (UPS) by promoting ubiquitin c (Ubc) expression via directly binding to the Ubc promoter. Activated UPS decreases transforming growth factor beta (TGFß) receptor signaling via ubiquitination to block developmental signaling to induce diapause. This study significantly advances the understanding of insect diapause by uncovering the detailed molecular mechanism of FoxO.

Activation of protein arginine methyltransferase 1 and subsequent extension of moth lifespan is effected by the ROS/JNK/CREB signaling axis.

Previous studies have demonstrated that high physiological levels of reactive oxygen species induce pupal diapause and extend lifespan in the moth Helicoverpa armigera. This has been shown to occur via protein arginine methyltransferase 1 (PRMT1) blockade of Akt-mediated phosphorylation of the transcription factor FoxO, after which activated FoxO promotes the initiation of diapause. However, it is unclear how PRMT1 is activated upstream of FoxO activity. Here, we show that high reactive oxygen species levels in the brains of H. armigera diapause-destined pupae activate the expression of c-Jun N-terminal kinase, which subsequently activates the transcription factor cAMP-response element binding protein. We show that cAMP-response element binding protein then directly binds to the PRMT1 promoter and upregulates its expression to prevent Akt-mediated FoxO phosphorylation and downstream FoxO nuclear localization. This novel finding that c-Jun N-terminal kinase promotes FoxO nuclear localization in a PRMT1-dependent manner to regulate pupal diapause reveals a complex regulatory mechanism in extending the healthspan of H. armigera.

Re-Engineering Therapeutic Anti-Aß Monoclonal Antibody to Target Amyloid Light Chain.

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and ß-amyloid peptide (Aß) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aß antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aß42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aß42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases.

Identity-Based Matchmaking Encryption with Equality Test.

The identity-based encryption with equality test (IBEET) has become a hot research topic in cloud computing as it provides an equality test for ciphertexts generated under different identities while preserving the confidentiality. Subsequently, for the sake of the confidentiality and authenticity of the data, the identity-based signcryption with equality test (IBSC-ET) has been put forward. Nevertheless, the existing schemes do not consider the anonymity of the sender and the receiver, which leads to the potential leakage of sensitive personal information. How to ensure confidentiality, authenticity, and anonymity in the IBEET setting remains a significant challenge. In this paper, we put forward the concept of the identity-based matchmaking encryption with equality test (IBME-ET) to address this issue. We formalized the system model, the definition, and the security models of the IBME-ET and, then, put forward a concrete scheme. Furthermore, our scheme was confirmed to be secure and practical by proving its security and evaluating its performance.

Patients with chronic myeloid leukemia and coronavirus disease 2019 in the Omicron era.

To explore the prevalence and severity of COVID-19 and the mental health during the Omicron pandemic in patients with chronic myeloid leukemia (CML), a cross-sectional survey from 2609 respondents with CML was performed. A total of 1725 (66%) reported that they had COVID-19 during this period. Among them, 1621 (94%) were mild; 97 (6%), moderate; 7 (0.4%), severe; and 0, critical or death. Four hundred three (15%), 199 (8%), and 532 (20%) had moderate to severe depression, anxiety, and distress, respectively. Eight hundred ninety (34%), 667 (26%), and 573 (22%), avoidance, intrusion, and hyper-arousal, respectively. In multivariate analyses, longer TKI-therapy duration was significantly associated with a lower prevalence of COVID-19 (odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.95, 0.99; p = 0.043); however, living in urban areas (OR = 1.6 [1.3, 2.0]; p < 0.001) and having family members with COVID-19 (OR = 18.6 [15.1, 22.8]; p < 0.001), a higher prevalence of COVID-19. Increasing age (OR = 1.2 [1.1, 1.4]; p = 0.009), comorbidity(ies) (OR = 1.7 [1.1, 2.7]; p = 0.010), and multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents (OR = 2.2 [1.2, 4.2]; p = 0.010) were significantly associated with moderate or severe COVID-19. Female, comorbidity(ies), unvaccinated, and moderate or severe COVID-19 were significantly associated with almost all adverse mental health consequences; increasing age or forced TKI dose reduction because of various restriction during the pandemic, moderate to severe distress, avoidance, or intrusion; however, mild COVID-19, none or mild anxiety, distress, avoidance, or intrusion. In conclusion, shorter TKI-therapy duration, increasing age, comorbidity(ies), or multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents had a higher prevalence of COVID-19 or higher risk of moderate or severe disease in patients with CML; increasing age, female, comorbidity(ies), forced TKI dose reduction due to the pandemic, moderate or severe COVID-19, unvaccinated, a higher likelihood of worse mental health.

Association between autoimmune diseases of the nervous system and schizophrenia: A systematic review and meta-analysis of cohort studies.

INTRODUCTION: Numerous studies have found an association between autoimmune diseases of the nervous system (ADNS) and schizophrenia (SCZ), but the findings remain controversial. We conducted the first meta-analysis to summarize the current evidence from cohort studies that evaluated the association between ADNS and SCZ. METHODS: PubMed, Web of Science, and Embase were comprehensively searched until May 30, 2022 for articles on the association between ADNS and SCZ. Every included study was reported effect size with 95% CIs for the association between ADNS and SCZ. Meta-regression and subgroup analysis were used to assess the heterogeneity. RESULTS: A total of 8 cohort studies with 12 cohorts were included in the meta-analysis. We observed a significant association between ADNS and SCZ (RR = 1.42; 95%CI, 1.18-1.72). Subgroup analysis showed that the risk of SCZ was significantly increased when ADNS were used as exposure factors (RR = 1.48; 95%CI, 1.15-1.89), whereas with SCZ did not observe an increased risk of subsequent ADNS (RR = 1.33; 95%CI, 0.92-1.92); multiple sclerosis (MS) was positively associated with SCZ (RR = 1.36; 95%CI, 1.12-1.66), but no significant association was found between Guillain-Barre syndrome (GBS) and SCZ (RR = 1.90; 95%CI, 0.87-4.17). Meanwhile, we found location was the source of heterogeneity. LIMITATIONS: High heterogeneity was observed (I2 = 92.0%), and only English literature was included in the meta-analysis. CONCLUSIONS: We found a positive association between ADNS and SCZ, and the association was different across the different types of ADNS. The results of the study are helpful for clinicians to carry out targeted preventive measures for ADNS and SCZ.

A nomogram prediction of outcome in patients with COVID-19 based on individual characteristics incorporating immune response-related indicators.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has quickly become a global threat to public health, and it is difficult to predict severe patients and their prognosis. Here, we intended developing effective models for the late identification of patients at disease progression and outcome. METHODS: A total of 197 patients were included with a 20-day median follow-up time. We first developed a nomogram for disease severity discrimination, then created a prognostic nomogram for severe patients. RESULTS: In total, 40.6% of patients were severe and 59.4% were non-severe. The multivariate logistic analysis indicated that IgG, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase, platelet, albumin, and blood urea nitrogen were significant factors associated with the severity of COVID-19. Using immune response phenotyping based on NLR and IgG level, the logistic model showed patients with the NLRhi IgGhi phenotype are most likely to have severe disease, especially compared to those with the NLRlo IgGlo phenotype. The C-indices of the two discriminative nomograms were 0.86 and 0.87, respectively, which indicated sufficient discriminative power. As for predicting clinical outcomes for severe patients, IgG, NLR, age, lactate dehydrogenase, platelet, monocytes, and procalcitonin were significant predictors. The prognosis of severe patients with the NLRhi IgGhi phenotype was significantly worse than the NLRlo IgGhi group. The two prognostic nomograms also showed good performance in estimating the risk of progression. CONCLUSIONS: The present nomogram models are useful to identify COVID-19 patients with disease progression based on individual characteristics and immune response-related indicators. Patients at high risk for severe illness and poor outcomes from COVID-19 should be managed with intensive supportive care and appropriate therapeutic strategies.

Factors associated with suicidal ideation among Chinese adults in the labour force.

This study aims to identify the risk factors of suicidal ideation (SI) in a large sample of Chinese adults in the labour force. A total of 4136 eligible participants in the labour force were recruited from the routine health check-up cohort. Univariate and multivariate logistic regression were used to identify the factors associated with 12-month and lifetime SI. 175 (4.2%) subjects reported SI in the past twelve months, and 223 (5.4%) reported SI during their lifetime. The results showed that being divorced or widowed, religious belief, personal history of chronic disease and mental illness, family history of mental illness and suicide, and self-assessed childhood happiness were associated with both 12-month and lifetime SI. Additional associations were found between 12-month SI and the following factors: working overtime frequently, low monthly income, and having bachelor's degree. Moreover, being single is a risk factor of lifetime SI while not significant for 12-month SI. The present study identified several risk factors of 12-month and lifetime SI, which could potentially help develop targeted interventions for high-risk suicidal Chinese adults in the labour force.

Reactive oxygen species extend insect life span using components of the insulin-signaling pathway.

Reactive oxygen species (ROS) are well-known accelerants of aging, but, paradoxically, we show that physiological levels of ROS extend life span in pupae of the moth Helicoverpa armigera, resulting in the dormant state of diapause. This developmental switch appears to operate through a variant of the conventional insulin-signaling pathway, as evidenced by the facts that Akt, p-Akt, and PRMT1 are elevated by ROS, but not insulin, and that high levels of p-Akt fail to phosphorylate FoxO through PRMT1-mediated methylation. These results suggest a distinct signaling pathway culminating in the elevation of FoxO, which in turn promotes the extension of life span characteristic of diapause.

A Challenge-Response Assisted Authorisation Scheme for Data Access in Permissioned Blockchains.

Permissioned blockchains can be applied for sharing data among permitted users to authorise the data access requests in a permissioned blockchain. A consensus network constructed using pre-selected nodes should verify a data requester's credentials to determine if he or she have the correct permissions to access the queried data. However, current studies do not consider how to protect users' privacy for data authorisation if the pre-selected nodes become untrusted, e.g., the pre-selected nodes are manipulated by attackers. When a user's credentials are exposed to pre-selected nodes in the consensus network during authorisation, the untrusted (or even malicious) pre-selected nodes may collect a user's credentials and other private information without the user's right to know. Therefore, the private data exposed to the consensus network should be tightly restricted. In this paper, we propose a challenge-response based authorisation scheme for permissioned blockchain networks named Challenge-Response Assisted Access Authorisation (CRA3) to protect users' credentials during authorisation. In CRA3, the pre-selected nodes in the consensus network do not require users' credentials to authorise data access requests to prevent privacy leakage when these nodes are compromised or manipulated by attackers. Furthermore, the computational burden on the consensus network for authorisation is reduced because the major computing work of the authorisation is executed by the data requester and provider in CRA3.

Hitherto-Unexplored Photodynamic Therapy of Ag2 S and Enhanced Regulation Based on Polydopamine In Vitro and Vivo.

Given their superior penetration depths, photosensitizers with longer absorption wavelengths present broader application prospects in photodynamic therapy (PDT). Herein, Ag2 S quantum dots were discovered, for the first time, to be capable of killing tumor cells through the photodynamic route by near-infrared light irradiation, which means relatively less excitation of the probe compared with traditional photosensitizers absorbing short wavelengths. On modification with polydopamine (PDA), PDA-Ag2 S was obtained, which showed outstanding capacity for inducing reactive oxygen species (increased by 1.69 times). With the addition of PDA, Ag2 S had more opportunities to react with surrounding O2 , which was demonstrated by typical triplet electron spin resonance (ESR) analysis. Furthermore, the PDT effects of Ag2 S and PDA-Ag2 S achieved at longer wavelengths were almost identical to the effects produced at 660 nm, which was proved by studies in vitro. PDA-Ag2 S showed distinctly better therapeutic effects than Ag2 S in experiments in vivo, which further validated the enhanced regulatory effect of PDA. Altogether, a new photosensitizer with longer absorption wavelength was developed by using the hitherto-unexplored photodynamic function of Ag2 S quantum dots, which extended and enhanced the regulatory effect originating from PDA.

Bioprocess development of a stable FUT8-/--CHO cell line to produce defucosylated anti-HER2 antibody.

In recent years, an increasing number of defucosylated therapeutic antibodies have been applied in clinical practices due to their better efficacy compared to fucosylated counterparts. The establishment of stable and clonal manufacturing cell lines is the basis of therapeutic antibodies production. Bioprocess development of a new cell line is necessary for its future applications in the biopharmaceutical industry. We engineered a stable cell line expressing defucosylated anti-HER2 antibody based on an established α-1,6-fucosyltransferase (FUT8) gene knockout CHO-S cell line. The optimization of medium and feed was evaluated in a small-scale culture system. Then the optimal medium and feed were scaled up in a bioreactor system. After fed-batch culture over 13 days, we evaluated the cell growth, antibody yield, glycan compositions and bioactivities. The production of anti-HER2 antibody from the FUT8 gene knockout CHO-S cells in the bioreactor increased by 37% compared to the shake flask system. The N-glycan profile of the produced antibody was consistent between the bioreactor and shake flask system. The antibody-dependent cellular cytotoxicity activity of the defucosylated antibody increased 14-fold compared to the wild-type antibody, which was the same as our previous results. The results of our bioprocess development demonstrated that the engineered cell line could be developed to a biopharmaceutical industrial cell line.

The potential agents from food for preventing leukopenia induced by benzene: garlic preparations.

Leukopenia is the early clinical manifestation of benzene poisoning. The aim of our research was to evaluate the preventive effects of three kinds of garlic preparations on benzene induced leukopenia. The mouse model of Leukopenia was established with benzene orally. At the same time, mice were administrated with garlic homogenate (GH), garlic oil (GO) or diallyl trisulfide (DATS) as preventional measures. The counts of white blood cells (WBC), the organ indexes, pathological examinations, blood biochemical parameters, weight gains, and food intakes were evaluated to observe the protective effect and potential adverse events. The results demonstrated that the counts of WBC increased by 144.04%, 140.07%, and 148.34%, respectively, after intervention by GH (400 mg/kg), GO (60 mg/kg) and DATS (30 mg/kg), compared with that in the model group. The spleen and thymus indexes in the benzene model group were 44.99% and 54.04% lower than those in the blank control group, the number of spleen nodules reduced and the thymus atrophy, which were restored by three garlic preparations at different degree. The results suggested that the three preparations all could prevent the leukopenia and protect the organ injuries induced by benzene. However, the spleen index and weight gains revealed that GH and GO brought more adverse events than DATS.

Targeting N-doped graphene quantum dot with high photothermal conversion efficiency for dual-mode imaging and therapy in vitro.

A graphene quantum dot (GQD) is a novel carbon nanomaterial with the advantages of low cost and no pollution. It has attracted serious attention in the biomedical fields because of its stabilities and tunable fluorescence wavelength. In this manuscript, an N-doped graphene quantum dot (N-GQD) was synthesized by a hydrothermal method using citric acid as the carbon source and urea as the nitrogen source. X-ray diffraction, Raman spectroscopy, transmission electron microscopy, UV-vis absorption spectrum, and fluorescence spectrum were used to characterize the N-GQD. The results showed that the N-GQD had a uniform size of about 5 nm. The two fluorescence emission peaks, one in the visible light region showed a 49.75% quantum yield, while another in the near infrared region was 2.49%. The photothermal conversion efficiency was 62.53%, higher than any kind of carbon nanomaterial in existence today. MTT and a long-term cytotoxicity experiment confirmed that the N-GQD had low cytotoxicity. The probe also had the ability of photoacoustic response at the same time. After coupling with folic acid, it presented imaging and photothermal therapy on the cells, which has great application prospects in the early diagnosis and treatment of tumors.

A multifunctional targeting probe with dual-mode imaging and photothermal therapy used in vivo.

BACKGROUND: Ag2S has the characteristics of conventional quantum dot such as broad excitation spectrum, narrow emission spectrum, long fluorescence lifetime, strong anti-bleaching ability, and other optical properties. Moreover, since its fluorescence emission is located in the NIR-II region, has stronger penetrating ability for tissue. Ag2S quantum dot has strong absorption during the visible and NIR regions, it has good photothermal and photoacoustic response under certain wavelength excitation. RESULTS: 200 nm aqueous probe Ag2S@DSPE-PEG2000-FA (Ag2S@DP-FA) with good dispersibility and stability was prepared by coating hydrophobic Ag2S with the mixture of folic acid (FA) modified DSPE-PEG2000 (DP) and other polymers, it was found the probe had good fluorescent, photoacoustic and photothermal responses, and a low cell cytotoxicity at 50 µg/mL Ag concentration. Blood biochemical analysis, liver enzyme and tissue histopathological test showed that no significant influence was observed on blood and organs within 15 days after injection of the probe. In vivo and in vitro fluorescence and photoacoustic imaging of the probe further demonstrated that the Ag2S@DP-FA probe had good active targeting ability for tumor. In vivo and in vitro photothermal therapy experiments confirmed that the probe also had good ability of killing tumor by photothermal. CONCLUSIONS: Ag2S@DP-FA was a safe, integrated diagnosis and treatment probe with multi-mode imaging, photothermal therapy and active targeting ability, which had a great application prospect in the early diagnosis and treatment of tumor.

Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.

Design, synthesis and potent cytotoxic activity of novel 7-(N-[(substituted-sulfonyl)piperazinyl]-methyl)-camptothecin derivatives.

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low µM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC50, 1.2nM) and 12k (IC50, 20.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives.