Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover ...novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10
) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.
A one‐pot strategy for the synthesis of substituted isocoumarin, flavone, and isoquinolinedione derivatives through a switchable C‐arylation/lactonization or SNAr reaction from a wide range of soft ...nucleophiles and o‐quinol acetates has been developed. This base‐mediated protocol proceeds under transition‐metal‐free conditions and selectively affords various heteroarenes in 13–98% yields from readily prepared or commercially available 1,3‐dicarbonyl and α‐EWG‐substituted carbonyl compounds. The synthetic utility is further demonstrated in the synthesis of potential anti‐HIV and anti‐coronavirus derivatives and COX‐2 inhibitors. In addition, detailed experimental and computational studies are performed to provide an intensive understanding and strong support of the reaction mechanism.
Stenotrophomonas maltophilia is a Gram-negative, biofilm-forming bacterium. Although generally regarded as an organism of low virulence, S. maltophilia is an emerging multi-drug resistant ...opportunistic pathogen in hospital and community settings, especially among immunocompromised hosts. Risk factors associated with S. maltophilia infection include underlying malignancy, cystic fibrosis, corticosteroid or immunosuppressant therapy, the presence of an indwelling central venous catheter and exposure to broad spectrum antibiotics. In this review, we provide a synthesis of information on current global trends in S. maltophilia pathogenicity as well as updated information on the molecular mechanisms contributing to its resistance to an array of antimicrobial agents. The prevalence of S. maltophilia infection in the general population increased from 0.8-1.4% during 1997-2003 to 1.3-1.68% during 2007-2012. The most important molecular mechanisms contributing to its resistance to antibiotics include β-lactamase production, the expression of Qnr genes, and the presence of class 1 integrons and efflux pumps. Trimethoprim/sulfamethoxazole (TMP/SMX) is the antimicrobial drug of choice. Although a few studies have reported increased resistance to TMP/SMX, the majority of studies worldwide show that S. maltophilia continues to be highly susceptible. Drugs with historically good susceptibility results include ceftazidime, ticarcillin-clavulanate, and fluoroquinolones; however, a number of studies show an alarming trend in resistance to those agents. Tetracyclines such as tigecycline, minocycline, and doxycycline are also effective agents and consistently display good activity against S. maltophilia in various geographic regions and across different time periods. Combination therapies, novel agents, and aerosolized forms of antimicrobial drugs are currently being tested for their ability to treat infections caused by this multi-drug resistant organism.
Cells in the tumor microenvironment (TME) communicate via membrane‐bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal ...cells. In this study, we showed that the loss of core‐1 β1,3‐galactosyltransferase (C1GALT1)‐mediated O‐glycosylation suppressed tumor growth in syngeneic head and neck cancer mouse models. O‐glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T‐cell‐mediated cytotoxicity, and reduced interleukin‐6 (IL‐6) levels in the secretome. Proteasomal degradation of IL‐6 was controlled by the O‐glycan at threonine 166. Both IL‐6/IL‐6R blockade and O‐glycan truncation in tumor cells induced similar pro‐inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O‐glycosylation inhibitor itraconazole and anti‐programmed cell death protein 1 (anti‐PD‐1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O‐glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O‐glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti‐PD‐1 therapy.
This study found that O‐glycan truncation induced proteasomal degradation of interleukin‐6 to suppress tumor growth by promoting M1 macrophage polarization and enhancing T cell‐mediated cytotoxicity in head and neck cancer in vitro and in vivo. Combining an O‐glycosylation inhibitor with anti‐programmed cell death protein 1 antibody effectively suppressed tumor growth, emphasizing the role of O‐glycosylation in modulating the tumor microenvironment.
Diabetic ketoacidosis (DKA) is associated with dehydration and which can cause acute kidney injury (AKI). The proportion of AKI in children and adolescents with DKA has not been reported in East ...Asian population. This study aimed to identify the prevalence of AKI and to determine whether there is an association between AKI severity and recovery time from metabolic acidosis in children and adolescents with DKA. Medical records of children and adolescents (aged 1.5 times the calculated expected baseline creatinine level. Patients were divided into three groups based on AKI severity: no AKI, mild AKI, and severe AKI. In total, 170 (56.5%) patients with DKA presented AKI (mild AKI, 116 38.5%; severe AKI, 54 18.0%). Heart rate and laboratory parameters related to dehydration, such as corrected sodium level and blood urea nitrogen, were strongly associated with AKI development (P0.01). Blood pH, plasma glucose, and potassium levels were also associated with AKI. A negative correlation with borderline significance between the estimated glomerular filtration rate (eGFR) and recovery time from metabolic acidosis was observed in the severe AKI group. AKI was highly prevalent in children and adolescents with DKA. An association between AKI and biomarkers indicating dehydration was noted. The recovery time from metabolic acidosis following treatment may be longer in children with a decreased eGFR who present with severe AKI. AKI is a common complication in children with DKA.
Background
Glofitamab is a bispecific antibody with promise for treating relapsed/refractory B‐cell lymphoma according to a phase 1/2 clinical trial. This study examined its real‐world effectiveness.
...Methods
This was an investigator‐initiated, multicenter retrospective study including 34 patients who had relapsed/refractory B‐cell lymphomas after at least three prior lines of therapy and received glofitamab monotherapy in a compassionate use program in Taiwan between January 2021 and October 2022.
Results
At a median follow‐up of 15.9 months, 56% of patients responded to glofitamab and 23% achieved complete remission. Response to the previous line of therapy significantly correlated with response to glofitamab (p = .020). Most responses were durable; only five out of the 19 responders had documented disease recurrence at the data cutoff date. The estimated progression‐free survival (PFS) was 3.2 months, and the estimated 1‐year PFS was 33% for the entire cohort. PFS was better for responders than nonresponders (median PFS, 16.9 vs. 1.8 months; 1‐year PFS, 60% vs. 0%). Forty‐three cytokine release syndrome (CRS) events were observed, three of which were grade 3; all were manageable without glofitamab discontinuation. No immune effector cell–associated neurotoxicity was reported. Among seven hepatitis B virus (HBV) carriers (six had antiviral prophylaxis) and 14 patients with remote HBV (four had antiviral prophylaxis), no HBV reactivation was observed.
Conclusions
In this real‐world cohort, glofitamab exhibited effectiveness comparable to trial results without excessive CRS or new safety issues. With appropriate prophylaxis, glofitamab‐treated patients with chronic or remote HBV infection are unlikely to experience virus reactivation.
Glofitamab is an effective treatment for relapsed and refractory B‐cell lymphomas according to real‐world clinical data from 34 patients in Taiwan, which confirms clinical trial results. Glofitamab is not associated with an apparent risk of hepatitis B virus reactivation.
Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and ...mechanistic analyses and proposes a potential targeted therapeutic approach.
In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T.
In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T.
CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.
This paper presents a recurrent neural classifier for automatically classifying sleep stages based on energy features from the EEG signal of the Fpz−Cz channel. The energy features were extracted ...from characteristic waves of EEG signals which were then used to classify different sleep stages. The recurrent neural classifier, utilizing energy features extracted from EEG signals, assigned each 30-s epoch to one of five possible sleep stages: wakefulness, NREM 1, NREM 2, SWS, and REM. Eight sleep recordings obtained from the Sleep-EDF database, which is available from the PhysioBank, were utilized to validate the proposed method. Using the features extracted by our research, classification performance of a feedforward neural network (FNN) and a probabilistic neural network (PNN) were compared to that of the proposed recurrent neural classifier. The classification rate of the recurrent neural classifier was found to be better (87.2%) than those of the two neural classifiers (81.1% for FNN and 81.8% for PNN). The result demonstrates that the proposed recurrent neural classifier using the energy features extracted from characteristic waves of EEG signals can classify sleep stages more efficiently and accurately using only a single EEG channel.
•The initiative of STEM IPBL course is one of the frontiers in engineering education and evidence-based practice.•STEM Interdisciplinary PBL is an effective approach to improve college student’s ...learning motivation, self-efficacy, and creativity.•Interdisciplinary collaboration between engineering and design majored students can benefit the student’s development of human-computer interaction systems.
In recent years, STEM (Science, Technology, Engineering, and Mathematics) has been extensively advocated and implemented in education, as it is suggested to be very impactful on student’s interdisciplinary learning, which can be seen as a significant driving force for a country’s advancement in scientific and technical knowledge, innovation, economy, and international competitiveness. Developing a human-computer interaction (HCI) system to solve real-world problems requires the inventors to have interdisciplinary STEM knowledge and skills. Thus a STEM Interdisciplinary Project-based Learning (IPBL) approach was applied to teach a total number of 45 college students registered in the departments of engineering and design. Inspired by Design Thinking, the 18-week STEM IPBL course was delivered through four phases, including discover, define, develop, and deliver. All the finished HCI projects applied the interdisciplinary knowledge and skills from the domains of STEM. Evidence drawn from the 6-point Likert ‘Motivated Strategies for Learning Questionnaire (MSLQ)’ indicated that the STEM IPBL course was very impactful on student’s learning, which improved the participants’ (a) overall learning motivation (Pre M = 4.4, Post M = 4.64; p = .012), (b) self-efficacy of learning (Pre M = 4.03, Post M = 4.43; p = .003), (c) enjoyableness of learning STEM (Pre M = 4.68, Post M = 4.75; p = .556), and (d) recognizing the significance of learning STEM on future career development (Pre M = 4.73, Post M = 4.94; p = .077). It is also found that compared with design majored students, the course had a better effect on the engineering majored students. Evidence collected from ‘Abbreviated Torrance Test for Adults (ATTA)’ indicated that the student’s overall creativity was significantly improved (Pre M = 63.36, Post M = 68.44; p = .000). More specifically, among the four facets of creativity, the improvements were as follows: fluency (Pre M = 14.89, Post M = 16.2; p = .001), elaboration (Pre M = 16.69, Post M = 18.62; p = .000), flexibility (Pre M = 14.82, Post M = 16.04; p = .009), and originality (Pre M = 16.96, Post M = 17.58; p = .136). It is found that the STEM IPBL course had a different impact on the student's originality, while the originality of engineering majored students significantly improved (p = .006), the originality of design majored students did not change. Some educational implications were also provided in the article.
PDF
