Discharge teaching quality positively predicts quality of life in colorectal cancer patients with temporary enterostomy: The mediating role of readiness for hospital discharge and stoma self-efficacy.

OBJECTIVES: This study aimed to examine the mediating role of readiness for hospital discharge (RHD) and stoma self-efficacy (SSE) in the relationship between quality of discharge teaching (QDT) and health-related quality of life (HRQOL) in colorectal cancer patients with temporary enterostomy, and the gender difference of mediating effect. BACKGROUND: It is not clear how RHD, QDT, SSE and HRQOL interact in colorectal cancer patients with temporary enterostomy. METHODS: This was a prospective follow-up survey. 221 colorectal cancer patients with temporary enterostomy were conveniently recruited from a general hospital in Southeast China. The Quality of Discharge Teaching Scale, Readiness for Hospital Discharge Scale, Stoma Self-Efficacy Scale, and Stoma Quality of Life Scale were used to collect data. Pearson's correlation and structural equation models were used to analyze the data. SPSS 26.0 and Amos 28.0 software were used for analysis the collected data. RESULTS: Regarding the relationship of QDT and HRQOL, only QDT-T had a direct effect among colorectal cancer patients with stomas (b = 0.233, P<0.001, percentile 95% CI = [0.145, 0.314]). However, both QDT-T and QDT-R can predict HRQOL indirectly through three paths: (1) the mediating role of SSE (b = 0.050, P = 0.009, percentile 95% CI = [0.013, 0.098]; b = 0.077, P = 0.008, percentile 95% CI = [0.021, 0.164]), (2) the mediating role of RHD (b = 0.044, P = 0.004, percentile 95% CI = [0.014, 0.085]; b = 0.044, P = 0.005, percentile 95% CI = [0.010, 0.102]), and (3) the chain mediating role of SSE and RHD (b = 0.030, P = 0.003, percentile 95% CI = [0.011, 0.059]; b = 0.047, P = 0.003, percentile 95% CI = [0.015, 0.103]). The similar chain mediating effect in male stoma patients was also found (b = 0.041, P = 0.002, percentile 95% CI = [0.016, 0.080]; b = 0.046, P = 0.004, percentile 95% CI = [0.011, 0.114]). CONCLUSIONS: Stoma self-efficacy and readiness for hospital discharge played important intermediary roles in the relationship between quality of discharge teaching and health-related quality of life in colorectal cancer patients with stomas. Health care providers can design SSE-enhancing and RHD-enhancing discharge planning for colorectal cancer patients with temporary enterostomies.

Advancing Recyclable Thermosets through C═C/C═N Dynamic Covalent Metathesis Chemistry.

Thermoset polymers have become integral to our daily lives due to their exceptional durability, making them feasible for a myriad of applications; however, this ubiquity also raises serious environmental concerns. Covalent adaptable networks (CANs) with dynamic covalent linkages that impart efficient reprocessability and recyclability to thermosets have garnered increasing attention. While various dynamic exchange reactions have been explored in CANs, many rely on the stimuli of active nucleophilic groups and/or catalysts, introducing performance instability and escalating the initial investment. Herein, we propose a new direct and catalyst-free C═C/C═N metathesis reaction between α-cyanocinnamate and aldimine as a novel dynamic covalent motif for constructing recyclable thermosets. This chemistry offers mild reaction conditions (room temperature and catalyst-free), ensuring high yields and simple isolation procedures. By incorporating dynamic C═C/C═N linkages into covalently cross-linked polymer networks, we obtained dynamic thermosets that exhibit both malleability and reconfigurability. The resulting tunable dynamic properties, coupled with the high thermal stability and recyclability of the C═C/C═N linkage-based networks, enrich the toolbox of dynamic covalent chemistry.

Trends in heart failure costs for commercially insured patients in the United States (2006-2021).

BACKGROUND: Although prior research has estimated the overarching cost burden of heart failure (HF), a thorough analysis examining medical expense differences and trends, specifically among commercially insured patients with heart failure, is still lacking. Thus, the study aims to examine historical trends and differences in medical costs for commercially insured heart failure patients in the United States from 2006 to 2021. METHODS: A population-based, cross-sectional analysis of medical and pharmacy claims data (IQVIA PharMetrics® Plus for Academic) from 2006 to 2021 was conducted. The cohort included adult patients (age > = 18) who were enrolled in commercial insurance plans and had healthcare encounters with a primary diagnosis of HF. The primary outcome measures were the average total annual payment per patient and per cost categories encompassing hospitalization, surgery, emergency department (ED) visits, outpatient care, post-discharge care, and medications. The sub-group measures included systolic, diastolic, and systolic combined with diastolic, age, gender, comorbidity, regions, states, insurance payment, and self-payment. RESULTS: The study included 422,289 commercially insured heart failure (HF) patients in the U.S. evaluated from 2006 to 2021. The average total annual cost per patient decreased overall from $9,636.99 to $8,201.89, with an average annual percentage change (AAPC) of -1.11% (95% CI: -2% to -0.26%). Hospitalization and medication costs decreased with an AAPC of -1.99% (95% CI: -3.25% to -0.8%) and - 3.1% (95% CI: -6.86-0.69%). On the other hand, post-discharge, outpatient, ED visit, and surgery costs increased by an AAPC of 0.84% (95% CI: 0.12-1.49%), 4.31% (95% CI: 1.03-7.63%), 7.21% (95% CI: 6.44-8.12%), and 9.36% (95% CI: 8.61-10.19%). CONCLUSIONS: The study's findings reveal a rising trend in average total annual payments per patient from 2006 to 2015, followed by a subsequent decrease from 2016 to 2021. This decrease was attributed to the decline in average patient costs within the Medicare Cost insurance category after 2016, coinciding with the implementation of the Medicare Access and CHIP Reauthorization Act (MACRA) of 2015. Additionally, expenses related to surgical procedures, emergency department (ED) visits, and outpatient care have shown substantial growth over time. Moreover, significant differences across various variables have been identified.

Reactive oxygen species play key roles in the nitrite formation by the inorganic nitrate photolysis in the presence of urban water-soluble organic carbon.

Inorganic nitrates were considered to be a potential source of atmospheric NO2-/HONO during the daytime. To better evaluate the contribution of nitrate photochemistry on NO2-/HONO formation, the photolysis of nitrates in the real atmospheric environment needs to be further explored. Here, the NO2- generation by the photolysis of inorganic nitrates in the presence of total water-soluble organic carbon (WSOC) was quantified. The physicochemical properties of WSOC were measured to understand the underlying mechanism for the photolysis of inorganic nitrates with WSOC. WSOC enhanced or suppressed the photochemical conversion of nitrates to NO2-, with the quantum yield of NO2- (ΦNO2-) varying from (0.07 ± 0.02)% to (3.11 ± 0.04)% that depended on the light absorption properties of WSOC. Reactive oxygen species (ROS) generated from WSOC, including O2-/HO2 and OH, played a dual role in the NO2- formation. Light-absorbing substances in WSOC, such as N-containing and carbonyl aromatics, produced O2-/HO2 that enhanced the secondary conversion of NO2 to NO2-. On the other hand, OH deriving from the WSOC photochemistry inhibited the nitrate photodegradation and the NO2- formation. HONO source strength by the aqueous photolysis of nitrates with WSOC was estimated to be lower than 100 ppt h-1, which may partly contribute to the atmospheric HONO source in some cases.

Impact of butylparaben on growth dynamics and microcystin-LR production in Microcystis aeruginosa.

The presence of butylparaben (BP), a prevalent pharmaceutical and personal care product, in surface waters has raised concerns regarding its impact on aquatic ecosystems. Despite its frequent detection, the toxicity of BP to the cyanobacterium Microcystis aeruginosa remains poorly understood. This study investigates the influence of BP on the growth and physiological responses of M. aeruginosa. Results indicate that low concentrations of BP (below 2.5 mg/L) have negligible effects on M. aeruginosa growth, whereas higher concentrations (5 mg/L and 10 mg/L) lead to significant growth inhibition. This inhibition is attributed to the severe disruption of photosynthesis, evidenced by decreased Fv/Fm values and chlorophyll a content. BP exposure also triggers the production of reactive oxygen species (ROS), resulting in elevated activity of antioxidant enzymes. Excessive ROS generation stimulates the production of microcystin-LR (MC-LR). Furthermore, lipid peroxidation and cell membrane damage indicate that high BP concentrations cause cell membrane rupture, facilitating the release of MC-LR into the environment. Transcriptome analysis reveals that BP disrupts energy metabolic processes, particularly affecting genes associated with photosynthesis, carbon fixation, electron transport, glycolysis, and the tricarboxylic acid cycle. These findings underscore the profound physiological impact of BP on M. aeruginosa and highlight its role in stimulating the production and release of MC-LR, thereby amplifying environmental risks in aquatic systems.

Protective effect of dexmedetomidine against delayed bone healing caused by morphine via PI3K/Akt mediated Nrf2 antioxidant defense system.

Background: As a class of analgesics, opioids are frequently used to treat both acute and chronic moderate to severe pain. Patients frequently receive opioid painkillers after orthopedic accidents or surgeries. Evidence suggests that opioid drug users have a 55.1% higher risk of fracture and poor bone repair than non-users of opioid drugs. The key pathogenic alterations in the incidence and progression of poor bone repair are over apoptosis and aging of osteoblasts due to the stress caused by oxidation. Dexmedetomidine (Dex) has been proven to protect against a variety of degenerative illnesses by reducing oxidative stress. However, nothing is known about how it affects bone repair. Methods: PI3K/Akt/Nrf2 pathway was detected by immunofluorescence and Western blot. SOD, CAT, JC-1, dihydroethidium and mitosox were used in the Oxidative Stress. Micro-CT, H&E and Masson's staining, immunohistochemically were performed to evaluate the therapeutic effects of DEX on calvarial defects in the morphine-induced rat model. Results: We found that morphine-induced an imbalance in the metabolism and catabolism of primary rat Osteoblasts. However, these conditions could be inhibited by DEX treatment. In the meantime, DEX induced the expression of Nrf2-regulated antioxidant enzymes such as NQO1, HO-1, GCLm, GCLc, and TrxR1. DEX-mediated Nrf2 activation is linked to the PI3K/Akt signaling system. Furthermore, it has been established that intravenous DEX enhanced the growth of bone healing in a model of a surgically produced rat cranial lesion. Conclusion: This is the first description of the unique DEX mechanism acting as a Nrf2 activator against morphine-mediated oxidative harm, raising the possibility that the substance may be used to prevent bone defects.

Combined use of Donepezil and Memantine increases the probability of five-year survival of Alzheimer's disease patients.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be beneficial in demonstrating which drugs reduce the disease burden and increase survival. METHODS: We conducted a comprehensive causal inference study implementing doubly robust estimators and using one of the largest high-quality medical databases, the Oracle Electronic Health Records (EHR) Real-World Data. Our work was focused on the estimation of the effects of the two common Alzheimer's disease drugs, Donepezil and Memantine, and their combined use on the five-year survival since initial diagnosis of AD patients. Also, we formally tested for the presence of interaction between these drugs. RESULTS: Here, we show that the combined use of Donepezil and Memantine significantly elevates the probability of five-year survival. In particular, their combined use increases the probability of five-year survival by 0.050 (0.021, 0.078) (6.4%), 0.049 (0.012, 0.085), (6.3%), 0.065 (0.035, 0.095) (8.3%) compared to no drug treatment, the Memantine monotherapy, and the Donepezil monotherapy respectively. We also identify a significant beneficial additive drug-drug interaction effect between Donepezil and Memantine of 0.064 (0.030, 0.098). CONCLUSIONS: Based on our findings, adopting combined treatment of Memantine and Donepezil could extend the lives of approximately 303,000 people with AD living in the USA to be beyond five-years from diagnosis. If these patients instead have no drug treatment, Memantine monotherapy or Donepezil monotherapy they would be expected to die within five years.

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. In this study, we investigated the effects of two drugs commonly prescribed to people with Alzheimer's disease called Donepezil and Memantine to see whether they had an impact on when people died. We found that the combined use of Donepezil and Memantine significantly increased the probability of a person surviving five years compared to no drug treatment or treatment with Donepezil or Memantine alone. Our results suggest that the lives of many Alzheimer's patients in the USA who are currently on no drug treatment or just Donepezil or Memantine could be extended if they were treated with both drugs simultaneously.

Heatstroke: a multicenter study in Southwestern China.

Background: An increase in Heatstroke cases occurred in southwest China in 2022 due to factors like global warming, abnormal temperature rise, insufficient power supply, and other contributing factors. This resulted in a notable rise in Heatstroke patients experiencing varying degrees of organ dysfunction. This descriptive study aims to analyze the epidemiology and clinical outcomes of Heatstroke patients in the ICU, providing support for standardized diagnosis and treatment, ultimately enhancing the prognosis of Heatstroke. Methods: A retrospective, multicenter, descriptive analysis was conducted on Heatstroke patients admitted to ICUs across 83 hospitals in southwest China. Electronic medical records were utilized for data collection, encompassing various aspects such as epidemiological factors, onset symptoms, complications, laboratory data, concurrent infections, treatments, and patient outcomes. Results: The dataset primarily comprised classic heatstroke, with 477 males (55% of total). The patient population had a median age of 72 years (range: 63-80 years). The most common initial symptoms were fever, mental or behavioral abnormalities, and fainting. ICU treatment involved respiratory support, antibiotics, sedatives, and other interventions. Among the 700 ICU admissions, 213 patients had no infection, while 487 were diagnosed with infection, predominantly lower respiratory tract infection. Patients presenting with neurological symptoms initially (n = 715) exhibited higher ICU mortality risk compared to those without neurological symptoms (n = 104), with an odds ratio of 2.382 (95% CI 1.665, 4.870) (p = 0.017). Conclusion: In 2022, the majority of Heatstroke patients in southwest China experienced classical Heatstroke, with many acquiring infections upon admission to the ICU. Moreover, Heatstroke can result in diverse complications.

Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma.

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

Development and psychometric evaluation of the death risk perception scale for advanced cancer patients.

BACKGROUND: An accurate perception of death risk is a prerequisite for advanced cancer patients to make informed end-of-life care decisions. However, there is to date no suitable scale to measure death risk perception. This study was to develop and psychometrically test the death risk perception scale (DRPS) for advanced cancer patients. METHODS: Process of instrument development and psychometric evaluation were used. First, qualitative research, a literature review, brainstorming, a Delphi study, and cognitive interviews were conducted to construct a pretest scale of death risk perception. Second, a scale-based survey was administered to 479 advanced cancer patients. Item, exploratory factor, and confirmatory factor analyses were employed to optimize the scale. The Cronbach's alpha was calculated as a reliability analysis. The validity analysis included construct, convergent, discriminant, and content validity values. RESULTS: A three-dimension, 12-item scale was developed, including deliberative, affective, and experiential risk perception. The confirmatory factor analysis supported the three-factor model with satisfactory convergent and discriminant validity levels. The Cronbach's alpha coefficient for internal consistency was 0.807 and scale-level content validity index was 0.98. CONCLUSIONS: The 12-item DRPS is a reliable and valid instrument for assessing the level of death risk perception in advanced cancer patients. More studies are needed to examine its structure and robustness prior to use.

The effects of a nurse-led discharge planning on the health outcomes of colorectal cancer patients with stomas: A randomized controlled trial.

BACKGROUND: Nursing care of colorectal cancer patients with stomas presents unique challenges, particularly during the transition from hospital to home. Early discharge programs can assist patients during this critical period. However, the effects of delivering a nurse-led discharge planning program remain under-studied. OBJECTIVE: Evaluate the effects of a nurse-led discharge planning on the quality of discharge education, stoma self-efficacy, readiness for hospital discharge, stoma quality of life, incidence of stoma complications, unplanned readmission rate, and length of stays. DESIGN: Assessor-blind parallel-arm randomized controlled trial with a repeated-measures design. SETTING(S): Participants were recruited from inpatients in the colorectal surgery unit of a university-affiliated hospital in Fujian, China. PARTICIPANTS: A total of 160 patients with colorectal cancer who received enterostomy surgery and were scheduled to be discharged to their homes. METHOD: Participants were randomly allocated to the experimental and control groups. The former received nurse-led discharge planning in addition to the usual discharge education, while the control group received only the usual discharge education. The program included an assessment, health education, stoma care, stoma support, discharge review, discharge medication and checklist integration, discharge referral, and post-hospital follow-up. Baseline data were collected prior to the intervention (T0). Data on the quality of discharge teaching, readiness for hospital discharge, stoma self-efficacy, and stoma quality of life were measured on the day of discharge from the hospital (T1). Patients' stoma self-efficacy and quality of life were repeat-measured 30 (T2) and 90 days post-discharge (T3). Data on stoma complications (T1, T2, T3), length of stays (T1), and unplanned readmission (T2, T3) were collected from medical records. RESULTS: Participants in the intervention group showed significant improvement in the quality of discharge teaching, readiness for hospital discharge, stoma self-efficacy, stoma quality of life, complications, and unplanned readmission, compared to the control group (p < 0.001). However, no statistically significant differences were observed in length of stays (p > 0.05). CONCLUSIONS: The program was effective for improving quality of discharge teaching, readiness for hospital discharge, stoma self-efficacy, and stoma quality of life, as well as for reducing complications and unplanned readmission among stoma patients. Integration of discharge planning into the usual process of care is recommended for clinical practice to facilitate a successful transition from hospital to home. REGISTRATION: This study was registered at the Chinese clinical trial registry (ChiCTR2200058756) on April 16, 2022, and participant recruitment was initiated in May 2022.

Continuous selenite biotransformation and biofuel production by marine diatom in the presence of fulvic acid.

In this study, the biochemical response of Phaeodactylum tricornutum to varying concentrations of inorganic selenium (Se) was investigated. It was observed that, when combined with fulvic acid, P. tricornutum exhibited enhanced uptake and biotransformation of inorganic Se, as well as increased microalgal lipid biosynthesis. Notably, when subjected to moderate (5 and 10 mg/L) and high (20 and 40 mg/L) concentrations of selenite under fulvic acid treatment, there was a discernible redirection of carbon flux towards lipogenesis and protein biosynthesis from carbohydrates. In addition, the key parameters of microalgae-based biofuels aligned with the necessary criteria outlined in biofuel regulations. Furthermore, the Se removal capabilities of P. tricornutum, assisted by fulvic acid, were coupled with the accumulation of substantial amounts of organic Se, specifically SeCys. These findings present a viable and successful approach to establish a microalgae-based system for Se uptake and biotransformation.

Residual graph transformer for autism spectrum disorder prediction.

Brain functional connectivity (FC) based on resting-state functional magnetic resonance imaging (rs-fMRI) has been in vogue to predict Autism Spectrum Disorder (ASD), which is a neuropsychiatric disease up the plight of locating latent biomarkers for clinical diagnosis. Albeit massive endeavors have been made, most studies are fed up with several chronic issues, such as the intractability of harnessing the interaction flourishing within brain regions, the astriction of representation due to vanishing gradient within deeper network architecture, and the poor interpretability leading to unpersuasive diagnosis. To ameliorate these issues, a FC-learned Residual Graph Transformer Network, namely RGTNet, is proposed. Specifically, we design a Graph Encoder to extract temporal-related features with long-range dependencies, from which interpretable FC matrices would be modeled. Besides, the residual trick is introduced to deepen the GCN architecture, thereby learning the higher-level information. Moreover, a novel Graph Sparse Fitting followed by weighted aggregation is proposed to ease dimensionality explosion. Empirically, the results on two types of ABIDE data sets demonstrate the meliority of RGTNet. Notably, the achieved ACC metric reaches 73.4%, overwhelming most competitors with merely 70.9% on the AAL atlas using a five-fold cross-validation policy. Moreover, the investigated biomarkers concord closely with the authoritative medical knowledge, paving a viable way for ASD-clinical diagnosis. Our code is available at https://github.com/CodeGoat24/RGTNet.

Targeting RORγ inhibits the growth and metastasis of hepatocellular carcinoma.

Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.

Existential distress and associated factors in advanced cancer patients: A cross-sectional study.

BACKGROUND: Advanced cancer patients often experience existential distress (ED). However, the factors associated with ED remain unclear. This study investigated the current state of ED and identified the associated factors in Chinese patients with advanced cancer. METHODS: A cross-sectional study was conducted among 352 advanced cancer patients from 3 tertiary hospitals in Fujian, China. Participants were invited to complete the Existential Distress Scale, Number Rating Scale, Self-Perceived Burden Scale, Quality of Life Concerns in the End-of-Life Questionnaire, and Hospital Anxiety and Depression Scale. OBJECTIVES: This study aimed to investigate the level of existential distress among advanced cancer patients in China and identify the associated factors. RESULTS: A total of 352 advanced cancer patients were recruited for this study. The average score for ED was 8.48 ± 7.12 among the advanced cancer patients. Multiple regression showed that the associated factors included depression (ß = 0.32, p = 0.000), self-perceived burden (SPB) (ß = 0.18, p = 0.001), the presence of a spouse (ß = -0.10, p = 0.050), and reception of government subsidies (ß = 0.17, p = 0.001). The factors accounted for 30.1% of the total variance in ED (F = 8.472, p < 0.001). SIGNIFICANCE OF RESULTS: Among the advanced cancer patients queried, ED was found to be positively influenced by depression, SPB, and reception of government subsidies and negatively influenced by the presence of a spouse. Depression was the most important risk factor, and thus future ED interventions should target depression.

Targeting IL-6/STAT3 signaling abrogates EGFR-TKI resistance through inhibiting Beclin-1 dependent autophagy in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is featured by notorious EGFR tyrosine kinase inhibitor (TKI) resistance attributable to activation of parallel pathways. The numerous phase I/II trials have rarely shown encouraging clinical outcomes of EGFR-TKIs during treatment in HNSCC patients with advanced tumors. A unique IL-6/STAT3 signaling axis is reported to regulate multiple cancer-related pathways, but whether this signaling is correlated with reduced EGFR-TKI responsiveness is unclear. Here, we found that STAT3 signaling is compensatorily upregulated after EGFR-TKI exposure and confers anti-EGFR therapy resistance during HNSCC therapy. Targeting STAT3 using small molecule inhibitors promotes complete recovery or sustained elimination of HNSCC tumors through combination with EGFR-TKIs both in vitro and in diverse animal models. Mechanistically, phosphorylated STAT3 was proven to enhance oncogenic autophagic flux, protecting cancer cells and preventing EGFR-TKI-induced tumor apoptosis. Thus, blockade of STAT3 signaling simultaneously disrupts several key interactions during tumor progression and remodels the autophagic degradation system, thereby rendering advanced HNSCC eradicable through combination with EGFR-TKI therapy. These findings provide a clinically actionable strategy and suggest STAT3 as a predictive biomarker with therapeutic potential for EGFR-TKI resistant HNSCC patients.

Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer.

Nuclear receptor receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor and has been established as a key player in castration-resistant prostate cancers (CRPC) by driving androgen receptor (AR) overexpression, representing a potential therapeutical target for advanced prostate cancers. Here, we report the identification of the first-in-class RORγ covalent inhibitor 29 via the structure-based drug design approach following structure-activity relationship (SAR) exploration. Mass spectrometry assay validated its covalent inhibition mechanism. Compound 29 significantly inhibited RORγ transcriptional activity and remarkably suppressed the expression levels of AR and AR-targeted genes. Compound 29 also exhibited much superior activity in inhibiting the proliferation and colony formation and inducing apoptosis of the CRPC cell lines relative to the positive control 2 and noncovalent control 33. Importantly, it markedly suppressed the tumor growth in a 22Rv1 mouse tumor xenograft model with good safety. These results clearly demonstrate that 29 is a highly potent and selective RORγ covalent inhibitor.

Next-Generation Vitrimers Design through Theoretical Understanding and Computational Simulations.

Vitrimers are an innovative class of polymers that boast a remarkable fusion of mechanical and dynamic features, complemented by the added benefit of end-of-life recyclability. This extraordinary blend of properties makes them highly attractive for a variety of applications, such as the automotive sector, soft robotics, and the aerospace industry. At their core, vitrimer materials consist of crosslinked covalent networks that have the ability to dynamically reorganize in response to external factors, including temperature changes, pressure variations, or shifts in pH levels. In this review, the aim is to delve into the latest advancements in the theoretical understanding and computational design of vitrimers. The review begins by offering an overview of the fundamental principles that underlie the behavior of these materials, encompassing their structures, dynamic behavior, and reaction mechanisms. Subsequently, recent progress in the computational design of vitrimers is explored, with a focus on the employment of molecular dynamics (MD)/Monte Carlo (MC) simulations and density functional theory (DFT) calculations. Last, the existing challenges and prospective directions for this field are critically analyzed, emphasizing the necessity for additional theoretical and computational advancements, coupled with experimental validation.