Fumonisin B1 induces endoplasmic reticulum damage and inflammation by activating the NXR response and disrupting the normal CYP450 system, leading to liver damage in juvenile quail.

Fumonisin B1 (FB1) is a mycotoxin affecting animal health through the food chain and has been closely associated with several diseases such as pulmonary edema in pigs and diarrhea in poultry. FB1 is mainly metabolized in the liver. Although a few studies have shown that FB1 causes liver damage, the molecular mechanism of liver damage is unclear. This study aimed to evaluate the role of liver damage, nuclear xenobiotic receptor (NXR) response and cytochrome P450 (CYP450)-mediated defense response during FB1 exposure. A total of 120 young quails were equally divided into two groups (control and FB1 groups). The quails in the control group were fed on a normal diet, while those in the FB1 group were fed on a quail diet containing 30 mg/kg for 42 days. Histopathological and ultrastructural changes in the liver, biochemical parameters, inflammatory factors, endoplasmic reticulum (ER) factors, NXR response and CYP450 cluster system and other related genes were examined at 14 days, 28 days and 42 days. The results showed that FB1 exposure impaired the metabolic function and caused liver injury. FB1 caused ER stress and decreased adenosine triphosphatease activity, induced the expression of inflammation-related genes such as interleukin 6 and nuclear factor kappa-B, and promoted inflammation. In addition, FB1 disrupted the expression of multiple CYP450 isoforms by activating nuclear xenobiotic receptors (NXRs). The present study confirms that FB1 exposure disturbs the homeostasis of cytochrome P450 systems (CYP450s) in quail liver by activating NXR responses and thereby causing liver damage. This study's findings provide insight into the molecular mechanisms of FB1-induced hepatotoxicity.

Peripheral biomarkers to differentiate bipolar depression from major depressive disorder: a real-world retrospective study.

BACKGROUND: Bipolar depression (BPD) is often misdiagnosed as a major depressive disorder (MDD) in clinical practice, which may be attributed to a lack of robust biomarkers indicative of differentiated diagnosis. This study analysed the differences in various hormones and inflammatory markers to explore peripheral biomarkers that differentiate BPD from MDD patients. METHODS: A total of 2,048 BPD and MDD patients were included. A panel of blood tests was performed to determine the levels of sex hormones, stress hormones, and immune-related indicators. Propensity score matching (PSM) was used to control for the effect of potential confounders between two groups and further a receiver operating characteristic (ROC) curve was used to analyse the potential biomarkers for differentiating BPD from MDD. RESULTS: Compared to patients with MDD, patients with BPD expressed a longer duration of illness, more hospitalisations within five years, and an earlier age of onset, along with fewer comorbid psychotic symptoms. In terms of biochemical parameters, MDD patients presented higher IgA and IgM levels, while BPD patients featured more elevated neutrophil and monocyte counts. ROC analysis suggested that combined biological indicators and clinical features could moderately distinguish between BPD and MDD. In addition, different biological features exist in BPD and MDD patients of different ages and sexes. CONCLUSIONS: Differential peripheral biological parameters were observed between BPD and MDD, which may be age-sex specific, and a combined diagnostic model that integrates clinical characteristics and biochemical indicators has a moderate accuracy in distinguishing BPD from MDD.

Diagnostic efficacy of ACA, aß2-GP1, hs-CRP, and Hcy for cerebral infarction and their relationship with the disease severity.

OBJECTIVE: To evaluate the diagnostic efficacy of anti-cardiolipin antibodies (ACA), anti-ß2-glycoprotein I antibodies (aß2-GP1), high-sensitivity C-reactive protein (hs-CRP), and homocysteine (Hcy) in cerebral infarction and to explore their relationship with disease severity. METHODS: Medical records of 67 cerebral infarction patients admitted from May 2020 to January 2023 and 50 healthy individuals undergoing health checkups were retrospectively analyzed. The levels of ACA, aß2-GP1, hs-CRP, and Hcy were compared, their correlation with National Institutes of Health Stroke Scale (NIHSS) scores was assessed, and their diagnostic efficacy across different disease severities were evaluated. A joint predictive score formula, defined as -6.054712173 + aß2-GP1*1.906727231 + Hcy*0.576221974, which combines aß2-GP1 and Hcy levels, was developed to assess the likelihood of cerebral infarction in our study population. RESULTS: The levels of ACA, aß2-GP1, hs-CRP and Hcy, and joint predictive score were significantly higher in the patient group (all P < 0.001). ROC analysis yielded AUCs of 0.887 for ACA, 0.894 for aß2-GP1, 0.899 for hs-CRP, 0.880 for Hcy, and 0.954 for the joint predictive score. Delong's test showed no statistical difference in most indicators compared to the joint predictive score (P > 0.05), except aß2-GP1 (P < 0.05). Pearson's correlation analysis indicated that aß2-GP1, Hcy, and the joint predictive score were positively correlated of with NIHSS score (all P < 0.05), while ACA and hs-CRP were not (P > 0.05). Notable differences in aß2-GP1 and the joint predictive score were observed among varying severity levels (P < 0.01), with the joint predictive score showing superior diagnostic efficacy in distinguishing between mild and moderate/severe cases (P < 0.01). CONCLUSION: ACA, aß2-GP1, hs-CRP, and Hcy are effective biomarkers for diagnosing cerebral infarction, and are positively correlated with disease severity. The joint predictive score demonstrates enhanced accuracy in discerning degree of severity.

STING agonist-conjugated metal-organic framework induces artificial leukocytoid structures and immune hotspots for systemic antitumor responses.

Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, by conjugating a STING agonist, 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules (artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.

Sensitivity-Enhancing Modified Holographic Photopolymer of PQ/PMMA.

Phenanthrenequinone-doped poly(methyl methacrylate) (PQ/PMMA) photopolymers are potential holographic storage media owing to their high-density storage capacities, low costs, high stability, and negligible shrinkage in volume holographic permanent memory. However, because of the limitations of the substrate, conventional Plexiglas materials do not exhibit a good performance in terms of photosensitivity and molding. In this study, the crosslinked structure of PMMA was modified by introducing a dendrimer monomer, pentaerythritol tetraacrylate (PETA), which increases the photosensitivity of the material 2 times (from ~0.58 cm/J to ~1.18 cm/J), and the diffraction efficiency is increased 1.6 times (from ~50% to ~80%). In addition, the modified material has a superior ability to mold compared to conventional materials. Moreover, the holographic performance enhancement was evaluated in conjunction with a quantum chemical analysis. The doping of PETA resulted in an overall decrease in the energy required for the reaction system of the material, and the activation energy decreased by ~0.5 KJ/mol in the photoreaction stage.

IRF8 maintains mononuclear phagocyte and neutrophil function in acute kidney injury.

Immune cells are key players in acute tissue injury and inflammation, including acute kidney injury (AKI). Their development, differentiation, activation status, and functions are mediated by a variety of transcription factors, such as interferon regulatory factor 8 (IRF8) and IRF4. We speculated that IRF8 has a pathophysiologic impact on renal immune cells in AKI and found that IRF8 is highly expressed in blood type 1 conventional dendritic cells (cDC1s), monocytes, monocyte-derived dendritic cells (moDCs) and kidney biopsies from patients with AKI. In a mouse model of ischemia‒reperfusion injury (IRI)-induced AKI, Irf8 -/- mice displayed increased tubular cell necrosis and worsened kidney dysfunction associated with the recruitment of a substantial amount of monocytes and neutrophils but defective renal infiltration of cDC1s and moDCs. Mechanistically, global Irf8 deficiency impaired moDC and cDC1 maturation and activation, as well as cDC1 proliferation, antigen uptake, and trafficking to lymphoid organs for T-cell priming in ischemic AKI. Moreover, compared with Irf8 +/+ mice, Irf8 -/- mice exhibited increased neutrophil recruitment and neutrophil extracellular trap (NET) formation following AKI. IRF8 primarily regulates cDC1 and indirectly neutrophil functions, and thereby protects mice from kidney injury and inflammation following IRI. Our results demonstrate that IRF8 plays a predominant immunoregulatory role in cDC1 function and therefore represents a potential therapeutic target in AKI.

Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis.

Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.

Quality of Life Outcomes for Parotid Malignancies.

BACKGROUND: This study describes patient-reported outcome measures (PROMs) and associated factors in patients who underwent surgery for malignant parotid tumors (MPT). METHODS: This is a retrospective study of all surgically treated MPT patients in a multidisciplinary head and neck cancer (HNC) survivorship clinic (2017-2023). PROMs included University of Washington Quality of Life Questionnaire (UW-QOL), Eating Assessment Tool (EAT-10), Patient Health Questionnaire (PHQ-8), Generalized Anxiety Disorder (GAD-7), Neck Disability Index (NDI), and Insomnia Severity Index. Multivariable regression analysis was used to investigate clinical predictors associated with PROMs. RESULTS: In 62 MPT patients, the prevalence of clinically relevant dysphagia symptoms (EAT-10), elevated symptoms of depression (PHQ-8), moderate/severe symptoms of anxiety (GAD-7), moderate/severe neck pain with activities of daily living (NDI), and moderate/severe symptoms of insomnia at last follow-up was 32.3%, 15.5%, 7.1%, 17.7%, and 7.2%, respectively. Nonparametric one-sided test revealed that patients treated with adjuvant CRT had significantly worse physical QOL, social-emotional QOL, and swallowing scores than patients treated with surgery alone (p = 0.01, p = 0.02, p = 0.03, respectively); that patients treated with surgery and adjuvant RT had significantly worse physical QOL and social-emotional QOL than patients treated with surgery alone (p < 0.01, p = 0.01, respectively) and that patients treated with surgery and adjuvant CRT had significantly worse swallowing and neck pain than patients treated with surgery and adjuvant RT (p = 0.03, p = 0.05, respectively). CONCLUSIONS: In patients with surgically treated MPT, adjuvant CRT and RT were associated with worse PROMs. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Simultaneous Protonation and Metalation of a Porphyrin Covalent Organic Framework Enhance Photodynamic Therapy.

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

Anti-phasic oscillatory development for speech and noise processing in cochlear implanted toddlers.

Human brain demonstrates amazing readiness for speech and language learning at birth, but the auditory development preceding such readiness remains unknown. Cochlear implanted (CI) children (n = 67; mean age 2.77 year ± 1.31 SD; 28 females) with prelingual deafness provide a unique opportunity to study this stage. Using functional near-infrared spectroscopy, it was revealed that the brain of CI children was irresponsive to sounds at CI hearing onset. With increasing CI experiences up to 32 months, the brain demonstrated function, region and hemisphere specific development. Most strikingly, the left anterior temporal lobe showed an oscillatory trajectory, changing in opposite phases for speech and noise. The study provides the first longitudinal brain imaging evidence for early auditory development preceding speech acquisition.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

The platform business model selection of online ride-hailing giants based on the aggregation model.

Pure self-management model, pure aggregation business model and Self-support + aggregation model are three commonly used business modes on ride-hailing platforms. We use an analytical model to study these three business models and give the optimal business model decision of the platform. The research shows that the heterogeneity ratio of drivers, the cost of the platform under the Self-support model, the franchise fee received by the platform under the aggregation model and the dissatisfaction of the original users on the platform play a key role in the selection of the platform's business model. When the difference between the franchise fee under the aggregation mode and the platform cost under the Self-support mode fails to generate positive feedback on the platform profit, the platform should choose the pure Self-support mode. When riders are more sensitive to the heterogeneity of service quality of the platform and user stickiness can be ensured, the platform should choose the pure aggregation business model. When user stickiness can be guaranteed and the cost of the platform under the self-run model is controllable, the platform should choose the Self-support + aggregation business model.

Functional study of the soybean stamen-preferentially expressed gene GmFLA22a in regulating male fertility.

China has a high dependence on soybean imports, yield increase at a faster rate is an urgent problem that need to be solved at present. The application of heterosis is one of the effective ways to significantly increase crop yield. In recent years, the development of an intelligent male sterility system based on recessive nuclear sterile genes has provided a potential solution for rapidly harnessing the heterosis in soybean. However, research on male sterility genes in soybean has been lagged behind. Based on transcriptome data of soybean floral organs in our research group, a soybean stamen-preferentially expressed gene GmFLA22a was identified. It encodes a fasciclin-like arabinogalactan protein with the FAS1 domain, and subcellular localization studies revealed that it may play roles in the endoplasmic reticulum. Take advantage of the gene editing technology, the Gmfla22a mutant was generated in this study. However, there was a significant reduction in the seed-setting rate in the mutant plants at the reproductive growth stage. The pollen viability and germination rate of Gmfla22a mutant plants showed no apparent abnormalities. Histological staining demonstrated that the release of pollen grains in the mutant plants was delayed and incomplete, which may due to the locule wall thickening in the anther development. This could be the reason of the reduced seed-setting rate in Gmfla22a mutants. In summary, our study has preliminarily revealed that GmFLA22a may be involved in regulating soybean male fertility. It provides crucial genetic materials for further uncovering its molecular function and gene resources and theoretical basis for the utilization of heterosis in soybean.

DNA adductomics aided rapid screening of genotoxic impurities using nucleosides and 3D bioprinted human liver organoids.

Current genotoxicity assessment methods are mainly employed to verify the genotoxic safety of drugs, but do not allow for rapid screening of specific genotoxic impurities (GTIs). In this study, a new approach for the recognition of GTIs has been proposed. It is to expose the complex samples to an in vitro nucleoside incubation model, and then draw complete DNA adduct profiles to infer the structures of potential genotoxic impurities (PGIs). Subsequently, the genotoxicity is confirmed in human by 3D bioprinted human liver organoids. To verify the feasibility of the approach, lansoprazole chloride compound (Lanchlor), a PGI during the synthesis of lansoprazole, was selected as the model drug. After confirming genotoxicity by Comet assay, it was exposed to different models to map and compare the DNA adduct profiles by LC-MS/MS. The results showed Lanchlor could generate diverse DNA adducts, revealing firstly its genotoxicity at molecular mechanism of action. Furthermore, the largest variety and content of DNA adducts were observed in the nucleoside incubation model, while the human liver organoids exhibited similar results with rats. The results showed that the combination of DNA adductomics and 3D bioprinted organoids were useful for the rapid screening of GTIs.

Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin­mediated NLRP3 inflammasome activation.

Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)-treated HK-2 cells and murine peritoneal-derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase-1 and maturation of IL-1ß by suppressing NLRP3 inflammasome activation in H/R-treated HK-2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin-mediated activation of the NLRP3 inflammasome.

Prognostic Factors and Outcomes Associated With Neck Lymphedema in Head and Neck Cancer Survivors.

OBJECTIVES: The purpose of this study is to determine the predictors of neck lymphedema and to explore its association with symptoms and patient-reported outcomes (PROs) in Head and Neck Cancer (HNC) patients who underwent non-operative treatment. METHODS: This study involved a cross-sectional secondary analysis of data from patients diagnosed with head and neck squamous cell carcinoma who underwent radiation therapy (±chemotherapy). Patients with visits <6 weeks or >2 years following completion of radiation and those with recurrent or metastatic cancer were excluded. Presence of post-treatment lymphedema, demographics, clinical characteristics, health-related behaviors, and symptoms were collected. PROs were obtained using validated questionnaires that assessed depression, anxiety, swallowing dysfunction, and quality of life (QOL). Multivariable regression models were used to examine the relationship between lymphedema with predictors and symptoms. RESULTS: Of the 203 patients included, 88 (43.4%) developed post-treatment lymphedema. In multivariable analysis, pre-treatment Body Mass Index (BMI) (odds ratio [OR] = 1.07, 95% confidence interval [CI] [1.01, 1.14] p = 0.016) and N stage (OR = 1.96, 95% CI [1.06, 3.66], p = 0.032) were found to be independently associated with lymphedema. Regarding PROs, lymphedema was associated with greater swallowing dysfunction (3.48, 95% CI [0.20, 6.75], p = 0.038), decreased mouth opening (-3.70, 95% CI [-7.31, -0.10], p = 0.044), and increased fatigue (1.88, 95% CI [1.05, 3.38], p = 0.034). CONCLUSION: Higher pre-treatment BMI and greater N stage are identified as independent predictors for lymphedema development in non-operative HNC patients. Additionally, patients experiencing lymphedema reported worsening swallowing dysfunction and increased symptoms related to trismus and fatigue. Recognizing patients at elevated risk for lymphedema allows for early intervention, alleviation of symptom burden, and optimization of health care resources. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3656-3663, 2024.

Neighborhood Deprivation and Symptoms, Psychological Distress, and Quality of Life Among Head and Neck Cancer Survivors.

Importance: Socioeconomic deprivation is associated with increased risk of poor health and quality-of-life (QOL) outcomes in head and neck cancer (HNC) survivors. However, there are few data on how neighborhood deprivation affects patient-reported outcome measures (PROMs) in HNC survivors. Objective: To investigate whether neighborhood socioeconomic deprivation is associated with symptom burden, psychological distress, and QOL among HNC survivors. Design, Setting, and Participants: This cross-sectional study used prospectively collected data from patients seen in a university-affiliated multidisciplinary HNC survivorship clinic between September 2018 and September 2021 who received radiotherapy for squamous cell carcinoma of the oral cavity, oropharynx, and larynx or hypopharynx. Exposure: Neighborhood socioeconomic deprivation, measured using the Area Deprivation Index (ADI). Main Outcomes and Measures: The PROMs pertaining to symptom burden and severity of psychological distress were measured using the Neck Disability Index, Insomnia Severity Index, the 10-item Eating Assessment Tool, the Generalized Anxiety Disorder 7-item scale, and the 8-item Patient Health Questionnaire. Physical and social-emotional QOL were obtained using the University of Washington QOL questionnaire. Multivariable linear regression analysis adjusting for individual-level sociodemographic, comorbidity, and treatment characteristics investigated the association between ADI and PROMs. A subgroup analysis was performed to compare the lowest (most affluent areas: ADI, 0%-20%) and highest (most deprived areas: ADI, 80%-100%) ADI quintiles. Results: A total of 277 patients were included in the final analysis (mean [SD] age, 64.18 [9.60] years; 215 [77.6%] male). Cancer sites were the oral cavity (52 [18.8%]), oropharyngeal area (171 [61.7%]), and larynx or hypopharynx (54 [19.5%]). Multivariable analysis showed that for every 1-point increase in ADI, social-emotional QOL changed by -0.14 points (95% CI, -0.24 to -0.05 points), anxiety increased by 0.03 points (95% CI, 0.01-0.06 points), and neck disability worsened by 0.05 points (95% CI, 0.01-0.10 points). Compared with patients in the most affluent areas, those in the most deprived areas had significantly lower physical (-15.89 points; 95% CI, -25.96 to -2.31 points; Cohen d = -0.83) and social-emotional (-13.57 points; 95% CI, -22.79 to -3.49 points; Cohen d = -0.69) QOL and higher depression (2.60 points; 95% CI, 0.21-4.40 points; Cohen d = 0.52), anxiety (3.12 points; 95% CI, 1.56-4.66 points; Cohen d = 0.61), insomnia (3.55 points; 95% CI, 0.33-6.41 points; Cohen d = 0.54), and neck disability (5.65 points; 95% CI, 1.66-9.55 points; Cohen d = 0.66) scores. Conclusions and Relevance: In this cross-sectional study, a higher ADI score was associated with higher risk of increased psychological distress, higher symptom burden, and decreased QOL after treatment among HNC survivors. These findings suggest that proactive, patient-centered interventions are needed to address these disparities.

Spin effect on redox acceleration and regioselectivity in Fe-catalyzed alkyne hydrosilylation.

Iron catalysts are ideal transition metal catalysts because of the Earths abundant, cheap, biocompatible features of iron salts. Iron catalysts often have unique open-shell structures that easily undergo spin crossover in chemical transformations, a feature rarely found in noble metal catalysts. Unfortunately, little is known currently about how the open-shell structure and spin crossover affect the reactivity and selectivity of iron catalysts, which makes the development of iron catalysts a low efficient trial-and-error program. In this paper, a combination of experiments and theoretical calculations revealed that the iron-catalyzed hydrosilylation of alkynes is typical spin-crossover catalysis. Deep insight into the electronic structures of a set of well-defined open-shell active formal Fe(0) catalysts revealed that the spin-delocalization between the iron center and the 1,10-phenanthroline ligand effectively regulates the iron center's spin and oxidation state to meet the opposite electrostatic requirements of oxidative addition and reductive elimination, respectively, and the spin crossover is essential for this electron transfer process. The triplet transition state was essential for achieving high regioselectivity through tuning the nonbonding interactions. These findings provide an important reference for understanding the effect of catalyst spin state on reaction. It is inspiring for the development of iron catalysts and other Earth-abundant metal catalysts, especially from the point of view of ligand development.

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.