Synthesis and optical properties of tyramine-functionalized boron dipyrromethene dyes for cell bioimaging.

Tyramine signaling amplification (TSA) technology is generally applied in immunofluorescence, enzyme-linked immunoassays, in situ hybridization techniques, etc. Successful amplification of fluoresence signals cannot be achieved without excellent fluorescent dyes. BODIPY fluorophore is an ideal probe for cell fluorescence imaging, but pristine BODIPY cannot be direct used in the TSA system. In the paper, the new red-shifted tyramide-conjugated BODIPY (BDP-B/C/D) was synthesized via the Knoevenagel condensation reaction, which based on the tyramide-conjugated BODIPY (BDP-A). The synthesized dyes were combined with tyramine to obtain which could be used as a fluorescent substrate for enzymatic reaction of TSA. By using the selected substrate (BDP-C) in TSA, we found it to be more sensitive than the commercial dye 594 styramide for the detection of low-abundance antigen proteins.

Magnesium-promoted nickel-catalysed chlorination of aryl halides and triflates under mild conditions.

In this study, we present a ligand-free nickel(II)-catalyzed halogen exchange of aromatic halides with magnesium chloride. This method effectively facilitates the retro-Finkelstein reaction for a wide range of aryl bromides, iodides and triflates, demonstrating excellent functional group tolerance. Mechanistic studies reveal that magnesium plays a crucial role in the challenging reductive elimination from Ni(II) intermediates.

Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study.

Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.

Beyond the Liver: Neurologic Manifestations of Alcohol Use.

Alcohol use, while commonly associated with liver damage, also has significant neurologic implications, which often mimic hepatic encephalopathy and complicate diagnosis and management. Alcohol mediates its acute central nervous system effects by altering neurotransmitter balance, notably between gamma-aminobutyric acid and glutamate. Its chronic neurotoxicity, compounded by thiamine deficiency, results in chronic neurologic complications. Clinically, alcohol-related neurologic disorders present a spectrum from acute intoxication and withdrawal to chronic conditions like Korsakoff syndrome, dementia, cerebellar degeneration, and peripheral neuropathy. This review underscores differentiating these conditions from hepatic encephalopathy and highlights the importance of history-taking and physical examination in clinical practice.

Predicting the severity of mycoplasma pneumoniae pneumonia in pediatric and adult patients: a multicenter study.

The purpose of this study is to develop a nomogram model for early prediction of the severe mycoplasma pneumoniae pneumonia (SMPP) in Pediatric and Adult Patients. A retrospective analysis was conducted on patients with MPP, classifying them into SMPP and non-severe MPP (NSMPP) groups. A total of 550 patients (NSMPP 374 and SMPP 176) were enrolled in the study and allocated to training, validation cohorts. 278 patients (NSMPP 224 and SMPP 54) were retrospectively collected from two institutions and allocated to testing cohort. The risk factors for SMPP were identified using univariate analysis. For radiomic feature selection, Spearman's correlation and the least absolute shrinkage and selection operator (LASSO) were utilized. Logistic regression was used to build different models, including clinical, imaging, radiomics, and integrated models (combining clinical, imaging, and radiomics features selected). The model's discrimination was evaluated using a receiver operating characteristic curve, its calibration with a calibration curve, and the results were visualized using the Hosmer-Lemeshow goodness-of-fit test. Thirteen clinical features and fourteen imaging features were selected for constructing the clinical and imaging models. Simultaneously, a set of twenty-five radiomics features were utilized to build the radiomics model. The integrated model demonstrated good calibration and discrimination in the training cohorts (AUC, 0.922; 95% CI: 0.900, 0.942), validation cohorts (AUC, 0.879; 95% CI: 0.806, 0.920), and testing cohorts (AUC, 0.877; 95% CI: 0.836, 0.916). The discriminatory and predictive efficacy of the clinical model in testing cohorts increased further after clinical and radiological features were incorporated (AUC, 0.849 vs. 0.922, P = 0.002). The model demonstrated exemplary predictive efficacy for SMPP by leveraging a comprehensive set of inputs, encompassing clinical data, quantitative and qualitative radiological features, along with radiomics features. The integration of these three aspects in the predictive model further enhanced the performance of the clinical model, indicating the potential for extensive clinical applications.

New insights on the phylogeny, evolutionary history, and ecological adaptation mechanism in cycle-cup oaks based on chloroplast genomes.

Cycle-cup oaks (Quercus section Cyclobalanopsis) are one of the principal components of forests in the tropical and subtropical climates of East and Southeast Asia. They have experienced relatively recent increases in the diversification rate, driven by changing climates and the Himalayan orogeny. However, the evolutionary history and adaptive mechanisms at the chloroplast genome level in cycle-cup oaks remain largely unknown. Therefore, we studied this problem by conducting chloroplast genomics on 50 of the ca. 90 species. Comparative genomics and other analyses showed that Quercus section Cyclobalanopsis had a highly conserved chloroplast genome structure. Highly divergent regions, such as the ndhF and ycf1 gene regions and the petN-psbM and rpoB-trnC-GCA intergenic spacer regions, provided potential molecular markers for subsequent analysis. The chloroplast phylogenomic tree indicated that Quercus section Cyclobalanopsis was not monophyletic, which mixed with the other two sections of subgenus Cerris. The reconstruction of ancestral aera inferred that Palaeotropics was the most likely ancestral range of Quercus section Cyclobalanopsis, and then dispersed to Sino-Japan and Sino-Himalaya. Positive selection analysis showed that the photosystem genes had the lowest ω values among the seven functional gene groups. And nine protein-coding genes containing sites for positive selection: ndhA, ndhD, ndhF, ndhH, rbcL, rpl32, accD, ycf1, and ycf2. This series of analyses together revealed the phylogeny, evolutionary history, and ecological adaptation mechanism of the chloroplast genome of Quercus section Cyclobalanopsis in the long river of earth history. These chloroplast genome data provide valuable information for deep insights into phylogenetic relationships and intraspecific diversity in Quercus.

SOX4 promotes vascular abnormality in glioblastoma and is a novel target to improve drug delivery.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with dismal prognosis. Vascular abnormality is a hallmark of GBM, and aggravates diseases progression by increasing hypoxia, inducing life-threaten edema and hindering drug delivery. Nonetheless, the intricate mechanism underlying vascular abnormality remains inadequately understood. Here, we revealed a key role of SOX4 on vascular abnormality in GBM. SOX4 expression was increased in endothelial cells (ECs) from human brain tumors compared with ECs from paired normal brain tissue. Knockdown of SOX4 in mouse brain ECs restrained cell migration and proliferation. Furthermore, in vitro suppression of SOX4 in brain ECs and in vivo conditional knockout of SOX4 in tumor ECs led to the downregulation of genes linked with vascular abnormality. Notably, specific depletion of SOX4 in ECs enhanced drug delivery and sensitive tumor to chemotherapeutic drugs in GBM. Taken together, these results demonstrated that SOX4 is a novel regulator for tumor angiogenesis and vascular abnormality in GBM. Our findings identify SOX4 as a potential vascular therapeutic target to improve drug delivery for GBM treatment.

Efficacy and safety of concurrent chemoradiotherapy with paclitaxel-based or S-1 regimens in treating elderly patients with esophageal squamous cell carcinoma: A multi-center propensity-score matched study.

BACKGROUND: Elderly patients with esophageal cancer can benefit from concurrent chemoradiotherapy (CCRT). However, the optimal concurrent chemotherapy regimen remains undetermined. We aimed to compare the efficacy and safety of CCRT with paclitaxel-based or S-1 regimens in treating elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: From January 2016 to November 2022, a total of 349 patients aged 70 and above with ESCC were included. The patient population was divided into two treatment groups: patients receiving paclitaxel-based CCRT were allocated to the TP group, and those receiving S-1 regimen CCRT were allocated to the S-1 group. Propensity score matching (PSM) was used to balance potential biases. Survival outcomes, overall response rate, and treatment-related toxicities were assessed. RESULTS: After PSM, there were 82 patients in each group. The median follow up of the surviving patients was 42.6 months (IQR 28.0-58.8 months). The 2-year overall survival (OS) rate (71.4% vs 65.4%; log-rank P = 0.010) and progression-free survival (PFS) rate (64.4% vs 58.0%; log-rank P = 0.048) were significantly higher in the TP group. Compared with the S-1 group, the TP group experienced a higher rate of grade 3 and above hematologic toxicities, such as leukopenia (47.6% vs 15.9%, P < 0.001) and neutropenia (35.4% vs 6.1%, P < 0.001). One patient in the TP group and two patients in the S-1 group had grade 5 toxic effects. CONCLUSIONS: Our findings suggest that paclitaxel-based CCRT was well tolerated in elderly patients with ESCC and provided significant survival benefits over S-1 regimen.

Bimetal Fluorides with Adjustable Vacancy Concentration Reinforcing Ion Transport in Poly(ethylene oxide) Electrolyte.

The poor ambient ionic transport properties of poly(ethylene oxide) (PEO)-based SPEs can be greatly improved through filler introduction. Metal fluorides are effective in promoting the dissociation of lithium salts via the establishment of the Li-F bond. However, too strong Li-F interaction would impair the fast migration of lithium ions. Herein, magnesium aluminum fluoride (MAF) fillers are developed. Experimental and simulation results reveal that the Li-F bond strength could be readily altered by changing fluorine vacancy (VF) concentration in the MAF, and lithium salt anions can also be well immobilized, which realizes a balance between the dissociation degree of lithium salts and fast transport of lithium ions. Consequently, the Li symmetric cells cycle stably for more than 1400 h at 0.1 mA cm-2 with a LiF/Li3N-rich solid electrolyte interphase (SEI). The SPE exhibits a high ionic conductivity (0.5 mS cm-1) and large lithium-ion transference number (0.4), as well as high mechanical strength owing to the hydrogen bonding between MAF and PEO. The corresponding Li//LiFePO4 cells deliver a high discharge capacity of 160.1 mAh g-1 at 1 C and excellent cycling stability with 100.2 mAh g-1 retaining after 1000 cycles. The as-assembled pouch cells show excellent electrochemical stability even at rigorous conditions, demonstrating high safety and practicability.

Harnessing immune cells to leverage PARP inhibitors.

Homologous-recombination deficiency in DNA repair characterizes a unique group of cancers that are vulnerable to PARP inhibitors and cytotoxic chemotherapy. In this issue of Cell, Luo et al., demonstrated that this genetic attribute in cancer cells may reprogram tumor immune microenvironment and show promise of targeting effector-Treg cells.

Primary signet-ring cell carcinoma of the urinary bladder ‒ A rare bladder tumor.

AIM: Primary Signet Ring Cell Carcinoma (SRCC) of the bladder accounts for only 1%‒4% of all bladder malignancies. To date, few studies have been conducted to investigate the characteristics of SRCC. This study aimed to investigate the clinical features and treatments of SRCC and explore the independent risk factors of survival in SRCC patients. PATIENTS AND METHODS: A retrospective study was conducted on 32 eligible patients. The survival rate was calculated with the Kaplan-Meier method, and the COX proportional hazards model was used to investigate the independent risk factors of prognosis. RESULTS: In the present study, the 1-year and 2-year survival rates of SRCC patients were 53.1% and 9.4%, respectively. The TNM stage, tumor differentiation, and metastasis after treatment were risk factors for the prognosis of SRCC patients (p < 0.05), while surgical treatment, chemotherapy, and positive GATA3 expression were protective for prognosis (p < 0.05). Multivariate analysis showed that GATA3 was an independent protective factor for prognosis (p < 0.05), and T-stage was an independent risk factor (p < 0.05). CONCLUSIONS: Primary SRCC of the bladder is highly malignant and has a poor prognosis. Its clinical and imaging findings are usually non-specific. Early radical cystectomy and postoperative adjuvant systemic chemotherapy are helpful to improve the survival rate. T-stage is an independent risk factor for survival, and positive GATA3 expression is protective for primary SRCC of the bladder.

The Impact of Gamified Smartphone App Interventions on Behaviour and Metabolic Outcomes in Individuals at Risk of Cardiovascular Disease.

This study examines gamified smartphone app interventions for improving lifestyle choices and cardiometabolic health in adults at risk for cardiovascular disease. A systematic review of six databases compared gamified interventions with conventional methods. Despite a functionality rating of 4.07, user engagement was lacking. Findings suggest that incorporating game elements into health apps can promote lifestyle changes and improve cardiometabolic health, guiding future digital health strategies to reduce cardiovascular disease risk.

[Characteristics, Sources Analysis, and Environmental Impacts of VOCs Based on Photochemical Loss in Summer in Zhengzhou].

To clarify the pollution characteristics and sources of atmospheric VOCs in Zhengzhou City in the summer, multi-site offline sampling and laboratory analyses of atmospheric VOCs in Zhengzhou were carried out in August 2022. The observed and initial VOC volume fraction levels, OFP, SOAFP, and sources were compared. During the study period, the average values of three-site observation and initial φ（VOCs） during the study period were （31.83 ±13.51）×10-9 and （35.92 ±15.30）×10-9,respectively. Olefins （52.5 %） and aromatic hydrocarbons （29.7 %） were the components with a higher photochemical loss rate, and the spatial variations of the observed TVOCs concentration at each site were： Zhengzhou University （ZZU） > Gangli Reservoir （GLR） > Jingkaiqu （JKQ）, and the concentrations of alkanes and OVOCs at each site were higher. Olefins and aromatic hydrocarbons were the components that contributed greatly to the formation of O3 and SOA. Motor vehicle sources, solvent-use sources, and industrial sources were the main contributing sources of atmospheric VOCs in Zhengzhou. Compared with the source analysis results based on the initial concentration, the contribution rates of motor vehicle sources, industrial sources, and solvent use sources were relatively high, and the contribution rates of combustion sources, plant sources, and oil and gas volatilization sources were relatively low.

Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression.

Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation. While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an anti-tumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and FDA-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mTOR inhibitor, its ferroptosis-inducing effect is primarily attributed to its inhibition of FSP1 rather than mTOR activity. By performing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multi-target ferroptosis-inducing agents to circumvent resistance to ferroptosis in liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

OBJECTIVE: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. METHODS: Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. RESULTS: We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. INTERPRETATION: Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024.

[Effects of different genotypes soybean and maize intercropping on soil phosphorus fractions and crop phosphorus uptake]. / ä¸åŒåŸºå› åž‹å¤§è±†ä¸ŽçŽ‰ç±³é—´ä½œå¯¹åœŸå£¤ç£·ç»„åˆ†ä¸Žä½œç‰©ç£·å¸æ”¶çš„å½±å“.

Reasonable soybean-maize intercropping mode can effectively promote soil phosphorus turnover and crop phosphorus absorption, and reduce phosphorus fertilizer input. To optimize phosphorus (P)-use efficiency in soybean/maize intercropping system, we intercropped two genotypes of soybean with maize to investigate the rhizosphere processes and mechanisms underlying soil biological P fractions and crop P uptake. The results showed that intercropping significantly depleted the rhizosphere soluble inorganic P (CaCl2-P) content in soybean genotype Yuechun 03-3, without impact on the P fractions in the rhizosphere of soybean Essex. Similarly, intercropping significantly increased biomass and P uptake of soybean genotype Yuechun 03-3 by 42.2% and 46.9%, respectively, compared to monoculture. However, it did not affect P uptake and biomass of soybean Essex and maize. Intercropping significantly increased both the total root length and the quantity of root exudates in Yuechun 03-3 by 19.7% and 138.1%, respectively. There was a significant positive correlation between P uptake and total root length in Yuechun 03-3, while a significant negative correlation between soluble inorganic P content and P uptake. In summary, intercropping of soybean and maize exhibited noticeable genotype differences in its impact on soil P fractions and crop P uptake. Intercropping has the potential to improve soybean P uptake and rhizosphere P turnover, mainly by increasing root length and root exudates of P-efficient genotype. The study would provide scientific evidence for optimizing the pairing of soybean and maize varieties in intercropping systems, thereby enhancing phosphorus utilization efficiency and reducing fertilizer inputs.

Supplementation with dimethylglycine sodium salt improves lipid metabolism disorder in intrauterine growth-retarded pigs.

This study aims to elucidate the mechanism of lipid metabolism disorder in intrauterine growth retardation (IUGR) pigs and the potential alleviating effects of dimethylglycine sodium salt (DMG-Na). A total of 60 male newborn piglets were selected for this study. Within each litter, one normal birth weight (NBW) male piglet (1.53 ± 0.04 kg) and two IUGR male piglets (0.76 ± 0.06 kg) were chosen based on their birth weight. The piglets were divided into three groups for the study: NBW pigs received a PBS gavage and a common basal diet (NBW-C group), IUGR pigs received the same PBS gavage and common basal diet (IUGR-C group), and IUGR pigs received a 70-mg DMG-Na gavage along with a common basal diet supplemented with 0.1% DMG-Na (IUGR-D group). At 150 d of age, all piglets underwent euthanasia by exsanguination following electrical stunning, after which plasma, liver, and longissimus dorsi (LM) samples were promptly collected. The IUGR-D group demonstrated improvements in plasma parameters (P < 0.05), with lower triglyceride and free fatty acid (FFA) values, and hormone levels (P < 0.05), with lower growth hormone, insulin, and homeostasis model assessment of insulin resistance values. Restoration of lipid metabolism was observed (P < 0.05), with lower triglyceride and FFA, and higher hepatic lipase and total lipase values in the liver, and lower triglyceride and FFA values in the LM. Mitochondrial ETC complexes showed increased levels (P < 0.05), including higher complex III values in the liver, and higher complex I, complex III, and complex V values in the LM. Enhanced levels of energy metabolites were noted (P < 0.05), with higher NAD+, NAD+/NADH, adenosine triphosphate, and mtDNA values, and lower NADH values in the liver and LM. Additionally, meat quality parameters showed improvement (P < 0.05), with higher pH 24 h and a∗ values, and lower drip loss 48 h, L∗, and b∗ values. The expressions of lipid metabolism and mitochondrial function-related genes and proteins were upregulated (P < 0.05) compared to the IUGR-C group. In conclusion, it was indicated that IUGR pigs experienced lipid metabolism disorders and diminished performance. However, supplementation with DMG-Na showed promise in mitigating these adverse physiological effects by safeguarding body tissues and modulating energy metabolism.

ALTMAN: A Novel Method for Cell Cycle Analysis.

Accurate analysis of S-phase fraction is crucial for the assessment of cell proliferation levels, tumor malignancy and prognostic effects of treatment. Most of the currently developed methods for S-phase cell analysis rely on flow cytometric analysis of DNA content determination. However, the lack of standardized procedures for sample analysis and interpretation of cell cycle fitting graphs poses a significant limitation in clinical practice for utilizing flow cytometry to measure the cell cycle based on DNA content. Herein, we developed an approach for analyzing S-phase cells based on telomerase activity determination. Briefly, this approach distinguishes S-phase cells in cell populations via direct fluorescence tracking of telomerase activity within individual cells. The dynamic analysis of telomerase activity in different cell cycles was made possible by the ALTMAN strategy developed in our previous studies, which has been successfully employed to distinguish S-phase cells in cultured cells. This method offers a novel avenue for the assessment of cell cycle status and the evaluation of the proliferation status of tumor cells and the prognosis effect of tumor patients via analyzing the differences in telomerase activity during different cell cycle processes.

Beyond weight loss: the potential of glucagon-like peptide-1 receptor agonists for treating heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various phenotypes, and obesity is one of the most common and clinically relevant phenotypes of HFpEF. Obesity contributes to HFpEF through multiple mechanisms, including sodium retention, neurohormonal dysregulation, altered energy substrate metabolism, expansion of visceral adipose tissue, and low-grade systemic inflammation. Glucagon-like peptide-1 (GLP-1) is a hormone in the incretin family. It is produced by specialized cells called neuroendocrine L cells located in the distal ileum and colon. GLP-1 reduces blood glucose levels by promoting glucose-dependent insulin secretion from pancreatic ß cells, suppressing glucagon release from pancreatic α cells, and blocking hepatic gluconeogenesis. Recent evidence suggests that GLP-1 receptor agonists (GLP-1 RAs) can significantly improve physical activity limitations and exercise capacity in obese patients with HFpEF. The possible cardioprotective mechanisms of GLP-1 RAs include reducing epicardial fat tissue thickness, preventing activation of the renin-angiotensin-aldosterone system, improving myocardial energy metabolism, reducing systemic inflammation and cardiac oxidative stress, and delaying the progression of atherosclerosis. This review examines the impact of obesity on the underlying mechanisms of HFpEF, summarizes the trial data on cardiovascular outcomes of GLP-1 RAs in patients with type 2 diabetes mellitus, and highlights the potential cardioprotective mechanisms of GLP-1 RAs to give a pathophysiological and clinical rationale for using GLP-1 RAs in obese HFpEF patients.

Patterns of treatment failure in patients with sinonasal squamous cell carcinoma after chemoradiotherapy.

OBJECTIVE: To investigate the failure patterns based on precision radiation treatment and to determine the predictive factors of treatment failure for sinonasal squamous cell carcinoma (SNSCC) patients. MATERIALS: This was a retrospective study that included 214 cases of treatment failure from 441 consecutive patients. Two experienced radiation oncologists evaluated the tumor volume of cases with local recurrence. The 5-year overall survival (OS), progression-free survival rates (PFS), and distant-metastasis-free survival (DMFS) were estimated. Investigations were performed on the factors that predicted local failure or distant metastasis. RESULTS: 140 (31.7%) patients developed local recurrence, 24 (5.4%) experienced regional failure, and 65 (14.7%) underwent distant metastasis. In-field, marginal, and out-of-field failures occurred in 55.7% (78/140), 33.6% (47/140), and 10.7% (15/140) of patients with local recurrence, respectively. In logistic regression analysis, factors statistically significant for total local failure included treatment mode (p < 0.01), chemotherapy (p < 0.01), and surgical margins (p < 0.01). Primary tumors with poor differentiation (p = 0.018) and R2 resection margin (p = 0.009) were more prone to develop distant failure. The 5-year OS, PFS, and DMFS rates were 57.8%, 52.0%, and 56.7% for the whole cohort. In univariate and multivariate analysis, the skull base involvement was an independent predictor for poorer OS and PFS; orbital invasion was an independent predictor for poorer OS. CONCLUSIONS: Local recurrence and distant metastasis were the most common failure modes. Treatment mode, chemotherapy, and surgical margins were related to local recurrence. Poor differentiation and R2 resection margin were predictors for distant failure. ADVANCE IN KNOWLEDGE: Local recurrence is the most common failure pattern in patients with sinonasal squamous cell carcinoma who accepted chemoradiotherapy, and marginal and out-of-field failures occurred in 44.3% of patients with local recurrence.