Using empirical dynamic modeling to identify the impact of meteorological factors on hemorrhagic fever with renal syndrome in Weifang, Northeastern China, from 2011 to 2020.

BACKGROUND: Renal Syndrome Hemorrhagic Fever (HFRS) continues to pose a significant public health threat to the well-being of the population. Given that the spread of HFRS is susceptible to meteorological factors, we aim to probe into the meteorological drivers of HFRS. Thus, novel techniques that can discern time-delayed non-linear relationships from nonlinear dynamical systems are compulsory. METHODS: We analyze the epidemiological features of HFRS in Weifang City, 2011-2020, via the employment of the Empirical Dynamic Modeling (EDM) method. Our analysis delves into the intricate web of time-delayed non-linear associations between meteorological factors and HFRS. Additionally, we investigate the repercussions of minor perturbations in meteorological variables on future HFRS incidence. RESULTS: A total of 2515 HFRS cases were reported in Weifang from 2011 to 2020. The average weekly incidence was 4.81, and the average weekly incidence was 0.52 per 1,000,000. The propagation of HFRS is significantly impacted by the mean weekly temperature, relative humidity, cumulative rainfall, and wind speed, and the ρCCM converges to 0.55,0.48,0.38 and 0.39, respectively. The graphical representation of the relationship between temperature (lagged by 2 weeks) and the incidence of HFRS exhibits an inverted U-shaped curve, whereby the incidence of HFRS culminates as the temperature reaches 10 °C. Moreover, temperature, relative humidity, cumulative rainfall, and wind speed exhibit a positive correlation with HFRS incidence, with a time lag of 4-6 months. CONCLUSIONS: Our discoveries suggest that meteorological factors can drive the transmission of HFRS both at a macroscopic and microscopic scale. Prospective alterations in meteorological conditions, for instance, elevations in temperature, relative humidity, and precipitation will instigate an upsurge in the incidence of HFRS after 4-6 months, and thus, timely public health measures should be taken to mitigate these changes.

Patterns and correlates of potential range shifts of bat species in China in the context of climate change.

Climate change may diminish biodiversity; thus, it is urgent to predict how species' ranges may shift in the future by integrating multiple factors involving more taxa. Bats are particularly sensitive to climate change due to their high surface-to-volume ratio. However, few studies have considered geographic variables associated with roost availability and even fewer have linked the distributions of bats to their thermoregulation and energy regulation traits. We used species distribution models to predict the potential distributions of 12 bat species in China under current and future greenhouse gas emission scenarios (SSP1-2.6 and SSP5-8.5) and examined factors that could affect species' range shifts, including climatic, geographic, habitat, and human activity variables and wing surface-to-mass ratio (S-MR). The results suggest that Ia io, Rhinolophus ferrumequinum, and Rhinolophus rex should be given the highest priority for conservation in future climate conservation strategies. Most species were predicted to move northward, except for I. io and R. rex, which moved southward. Temperature seasonality, distance to forest, and distance to karst or cave were the main environmental factors affecting the potential distributions of bats. We found significant relationships between S-MR and geographic distribution, current potential distribution, and future potential distribution in the 2050s. Our work highlights the importance of analyzing range shifts of species with multifactorial approaches, especially for species traits related to thermoregulation and energy regulation, to provide targeted conservation strategies.

Patrones y correlaciones de los cambios potenciales en la distribución de las especies de murciélago de China en el contexto del cambio climático Resumen El cambio climático puede disminuir la biodiversidad, por lo que es urgente pronosticar cómo puede cambiar en el futuro la distribución de las especies mediante la integración de múltiples factores que involucren a más taxones. Los murciélagos son particularmente sensibles al cambio climático debido a que tienen una gran proporción superficie­volumen. Sin embargo, hay pocos estudios que han considerado las variables asociadas con la disponibilidad de nidos y son todavía menos los que han conectado la distribución de los murciélagos con sus rasgos de termorregulación y regulación de energía. Usamos modelos de distribución de especies para pronosticar la distribución potencial de doce especies de murciélago en China bajo escenarios actuales y futuros de emisión de gases de efecto invernadero (SSP1­2.6 y SSP5­8.5) y analizamos los factores que podrían afectar el cambio en la distribución de las especies, incluyendo las variables climáticas, geográficas, de hábitat y de actividad humana y la proporción entre la superficie del ala y la masa (P S­M). Los resultados sugieren que Ia io, Rhinolophus ferrumequinum y R. rex deberían ser la mayor prioridad de conservación para las estrategias de conservación climáticas en el futuro. Pronosticamos que la mayoría de las especies se desplazarían al norte, a excepción de I. io y R. rex, que se desplazarían hacia el sur. Los principales factores que afectaron la distribución potencial de los murciélagos fueron la estacionalidad de la temperatura, la distancia al bosque y la distancia a la cueva o al karst. Encontramos una relación significativa entre la P S­M y la distribución geográfica, la distribución potencial actual y la distribución potencial para la década de 2050. Nuestra investigación destaca la importancia del análisis de los cambios de distribución de las especies con enfoques multifactoriales, especialmente para los rasgos de especie relacionados con la termorregulación y la regulación de energía, para proporcionar estrategias de conservación focalizadas.

Constructing Photocatalytic Covalent Organic Frameworks with Aliphatic Linkers.

Photocatalytic covalent organic frameworks (COFs) are typically constructed with rigid aromatic linkers for crystallinity and extended π-conjugation. However, the essential hydrophobicity of the aromatic backbone can limit their performances in water-based photocatalytic reactions. Here, we for the first time report the synthesis of hydrophilic COFs with aliphatic linkers [tartaric acid dihydrazide (TAH) and butanedioic acid dihydrazide] that can function as efficient photocatalysts for H2O2 and H2 evolution. In these hydrophilic aliphatic linkers, the specific multiple hydrogen bonding networks not only enhance crystallization but also ensure an ideal compatibility of crystallinity, hydrophilicity, and light harvesting. The resulting aliphatic linker COFs adopt an unusual ABC stacking, giving rise to approximately 0.6 nm nanopores with an improved interaction with water guests. Remarkably, both aliphatic linker-based COFs show strong visible light absorption, along with a narrow optical band gap of ∼1.9 eV. The H2O2 evolution rate for TAH-COF reaches up to 6003 µmol h-1 g-1, in the absence of sacrificial agents, surpassing the performance of all previously reported COF-based photocatalysts. Theoretical calculations reveal that the TAH linker can enhance the indirect two-electron oxygen reduction reaction for H2O2 production by improving the O2 adsorption and stabilizing the *OOH intermediate. This study opens a new avenue for constructing semiconducting COFs using nonaromatic linkers.

Fertility preservation in male adolescents with cancer (2011-2020): A retrospective study in China.

BACKGROUND: According to the studies, more than 80% of pediatric patients with cancer can achieve a survival rate greater than 5 years; however, long-term chemotherapy and/or radiation therapy may seriously affect their reproductive ability. Fertility preservation in adolescents with cancer in China was initiated late, and related research is lacking. Analyze data to understand the current situation and implement measures to improve current practices. METHODS: From 2011 to 2020, data on 275 male adolescents with cancer whose age ranged from 0 to 19 years old were collected from 16 human sperm banks for this retrospective study. Methods include comparing the basic situation of male adolescents with cancer, the distribution of cancer types, and semen quality to analyze the status of fertility preservation. RESULTS: The mean age was 17.39 ± 1.46 years, with 13 cases (4.7%) aged 13-14 years and 262 cases (95.3%) aged 15-19 years. Basic diagnoses included leukemia (55 patients), lymphomas (76), germ cell and gonadal tumors (65), epithelial tumors (37), soft tissue sarcomas (14), osteosarcoma (7), brain tumors (5), and other cancers (16). There are differences in tumor types in different age stages and regions. The tumor type often affects semen quality, while age affects semen volume. Significant differences were found in sperm concentration and progressive motility before and after treatment (p < 0.001). Moreover, 90.5% of patients had sperm in their semen and sperm were frozen successfully in 244 patients (88.7%). CONCLUSIONS: The aim of this study is to raise awareness of fertility preservation in male adolescents with cancer, to advocate for fertility preservation prior to gonadotoxic therapy or other procedures that may impair future fertility, and to improve the fertility status of future patients.

Dose-response relationship between volume base dose and tumor local control in definitive radiotherapy for vaginal cancer.

OBJECTIVE: This study aimed to establish the dose-response relationship between volume base dose and tumor local control for vaginal cancer, including primary vaginal cancer and recurrent gynecologic malignancies in the vagina. MATERIALS AND METHODS: We identified studies that reported volume base dose and local control by searching the PubMed, the Web of Science, and the Cochrane Library Database through August 12, 2023. The regression analyses were performed using probit model between volume based dose versus clinical outcomes. Subgroup analyses were performed according to stratification: publication year, country, inclusion time of patients, patients with prior radiotherapy, age, primaries or recurrent, tumor size, concurrent chemoradiotherapy proportion, dose rate, image modality for planning, and interstitial proportion. RESULTS: A total of 879 patients with vaginal cancer were identified from 18 studies. Among them, 293 cases were primary vaginal cancer, 573 cases were recurrent cancer in the vagina, and 13 cases were unknown. The probit model showed a significant relationship between the HR-CTV (or CTV) D90 versus the 2-year and 3-year local control, P values were 0.013 and 0.014, respectively. The D90 corresponding to probabilities of 90% 2-year local control were 79.0 GyEQD2,10 (95% CI: 75.3-96.6 GyEQD2,10). CONCLUSIONS: A significant dependence of 2-year or 3-year local control on HR-CTV (or CTV) D90 was found. Our research findings encourage further validation of the dose-response relationship of radical radiotherapy for vaginal cancer through protocol based multicenter clinical trials.

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial.

BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

Pseudotargeted lipidomics analysis of scoparone on glycerophospholipid metabolism in non-alcoholic steatohepatitis mice by LC-MRM-MS.

As the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), the progression of nonalcoholic steatohepatitis (NASH) is associated with disorders of glycerophospholipid metabolism. Scoparone is the major bioactive component in Artemisia capillaris which has been widely used to treat NASH in traditional Chinese medicine. However, the underlying mechanisms of scoparone against NASH are not yet fully understood, which hinders the development of effective therapeutic agents for NASH. Given the crucial role of glycerophospholipid metabolism in NASH progression, this study aimed to characterize the differential expression of glycerophospholipids that is responsible for scoparone's pharmacological effects and assess its efficacy against NASH. Liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) was performed to get the concentrations of glycerophospholipids, clarify mechanisms of disease, and highlight insights into drug discovery. Additionally, pathologic findings also presented consistent changes in high-fat diet-induced NASH model, and after scoparone treatment, both the levels of glycerophospholipids and histopathology were similar to normal levels, indicating a beneficial effect during the observation time. Altogether, these results refined the insights on the mechanisms of scoparone against NASH and suggested a route to relieve NASH with glycerophospholipid metabolism. In addition, the current work demonstrated that a pseudotargeted lipidomic platform provided a novel insight into the potential mechanism of scoparone action.

The high-quality genome of Grona styracifolia uncovers the genomic mechanism of high levels of schaftoside, a promising drug candidate for treatment of COVID-19.

Recent study has evidenced that traditional Chinese medicinal (TCM) plant-derived schaftoside shows promise as a potential drug candidate for COVID-19 treatment. However, the biosynthetic pathway of schaftoside in TCM plants remains unknown. In this study, the genome of the TCM herb Grona styracifolia (Osbeck) H.Ohashi & K.Ohashi (GSO), which is rich in schaftoside, was sequenced, and a high-quality assembly of GSO genome was obtained. Our findings revealed that GSO did not undergo recent whole genome duplication (WGD) but shared an ancestral papilionoid polyploidy event, leading to the gene expansion of chalcone synthase (CHS) and isoflavone 2'-hydroxylase (HIDH). Furthermore, GSO-specific tandem gene duplication resulted in the gene expansion of C-glucosyltransferase (CGT). Integrative analysis of the metabolome and transcriptome identified 13 CGTs and eight HIDHs involved in the biosynthetic pathway of schaftoside. Functional studies indicated that CGTs and HIDHs identified here are bona fide responsible for the biosynthesis of schaftoside in GSO, as confirmed through hairy root transgenic system and in vitro enzyme activity assay. Taken together, the ancestral papilionoid polyploidy event expanding CHSs and HIDHs, along with the GSO-specific tandem duplication of CGT, contributes, partially if not completely, to the robust biosynthesis of schaftoside in GSO. These findings provide insights into the genomic mechanisms underlying the abundant biosynthesis of schaftoside in GSO, highlighting the potential of GSO as a source of bioactive compounds for pharmaceutical development.

The isosbestic point in the Raman spectra of the hydration shell.

Isosbestic point is often observed in a series of spectra, but their interpretation is still controversial, such as whether the continuum model can produce an isosbestic point. In order to answer this question, the Raman spectra of hydration shell with continuous distribution structure in different ionic aqueous solutions were separated by Raman ratio spectra, and an isosbestic point was successfully observed. Our experimental results show that the continuum model can indeed produce the isosbestic point. In order to deepen the understanding of the isosbestic point, we calculate the first moment of the Raman spectra and conduct molecular dynamics (MD) simulations. Both experimental and theoretical findings indicate that elevated temperatures lead to increased disorder among water molecules within the hydration shell.

Effect of nutrition impact symptoms on oral nutritional supplements energy intake and use days in patients with head and neck cancer: A cross-sectional study.

BACKGROUND: This study aims to explore the effect of nutritional impact symptoms (NIS) on oral nutritional supplements (ONS) energy intake and use days among head and neck cancer (HNC) patients. METHODS: A cross-sectional study was conducted among HNC patients in a hospital in western China between January 2019 and June 2020. The NIS was from the Patient-Generated Subjective Global Assessment (PG-SGA) scale. Mann-Whitney test was used to examine the differences between different kinds of NIS and ONS use days. Binary logistic regression was used to determine the effect of NIS on ONS energy intake. RESULTS: The most prevalent four NIS were no appetite (35.3%), dysphagia (29.4%), vomiting (13.2%) and oral pain (12.5%), respectively. All patients in the study were malnutrition. Patients with xerostomia or oral pain had less ONS use days than those without these symptoms. Patients with vomiting (OR 0.09, 95% CI 0.02-0.50) or pain (OR 0.15, 95% CI 0.02-0.89) were less likely to have ONS energy intake ≥400 kcal/day than those without these symptoms after adjusting the confounding factors. In addition, one-point increase in total NIS score was associated with a lower proportion of ONS energy intake ≥400 kcal/day (OR 0.77, 95% CI 0.59-0.99). CONCLUSION: Xerostomia, oral pain, vomiting and pain should be strengthened and intervened to improve ONS use and nutritional status among HNC patients with malnutrition.

Ring Fusion Elevates the Electronic Mobility of Azabenzannulated Perylene Diimide.

The backwardness of n-type organic semiconductors still exists compared with the p-type counterparts. Thus, the development of high-performance n-type organic semiconductors is of great importance for organic electronic devices and their integrated circuits. In recent years, azabenzannulated perylene diimide (PDI), as one of immense bay-region-annulated PDI derivatives, has drawn considerable attentions. However, the electronic mobilities of azabenzannulated PDI derivatives are barely satisfactory. In this contribution, the peripheral benzene ring in azabenzannulated PDI 2 was fused to the ortho position by intramolecular C-H arylation cyclization. This endows the resultant azabenzannulated PDI 4 a planar configuration as well as electron deficient pentagonal ring. As a result, the electronic mobility of 4 is almost two orders of magnitude higher than that of the nonfused azabenzannulated PDI 2. This work shall pave a new avenue in elevating the performance of azabenzannulated PDI in organic electronics.

Large-scale bacterial genomic and metagenomic analysis reveals Pseudomonas aeruginosa as potential ancestral source of tigecycline resistance gene cluster tmexCD-toprJ.

BACKGROUND: The global dissemination of the multidrug resistance efflux pump gene cluster tmexCD-toprJ has greatly weakened the effects of multiple antibiotics, including tigecycline. However, the potential origin and transmission mechanisms of the gene cluster remain unclear. METHODS: Here, we concluded a comprehensive bioinformatics analysis on integrated 73,498 bacterial genomes, including Pseudomonas spp., Klebsiella spp., Aeromonas spp., Proteus spp., and Citrobacter spp., along with 1,152 long-read metagenomic datasets to trace the origin and propagation of tmexCD-toprJ. RESULTS: Our results demonstrated that tmexCD-toprJ was predominantly found in Pseudomonas aeruginosa sourced from human hosts in Asian countries and North American countries. Phylogenetic and genomic feature analyses showed that tmexCD-toprJ was likely evolved from mexCD-oprJ of some special clones of P. aeruginosa. Furthermore, metagenomic analysis confirmed that P. aeruginosa is the only potential ancestral bacterium for tmexCD-toprJ. A putative mobile genetic structure harboring tmexCD-toprJ, int-int-hp-hp-tnfxB-tmexCD-toprJ, was the predominant genetic context of tmexCD-toprJ across various bacterial genera, suggesting that the two integrase genes play a pivotal role in the horizontal transmission of tmexCD-toprJ. CONCLUSIONS: Based on these findings, it is almost certain that the tmexCD-toprJ gene cluster was derived from P. aeruginosa and further spread to other bacteria.

Construction of 3-Methyl-2-Substituted Benzo[b]furans and 3-Methyl-2-Substituted Benzo[b]thiophenes Using Solid Calcium Carbide as a Substitute for Gaseous Acetylene.

A concise method for the facile construction of 3-methyl-2-substituted benzo[b]furans and 3-methyl-2-substituted benzo[b]thiophenes using low-cost, abundant, and easy-to-use solid calcium carbide instead of flammable and explosive gaseous acetylene as an original alkyne source, o-bromophenyl ethers or o-bromophenyl thioethers as substrates through an intramolecular carbanion-yne cyclization in a 5-exo-dig manner, and subsequent double-bond isomerization is described. The simultaneous formation of two C-C bonds is realized in a one-step route. The wide substrate scope, high yield, and simple workup manipulations are also merits of this method. The synthetic strategy can also be suitable for the gram scale.

Anti-Colon Cancer Activity of Copper-Doped Folate Carbon Dots/MnO2 Complexes Based on Oxygenation and Immune-Enhancing Effects.

In clinical practice, the treatment of colon cancer is faced with the dilemma of metastasis and recurrence, which is related to immunosuppression and hypoxia. Immune checkpoint blockade (ICB) is a negative regulatory pathway of immunity. Immune checkpoint blockade (ICB) is an important immunotherapy method. However, inadequate immunogenicity reduces the overall response rate of ICB. In this study, a tumor microenvironment-responsive nanomedicine (Cu-FACD@MnO2@FA) was prepared to increase host immune response and increase intracellular oxygen levels. Cu-FACD@MnO2@FA preferentially enriched at the tumor site, combined with the immune checkpoint inhibitor alpha PD-L1, induced sufficient immunogenicity to treat colon cancer. Immunofluorescence detection of tumor cells and tissues showed that the expression of hypoxa-inducing factor 1α was significantly down-regulated after treatment and the expression of immunoactivity-related proteins was significantly changed. In vivo treatment in a bilateral tumor mouse model showed complete ablation of the primary tumor and efficient inhibition of the distal tumor. In this study, for the first time, the oxygenation effects of MnO2-coated Cu-doped carbon dots and chemodynamic therapy and a strategy of combining with immuno-blocking therapy were used for treating colon cancer.

The influencing factors of college students' legal emotion and the mechanism of its effect on aggressive behavior.

Current research has increasingly focused on the preventive role of individual legal socialization in crime. The socialization of legal emotions is an important part of legal socialization. Building upon existing literature, this study, conducted through two sub-studies, investigated the influencing factors of legal emotions in N mainland Chinese university students and the mechanisms through which legal emotions impact aggressive behavior. In study 1, the results indicated that mother-child attachment, innovation spirit, and positive emotional expression positively predicted positive legal emotion, while mother-child attachment, dependency dimension in adult attachment, and positive emotional expression negatively predicted negative legal emotions. The anxiety dimension in adult attachment and negative emotional expression positively predicted negative legal emotions. In study 2, Positive legal emotion among university students could directly negatively predict aggressive behavior or exert influence through social alienation. Negative legal emotions could not only directly positively predict aggressive behavior but also partly affect it through social alienation. In summary, our study not only identified factors that influence legal emotions, but also found that legal emotions have an impact on aggressive behavior directly or indirectly through social alienation. Our research findings have significant implications for cultivating positive legal emotion in university students and curbing aggressive behavior. This can be achieved by promoting the legal socialization of university students and ultimately contributing to crime prevention.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Enhanced catalytic activity of Fe3O4-carbon dots complex in the Fenton reaction for enhanced immunotherapeutic and oxygenation effects.

Tumor metastasis and recurrence are closely related to immune escape and hypoxia. Chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) can induce immunogenic cell death (ICD), and their combination with immune checkpoint agents is a promising therapeutic strategy. Iron based nanomaterials have received more and more attention, but their low Fenton reaction efficiency has hindered their clinical application. In this study, Fe3O4-carbon dots complex (Fe3O4-CDs) was synthesized, which was modified with ferrocenedicarboxylic acid by amide bond, and crosslinked into Fe3O4-CDs@Fc nano complex. The CDs catalyzed the Fenton reaction activity of Fe3O4 by helping to improve the electron transfer efficiency, extended the reaction pH condition to 7.4. The Fe3O4-CDs@Fc exhibit exceptional optical activity, achieving a thermal conversion efficiency of 56.43 % under 808 nm light and a photosensitive single-line state oxygen quantum yield of 33 % under 660 nm light. Fe3O4-CDs@Fc improved intracellular oxygen level and inhibited hypoxia-inducing factor (HIF-1α) by in-situ oxygen production based on Fenton reaction. The multimodal combination of Fe3O4-CDs@Fc (CDT/PDT/PTT) strongly induced immune cell death (ICD). The expression of immune-related protein and HIF-1α was investigated by immunofluorescence method. In vivo, Fe3O4-CDs@Fc combined with immune checkpoint blocker (antibody PD-L1, αPD-L1) effectively ablated primary tumors and inhibited distal tumor growth. Fe3O4-CDs@Fc is a promising immune-antitumor drug.

Transhiatal bilateral cervical approach for mediastinoscopy-assisted esophagectomy: A retrospective cohort study.

BACKGROUND: The McKeown minimally invasive esophagectomy (McMIE) procedure has various limitations, including surgical contraindications and a high rate of postoperative pulmonary complications. A novel mediastinoscopic esophagectomy procedure was described in this study by using esophageal invagination and a transhiatal and bilateral cervical approach (EITHBC). METHODS: According to the mode of operation, a total of 259 patients were divided into two groups, among which 106 underwent EITHBC and 153 underwent McMIE. The number of lymph nodes dissected, intraoperative outcomes, and postoperative outcomes were compared between the two groups of patients. RESULTS: The results revealed that the average number of resected lymph node in the EITHBC group was significantly higher in the recL106 and TbL106 stations (recL106: 1.75 vs. 1.51, p = 0.016, TbL106: 1.53 vs. 1.19, p = 0.016) and significantly lower in the 107 stations (1. 74 vs. 2. 07, p < 0.001) than in the McMIE group. The intraoperative blood loss in the EITHBC group was significantly lower than that in the McMIE group (63.30 vs. 80.45 mL, p < 0.001). The incidence of postoperative pulmonary complications in the EITHBC group was lower than that in the McMIE group (14.15% vs. 27.45%, p = 0.008). The incidence of recurrent laryngeal nerve paralysis in the EITHBC group was significantly higher than that in the McMIE group (26.41% vs. 10.46%, p = 0.003). CONCLUSION: Compared with the McMIE procedure, the EITHBC procedure has advantages in terms of removing the upper mediastinal lymph nodes and reducing postoperative pulmonary complications.

Deciphering and predicting changes in antibiotic resistance genes during pig manure aerobic composting via machine learning model.

Livestock manure is one of the most important pools of antibiotic resistance genes (ARGs) in the environment. Aerobic composting can effectively reduce the spread of antibiotic resistance risk in livestock manure. Understanding the effect of aerobic composting process parameters on manure-sourced ARGs is important to control their spreading risk. In this study, the effects of process parameters on ARGs during aerobic composting of pig manure were explored through data mining based on 191 valid data collected from literature. Machine learning (ML) models (XGBoost and Random Forest) were utilized to predict the rate of ARGs changes during pig manure composting. The model evaluation index of the XGBoost model (R2 = 0.651) was higher than that of the Random Forest (R2 = 0.490), indicating that XGBoost had better prediction performance. Feature importance was further calculated for the XGBoost model, and the XGBoost black box model was interpreted by Shapley additive explanations analysis. Results indicated that the influencing factors on the ARGs variation in pig manure were sequentially divided into thermophilic period, total composting period, composting real time, and thermophilic stage average temperature. The findings gave an insight into the application of ML models to predict and decipher the ARG changes during manure composting and provided suggestions for better composting manipulation and optimization of process parameters.