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Abstract Although first-line immunochemotherapy has improved prognosis for patients with advanced esophageal squamous cell carcinoma (ESCC), more effective strategies still require further investigation. This multi-center, phase II study (ClinicalTrials.gov NCT05013697) assessed the feasibility of benmelstobart (a novel PD-L1 inhibitor) plus anlotinib (multitargeted TKI) and chemotherapy in advanced or metastatic/recurrent ESCC. Eligible patients received 4–6 cycles (21-day) of benmelstobart (1200 mg), anlotinib (10 mg) plus paclitaxel (135 mg/m2)/cisplatin (60–75 mg/m2), then maintained with benmelstobart and anlotinib. Primary endpoint was progression-free survival (PFS) assessed according to RECIST v1.1. Secondary endpoints were tumor response, overall survival (OS), and safety assessed by adverse events (AEs). From September 2021 to November 2023, 50 patients were enrolled and received study treatment. With median follow-up of 23.7 months as of April 1, 2024, median PFS was 14.9 months (95% CI, 11.4-not estimable [NE]) and the 1-year PFS was 58.5% (95% CI, 41.9%–71.9%). Among 50 patients, confirmed objective response rate was 72.0% and disease control rate was 84.0%. Median duration of response of 36 responders was 16.2 months (95% CI, 10.2-NE). At the cutoff date, 31 patients remained alive; median OS was not reached (95% CI, 13.2 months-NE) with 1-year OS of 74.8% (95% CI, 59.8%–84.8%). Forty-six (92.0%) patients reported treatment-related AEs, with 37 (74.0%) were grade ≥3. Overall, benmelstobart plus anlotinib and chemotherapy showed promising efficacy and acceptable toxicity in advanced or metastatic/recurrent ESCC.

Abstract Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

Sulfamethoxazole (SMX) is an extensively applied antibacterial drug, and it is also a pollutant that poses a serious threat to human and ecosystem health. In this research, a 3D hierarchical hollow ball-flower structure catalyst (CoAl-LDHs@CoSx-rGO) was tailored for the first time to efficiently degrade SMX via visible light coupling PMS activation. A series of characterizations confirm that the target catalyst is successfully prepared and the optimized 0.1CoAl-LDHs@CoSx-rGO sample possesses superior specific surface area of 306.0 m2/g, and significantly higher photocurrent response and lower electrochemical impedance. More importantly, 0.5 g/L of the sample can degrade 98.59 % of SMX within 50 min via visible light coupling PMS activation, and after 7 degradation cycles, the degradation rate only decreased by 8.49 %. A series of parameters that affect degradation rate have been optimized in detail. Capture experiments and ESR indicate that e−, •OH and SO4•− make major contributions to degradation, and visible light coupling PMS activation generates stronger signals than alone visible-light or PMS system. LC-MS, TEST toxicity assessment and theoretical calculation were conducted to elucidate degradation route and intermediate toxicity. The research provides a new approach to design catalysts with highly exposed activity sites for efficiently removing SMX from environmental water.

Analyzing the current trends and causes of carbon storage changes and accurately predicting future land use and carbon storage changes under different climate scenarios is crucial for regional land use decision-making and carbon management. This study focuses on Beijing as its study area and introduces a framework that combines the Markov model, the Patch-based Land Use Simulation (PLUS) model, and the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) model to assess carbon storage at the sub-district level. This framework allows for a systematic analysis of land use and carbon storage spatiotemporal evolution in Beijing from 2000 to 2020, including the influence of driving factors on carbon storage. Moreover, it enables the simulation and prediction of land use and carbon storage changes in Beijing from 2025 to 2040 under various scenarios. The results show the following: (1) From 2000 to 2020, the overall land use change in Beijing showed a trend of “Significant decrease in cropland area; Forest increase gradually; Shrub and grassland area increase first and then decrease; Decrease and then increase in water; Impervious expands in a large scale”. (2) From 2000 to 2020, the carbon storage in Beijing showed a “decrease-increase” fluctuation, with an overall decrease of 1.3 Tg. In future carbon storage prediction, the ecological protection scenario will contribute to achieving the goals of carbon peak and carbon neutrality. (3) Among the various driving factors, slope has the strongest impact on the overall carbon storage in Beijing, followed by Human Activity Intensity (HAI) and Nighttime Light Data (NTL). In the analysis of carbon storage in the built-up areas, it was found that HAI and DEM (Digital Elevation Model) have the strongest effect, followed by NTL and Fractional Vegetation Cover (FVC). The findings from this study offer valuable insights for the sustainable advancement of ecological conservation and urban development in Beijing.

Abstract In our previous study, the three-dimensional graphene-modified PbO2 (3DG-PbO2) anode was prepared for the effective degradation of perfluorooctanesulfonat (PFOS) by the electrochemical oxidation process. However, the mineralization efficiency of PFOS at the 3DG-PbO2 anode still needs to be further improved due to the recalcitrance of PFOS. Thus, in this study, the yttrium (Y) was doped into the 3DG-PbO2 film to further improve the electrochemical activity of the PbO2 anode. To optimize the doping amount of Y, three Y and 3DG codoped PbO2 anodes were fabricated with different Y3+ concentrations of 5, 15, and 30 mM in the electroplating solution, which were named Y/3DG-PbO2-5, Y/3DG-PbO2-15 and Y/3DG-PbO2-30, respectively. The results of morphological, structural, and electrochemical characterization revealed that doping Y into the 3DG-PbO2 anode further refined the β-PbO2 crystals, increased the oxygen evolution overpotential and active sites, and reduced the electron transfer resistance, resulting in a superior electrocatalytic activity. Among all the prepared anodes, the Y/3DG-PbO2-15 anode exhibited the best activity for electrochemical oxidation of PFOS. After 120 min of electrolysis, the TOC removal efficiency was 80.89% with Y/3DG-PbO2-15 anode, greatly higher than 69.13% with 3DG-PbO2 anode. In addition, the effect of operating parameters on PFOS removal was analyzed by response surface, and the obtained optimum values of current density, initial PFOS concentration, pH, and Na2SO4 concentration were 50 mA/cm2, 12.21 mg/L, 5.39, and 0.01 M, respectively. Under the optimal conditions, the PFOS removal efficiency reached up to 97.16% after 40 min of electrolysis. The results of the present study confirmed that the Y/3DG-PbO2 was a promising anode for electrocatalytic oxidation of persistent organic pollutants.

Cronkhite-Canada syndrome (CCS) is a rare cause of chronic diarrhea and malabsorption where patients develop multiple polyps throughout the gastrointestinal (GI) tract, accompanied by ectodermal changes. Due to its rarity, its early detection and diagnosis can be challenging for physicians. This case report described a 58-year-old male patient with CCS who presented with chronic watery diarrhea, hematochezia, weight loss, and skin changes including nail dystrophy and hyperpigmen-tation. Laboratory results showed anemia and hypoalbuminemia. He underwent CT enterography (CTE) which identified diffuse edematous polyposis in the GI tract. The CTE results were highly suspicious of CCS and a subsequent endoscopic examination confirmed the diagnosis. The patient received supportive treatment which improved his symptoms. Based on CTE and endoscopy at 1-year follow-up, the patient was deemed to be in remission. We included a literature review of CCS. The case report aimed to improve the understanding of CCS and explored the key CTE features relevant to its early diagnosis.

Small intestinal stromal tumor (SIST) is a common gastrointestinal tumor. Currently, SIST diagnosis relies on clinical radiologists reviewing CT images from medical imaging sensors. However, this method is inefficient and greatly affected by subjective factors. The automatic detection method for stromal tumors based on computer vision technology can better solve these problems. However, in CT images, SIST have different shapes and sizes, blurred edge texture, and little difference from surrounding normal tissues, which to a large extent challenges the use of computer vision technology for the automatic detection of stromal tumors. Furthermore, there are the following issues in the research on the detection and recognition of SIST. After analyzing mainstream target detection models on SIST data, it was discovered that there is an imbalance in the features at different levels during the feature fusion stage of the network model. Therefore, this paper proposes an algorithm, based on the attention balance feature pyramid (ABFP), for detecting SIST with unbalanced feature fusion in the target detection model. By combining weighted multi-level feature maps from the backbone network, the algorithm creates a balanced semantic feature map. Spatial attention and channel attention modules are then introduced to enhance this map. In the feature fusion stage, the algorithm scales the enhanced balanced semantic feature map to the size of each level feature map and enhances the original feature information with the original feature map, effectively addressing the imbalance between deep and shallow features. Consequently, the SIST detection model’s detection performance is significantly improved, and the method is highly versatile. Experimental results show that the ABFP method can enhance traditional target detection methods, and is compatible with various models and feature fusion strategies.

BackgroundThe EBSLN is vulnerable to damage during thyroidectomy, results in voice related complications, negatively affect patient quality of life, routine identification of the EBSLN prior to surgical manipulation is necessary for a complication-free thyroidectomy. We aimed to validate a video-assisted procedure for identifying and preserving the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy and analyze the EBSLN Cernea classification and the localization of the nerve entry point (NEP) from the insertion of the sternothyroid muscle.MethodsA prospective descriptive study was performed; 134 patients, who scheduled for lobectomy with an intraglandular tumor max diameter ≤ 4 cm and without extrathyroidal extension, were randomly divided into the video-assisted surgery (VAS) and conventional open surgery (COS) groups. We used the video-assisted surgical procedure for visually identifying the EBSLN directly, and compared the differences in the visual identification rate and total identification rate of the two groups. We also measured the localization of the NEP using the insertion of the sternothyroid muscle as a reference.ResultsThere was no statistically significant difference in clinical characteristics between the two groups. The visual identification rate and total identification rate were significantly higher in the VAS group than the COS group (91.04% vs. 77.61%, 100% vs. 89.6%). The EBSLN injury rate was 0 in both groups. The mean vertical distance (VD) of the NEP from the sternal thyroid insertion was 1.18 mm (SD 1.12 mm, range, 0–5 mm), with approximately 88.97% of the results occurring within the 0–2 mm range. The mean horizontal distance (HD) was 9.33 mm (SD 5.03 mm, range, 0–30 mm), with over 92.13% of the results occurring within the 5–15 mm range.ConclusionBoth the visual and total identification rates of the EBSLN were significantly higher in the VAS group. This method provided a good visual exposure rate of the EBSLN, aiding in identifying and protecting the EBSLN during thyroidectomy.

Background/ObjectivesThere is no predictive model available to address early stage malignant intraductal papillary mucinous neoplasm (IPMN) including high grade dysplasia (HGD) and pT1a (invasive component≤0.5 cm). The aim of this study was to establish an objective and sufficient model to predict the degree of malignancy in patients with IPMN, which can be easily applied in daily practice and adopted for any type of lesion.MethodsA retrospective cohort study of 309 patients who underwent surgical resection for IPMN was performed. Members of the cohort were randomly allocated to the training or testing set. A detection tree model and random forest model were used for a 3-class classification to distinguish low grade dysplasia (LGD), HGD/pT1a IPMN, and invasive intraductal papillary mucinous cancer (I-IPMC) beyond pT1a.ResultsOf the 309 patients, 54 (17.4%) had early stage malignancy (19 HGD, 35 pT1a), 49 (15.9%) had I-IPMC beyond pT1a, and 206 (66.7%) had LGD IPMN. We proposed a 3-class classification model using a random forest algorithm, and the model had an accuracy of 99.5% with the training set, and displayed an accuracy of 96.0% with the testing set. We used SHAP for interpretation of the model and showed the top five factors (mural nodule size, main pancreatic duct diameter, CA19-9 levels, lesion edge and common bile duct dilation) were most likely to influence the 3-class classification results in terms of interpretation of the random forest model.ConclusionsThis predictive model will help assess an individual’s risk for different stages of IPMN malignancy and may help identify patients with IPMN who require surgery.

Postoperative chyle leakage (CL) is a rare but severe complication after neck dissection, and most patients with this complication can be treated conservatively. However, in patients with high-flow leakage, efficient and well-tolerated conservative treatment options are still lacking, and the treatments can be complicated. In this study, we report a case with CL of 1100 ml/day after neck dissection that was successfully treated by balloon compression.

Self-accelerating beams have the unusual ability to remain diffraction-free while undergo the transverse shift during the free-space propagation. We theoretically identify that the transverse optical field distribution of 2D self-accelerating beam is determined by the selection of the transverse Cartesian coordinates, when the caustic method is utilized for its trajectory design. Based on the coordinate-rotation method, we experimentally demonstrate a scheme to flexibly manipulate the rotation of transverse optical field for 2D self-accelerating beams under the condition of a designated trajectory. With this scheme, the transverse optical field can be rotated within a range of 90 degrees, especially when the trajectory of 2D self-accelerating beams needs to be maintained for free-space photonic interconnection.

Analysis of the atmospheric Aerosol Particle Size Distribution (APSD) retrieved from Light Detection and Ranging (Lidar) data is one of the popular fields in atmospheric remote sensing. An APSD retrieval method based on the lognormal particle size distribution, the Mie theory, and the Second Simulation of the Satellite Signal in the Solar Spectrum (6S) were studied. According to the 6S, this method divides the main body of the aerosols into four basic components and calculates the APSD from Lidar data and the optical and microphysical characteristics of these components. Numerical simulation and experimental observations reveal that this method can obtain the APSD for particle sizes of >0.15 μm in the different vertical layers with good reliability.

Objective: To investigate the value of magnetically guided capsule endoscopy (MGCE) and magnetic resonance enterography (MRE) in assessing the activity of pediatric Crohn’s disease.Methods: Clinical data from 82 subjects with pediatric Crohn’s disease, who underwent MGCE and MRE from October 2018 to March 2021 were analyzed retrospectively. Pairwise comparisons of several indexes, including MaRIA, CECDAI, PCDAI, and SES-CD, were performed by Spearman’s rank correlation test and kappa consistency analysis. CECDAI and MaRIA values predicted whether patients were moderately or severely active (PCDAI ≥30) clinically by logistic regression analysis. The area under the receiver operating characteristic curve (AUC) quantified the evaluation value of moderate to severe activity of pediatric CD.Results: In judging the severity of CD in the small intestine, the correlation coefficient between CECDAI and MaRIA was 0.406 (p < 0.05), and the kappa value of the consistency analysis was 0.299 (p < 0.05). MaRIA was weakly correlated with PCDAI (r = 0.254, p < 0.05), and they were weakly consistent in assessing the activity of Crohn’s disease (kappa = 0.135, p < 0.05). For predicting clinically moderate to severe activity, the fitted AUC based on CECDAI and MarRIA was 0.917, which was higher than applying a single parameter (CECDAI = 0.725, MarRIA = 0.899, respectively). MaRIA and serum albumin were significantly and negatively correlated (r = −1.064, p < 0.05). The consistency of the detection rate of gastric ulcers by MGCE and gastroscopy was moderate (kappa = 0.586, p < 0.05), and the detection rate of ulcers in the terminal ileum between MGCE and colonoscopy showed high consistency (kappa = 0.609, p < 0.05).Conclusions: MGCE and MRE are valuable, non-invasive methods for evaluating small bowel lesions in children with CD. The combined application of MGCE and MRE can better characterize the disease activity.

BackgroundIL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma.MethodsRNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors.ResultsClinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma.ConclusionsIL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.

Favorable effects exerted by long-term administration of fingolimod therapy in multiple sclerosis (MS) patients have been reported, but sporadic side effects, such as reversible macular edema, also have been recorded. The present study aimed to determine whether fingolimod therapy is beneficial to the visual system in experimental autoimmune encephalomyelitis (EAE) mice. A decrease in demyelination and axon loss in the optic nerve as well as cellular infiltration, especially the recruited macrophages, was observed in EAE with fingolimod treatment. Fingolimod administration diminished hypergliosis of macroglia, including astrocytes and Müller cells in the retina and optic nerve in EAE. Microglia were hyperactivated in the retina and optic nerve in the EAE mice compared to controls, which could be alleviated by fingolimod treatment. Moreover, apoptosis of retinal ganglion cells (RGC) and oligodendrocytes in the optic nerve was significantly reduced with fingolimod treatment compared to that in the untreated EAE mice. These results suggested that fingolimod exerts neuroprotective and anti-inflammatory effects on the retina and optic nerve in a mouse model of EAE. Considering the paradox of favorable and side effects of fingolimod on visual system, we speculate that side effects including macular oedema caused by fingolimod during MS treatment is tendency to be vasogenic rather than hypergliosis in optic nerve and retina which warrants further neuroophthalmological investigation.

Nowadays, an increasing discharge of oxyanions to the natural environment has been attracting worldwide attention. TiO2-based photocatalysis is regarded as one of the most promising technologies for the conversion of toxic oxyanions (such as chromate, nitrate, nitrite, bromate, perchlorate and selenate) to harmless and/or less toxic substances in contaminated waters. Various types of TiO2-based catalysts have been developed, and each of them exhibits its own advantages in catalytic reduction of oxyanions. However, the application of these nanostructured TiO2 in real water bodies remains a challenge, with limitations associated with sunlight harvesting abilities, production costs, reuse stability and exposure risks. Herein, we aim to present a critical review on reported TiO2-based photocatalytic reduction of aqueous oxyanions, provide a comprehensive understanding of the possible reaction pathways of formed active species, and evaluate the reduction performance of different types of TiO2-based catalysts. In addition, the impact of operating parameters (such as solution pH, temperature, dissolved oxygen and coexisting substances) on catalytic reduction performance is discussed. Furthermore, the perspectives of TiO2-based photocatalytic reduction of oxyanions are also proposed. Keywords: Water treatment, Photocatalytic reduction, Titanium dioxide (TiO2), Oxyanions, Free radical

The Drosophila Cadherin Fat (Ft) has been identified as a crucial regulator of tissue size and Planar Cell Polarity (PCP). However, the precise mechanism by which Ft regulates these processes remains unclear. In order to advance our understanding of the action of Ft, we have sought to identify the crucial Ft effector domains. Here we report that a small region of the Ft cytoplasmic domain (H2 region) is both necessary and sufficient, when membrane localized, to support viability and prevent tissue overgrowth. Interestingly, the H2 region is dispensable for regulating PCP signaling, whereas the mutant Ft lacking the H2 region is fully capable of directing PCP. This result suggests that Ft's roles in PCP signaling and tissue size control are separable, and each can be carried out independently. Surprisingly, the crucial regions of Ft identified in our structure-function study do not overlap with the previously reported interaction regions with Atrophin, Dco, or Lowfat.

The development of nanozymes has emerged as a promising pathway for combating bacterial infections. In this work, Ag/Schiff base nanozymes are obtained through the in situ reduction method on [2 + 3] Schiff base macrocycles using eco-friendly reductant α-tocopherol. The silver prepared was found to be nanoscale by TEM, and Ag NPs grew and dispersed uniformly on the surface of the Schiff base macrocycle due to the abundance of the CN double bonds. The peroxidase-like catalytic activity of the Ag/Schiff base was evaluated toward 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, and the Km values of 0.350 and 0.090 mM confirm the strong affinity of Ag/Schiff base for H2O2 and TMB. Moreover, the nanozyme exhibited good antibacterial properties against Streptococcus sanguinis, Pseudomonas aeruginosa, and Staphylococcus aureus, and in vivo tests confirmed that the Ag/Schiff base had negligible biotoxicity. Benefiting from the good antimicrobial and biosafety properties, the nanozymes were explored to prepare antibacterial films, and the bacterial inhibition zones demonstrated that the introduction of the Ag/Schiff base could prevent the growth of bacteria. [ABSTRACT FROM AUTHOR]