A New Age of Drug Delivery: A Comparative Perspective of Ferritin-Drug Conjugates (FDCs) and Antibody-Drug Conjugates (ADCs).

Ferritin-drug conjugates (FDCs) and antibody-drug conjugates (ADCs) respectively represent the innovative and traditional mainstream approaches in drug delivery systems, each offering unique advantages and challenges. This viewpoint delves into the evolving landscape of drug delivery technologies, specifically focusing on FDCs and ADCs. Each method exhibits unique advantages and inherent challenges, shaping their roles in therapeutic applications. The article provides a comparative analysis of two delivery systems, FDCs and ADCs, in terms of targeting accuracy, drug loading capacity, and the nature of the payload itself. This comparison offers valuable insights into the distinct advantages and disadvantages associated with each system, enabling a clearer understanding of their potential applications and limitations in therapeutic contexts. This analysis is crucial for optimizing the use of these delivery systems across varying medical contexts, offering a comprehensive overview of their impact on the field of drug delivery.

ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration.

Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.

A Strategy for Fabricating Ultra-Flexible Thermoelectric Films Using Ag2Se-Based Ink.

Flexible thermoelectric materials have drawn significant attention from researchers due to their potential applications in wearable electronics and the Internet of Things. Despite many reports on these materials, it remains a significant challenge to develop cost-effective methods for large-scale, patterned fabrication of materials that exhibit both excellent thermoelectric performance and remarkable flexibility. In this study, we have developed an Ag2Se-based ink with excellent printability that can be used to fabricate flexible thermoelectric films by screen printing and low-temperature sintering. The printed films exhibit a Seebeck coefficient of -161 µV/K and a power factor of 3250.9 µW/m·K2 at 400 K. Moreover, the films demonstrate remarkable flexibility, showing minimal changes in resistance after being bent 5000 times at a radius of 5 mm. Overall, this research offers a new opportunity for the large-scale patterned production of flexible thermoelectric films.

Isomeric Effects of Au28(S-c-C6H11)20 Nanoclusters on Photoluminescence: Roles of Electron-Vibration Coupling and Higher Triplet State.

The exploration of near-infrared photoluminescence (PL) from atomically precise nanoclusters is currently a prominent area of interest owing to its importance in both fundamental research and diverse applications. In this work, we investigate the near-infrared (NIR) photoluminescence mechanisms of two structural isomers of atomically precise gold nanoclusters of 28 atoms protected by cyclohexanethiolate (CHT) ligands, i.e., Au28i(CHT)20 and Au28ii(CHT)20. Based on their structures, analysis of 3O2 (triplet oxygen) quenching of the nanocluster triplet states, temperature-dependent photophysical studies, and theoretical calculations, we have elucidated the intricate processes governing the photoluminescence of these isomeric nanoclusters. For Au28i(CHT)20, its emission characteristics are identified as phosphorescence plus thermally activated delayed fluorescence (TADF) with a PL quantum yield (PLQY) of 0.3% in dichloromethane under ambient conditions. In contrast, the Au28ii(CHT)20 isomer exhibits exclusive phosphorescence with a PLQY of 3.7% in dichloromethane under ambient conditions. Theoretical simulations reveal a larger singlet (S1)-triplet (T1) gap in Au28ii than that in Au28i, and the higher T2 state plays a critical role in both isomers' photophysical processes. The insights derived from this investigation not only contribute to a more profound comprehension of the fundamental principles underlying the photoluminescence of atomically precise gold nanoclusters but also provide avenues for tailoring their optical properties for diverse applications.

CD122 is an activation marker ensuring proper proliferation of T cells in teleost.

As one of subunits for interleukin-2 receptor (IL-2R), CD122 can bind to IL-2 and then activate downstream signal transduction to participate in adaptive immune response. Although CD122 has been identified and investigated from several teleost species, studies on its function at T-cell level are still scarce for lack of specific antibodies. In this study, a typical CD122 in Nile tilapia (Oreochromis niloticus) was characterized by bioinformatics analysis, cloned to produce retrovirus infected NIH/3T3 cells for mouse immunization. After cell fusion and screening, we successfully developed a mouse anti-tilapia CD122 monoclonal antibody (mAb), which could specifically recognize CD122 and identify CD122-producing T cells of tilapia. Using the mAb to detect, CD122 was found to widely distribute in immune-related tissues, and significantly elevate post Edwardsiella piscicida infection or T-cell activation. More importantly, the expansion of CD122+ T cells and up-regulation of CD122 occurred both in total T cells and T-cell subsets during T-cell activation upon in vitro stimulation or in vivo infection. These results indicate that CD122 can be used as a T-cell activation marker in tilapia. Notably, CD122 mAb blocking blunted the activation of MAPK/Erk and mTORC1 pathways, and inhibited T-cell proliferation, suggesting a critical role of CD122 in ensuring proper proliferation of tilapia T cells. Therefore, this study enriches the knowledge of T-cell responses in fish and provides new evidence for understanding the evolution of lymphocyte-mediated adaptive immunity.

Wedelolactone inhibits ferroptosis and alleviates hyperoxia-induced acute lung injury via the Nrf2/HO-1 signaling pathway.

Hyperoxia-induced acute lung injury (HALI) is a complication of oxygen therapy. Ferroptosis is a vital factor in HALI. This paper was anticipated to investigate the underlying mechanism of Wedelolactone (WED) on ferroptosis in HALI. The current study used hyperoxia to injure two models, one HALI mouse model and one MLE-12 cell injury model. We found that WED treatment attenuated HALI by decreasing the lung injury score and lung wet/dry weight ratio and alleviating pathomorphological changes. Then, the inflammatory reaction and apoptosis in HALI mice and hyperoxia-mediated MLE-12 cells were inhibited by WED treatment. Moreover, WED alleviated ferroptosis with less iron accumulation and reversed expression alterations of ferroptosis markers, including MDA, GSH, GPX4, SLC7A11, FTH1, and TFR1 in hyperoxia-induced MLE-12 cells in vitro and in vivo. Nrf2-KO mice and Nrf2 inhibitor (ML385) decreased WED's ability to protect against apoptosis, inflammatory response, and ferroptosis in hyperoxia-induced MLE-12 cells. Collectively, our data highlighted the alleviatory role of WED in HALI by activating the Nrf2/HO-1 pathway.

Boosting Your Context by Dual Similarity Checkup for In-Context Learning Medical Image Segmentation.

The recent advent of in-context learning (ICL) capabilities in large pre-trained models has yielded significant advancements in the generalization of segmentation models. By supplying domain-specific image-mask pairs, the ICL model can be effectively guided to produce optimal segmentation outcomes, eliminating the necessity for model fine-tuning or interactive prompting. However, current existing ICL-based segmentation models exhibit significant limitations when applied to medical segmentation datasets with substantial diversity. To address this issue, we propose a dual similarity checkup approach to guarantee the effectiveness of selected in-context samples so that their guidance can be maximally leveraged during inference. We first employ large pre-trained vision models for extracting strong semantic representations from input images and constructing a feature embedding memory bank for semantic similarity checkup during inference. Assuring the similarity in the input semantic space, we then minimize the discrepancy in the mask appearance distribution between the support set and the estimated mask appearance prior through similarity-weighted sampling and augmentation. We validate our proposed dual similarity checkup approach on eight publicly available medical segmentation datasets, and extensive experimental results demonstrate that our proposed method significantly improves the performance metrics of existing ICL-based segmentation models, particularly when applied to medical image datasets characterized by substantial diversity.

Metrnl: a promising biomarker and therapeutic target for cardiovascular and metabolic diseases.

Modern human society is burdened with the pandemic of cardiovascular and metabolic diseases. Metrnl is a widely distributed secreted protein in the body, involved in regulating glucose and lipid metabolism and maintaining cardiovascular system homeostasis. In this review, we present the predictive and therapeutic roles of Metrnl in various cardiovascular and metabolic diseases, including atherosclerosis, ischemic heart disease, cardiac remodeling, heart failure, hypertension, chemotherapy-induced myocardial injury, diabetes mellitus, and obesity.

Deblurring masked image modeling for ultrasound image analysis.

Recently, large pretrained vision foundation models based on masked image modeling (MIM) have attracted unprecedented attention and achieved remarkable performance across various tasks. However, the study of MIM for ultrasound imaging remains relatively unexplored, and most importantly, current MIM approaches fail to account for the gap between natural images and ultrasound, as well as the intrinsic imaging characteristics of the ultrasound modality, such as the high noise-to-signal ratio. In this paper, motivated by the unique high noise-to-signal ratio property in ultrasound, we propose a deblurring MIM approach specialized to ultrasound, which incorporates a deblurring task into the pretraining proxy task. The incorporation of deblurring facilitates the pretraining to better recover the subtle details within ultrasound images that are vital for subsequent downstream analysis. Furthermore, we employ a multi-scale hierarchical encoder to extract both local and global contextual cues for improved performance, especially on pixel-wise tasks such as segmentation. We conduct extensive experiments involving 280,000 ultrasound images for the pretraining and evaluate the downstream transfer performance of the pretrained model on various disease diagnoses (nodule, Hashimoto's thyroiditis) and task types (classification, segmentation). The experimental results demonstrate the efficacy of the proposed deblurring MIM, achieving state-of-the-art performance across a wide range of downstream tasks and datasets. Overall, our work highlights the potential of deblurring MIM for ultrasound image analysis, presenting an ultrasound-specific vision foundation model.

A single-gold-atom addition regulates sharp redshift in the fluorescence of atomically precise nanoclusters.

The manipulation of emission peaks at the atomic level and the investigation of the fluorescent origin mechanism are important issues. In this study, a phosphine-mediated modification method was employed on Au36(TBBT)24 nanocluster to produce a new gold nanocluster Au37(TBBT)21(TPP)2. The structural comparison revealed that Au37(TBBT)21(TPP)2 has a structural framework similar to that of Au36(TBBT)24 except for the reconstruction of its surface motifs, the addition of one gold atom into the kernel, and local structural distortion. Interestingly, compared with Au36(TBBT)24, the emission peak of Au37(TBBT)21(TPP)2 is red-shifted into the NIR-II windows (972 nm vs. 1152 nm in CDCl3) with a quantum yield of 1.5%. Furthermore, the origin of the NIR-II fluorescence in Au37(TBBT)21(TPP)2 and the red-shift mechanism of the emission peak were explored by combining the crystal structure and DFT calculations. The results reveal that the insertion of the 37th gold atom into the core can increase the contribution of the gold atoms to the HOMO orbitals and change the origin of their fluorescence from local excitation (LE) to inter fragment charge transfer (IFCT).

Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia.

High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC.

Data Set and Benchmark (MedGPTEval) to Evaluate Responses From Large Language Models in Medicine: Evaluation Development and Validation.

Background: Large language models (LLMs) have achieved great progress in natural language processing tasks and demonstrated the potential for use in clinical applications. Despite their capabilities, LLMs in the medical domain are prone to generating hallucinations (not fully reliable responses). Hallucinations in LLMs' responses create substantial risks, potentially threatening patients' physical safety. Thus, to perceive and prevent this safety risk, it is essential to evaluate LLMs in the medical domain and build a systematic evaluation. Objective: We developed a comprehensive evaluation system, MedGPTEval, composed of criteria, medical data sets in Chinese, and publicly available benchmarks. Methods: First, a set of evaluation criteria was designed based on a comprehensive literature review. Second, existing candidate criteria were optimized by using a Delphi method with 5 experts in medicine and engineering. Third, 3 clinical experts designed medical data sets to interact with LLMs. Finally, benchmarking experiments were conducted on the data sets. The responses generated by chatbots based on LLMs were recorded for blind evaluations by 5 licensed medical experts. The evaluation criteria that were obtained covered medical professional capabilities, social comprehensive capabilities, contextual capabilities, and computational robustness, with 16 detailed indicators. The medical data sets include 27 medical dialogues and 7 case reports in Chinese. Three chatbots were evaluated: ChatGPT by OpenAI; ERNIE Bot by Baidu, Inc; and Doctor PuJiang (Dr PJ) by Shanghai Artificial Intelligence Laboratory. Results: Dr PJ outperformed ChatGPT and ERNIE Bot in the multiple-turn medical dialogues and case report scenarios. Dr PJ also outperformed ChatGPT in the semantic consistency rate and complete error rate category, indicating better robustness. However, Dr PJ had slightly lower scores in medical professional capabilities compared with ChatGPT in the multiple-turn dialogue scenario. Conclusions: MedGPTEval provides comprehensive criteria to evaluate chatbots by LLMs in the medical domain, open-source data sets, and benchmarks assessing 3 LLMs. Experimental results demonstrate that Dr PJ outperforms ChatGPT and ERNIE Bot in social and professional contexts. Therefore, such an assessment system can be easily adopted by researchers in this community to augment an open-source data set.

A Facile One-Step Self-Assembly Strategy for Novel Carbon Dots Supramolecular Crystals with Ultralong Phosphorescence Controlled by NH4.

A new methodological design is proposed for carbon dots (CDs)-based crystallization-induced phosphorescence (CIP) materials via one-step self-assembled packaging controlled by NH4 +. O-phenylenediamine (o-PD) as a nitrogen/carbon source and the ammonium salts as oxidants are used to obtain CDs supramolecular crystals with a well-defined staircase-like morphology, pink fluorescence and ultralong green room-temperature phosphorescence (RTP) (733.56 ms) that is the first highest value for CDs-based CIP materials using pure nitrogen/carbon source by one-step packaging. Wherein, NH4 + and o-PD-derived oxidative polymers are prerequisites for self-assembled crystallization so as to receive the ultralong RTP. Density functional theory calculation indicates that NH4 + tends to anchor to the dimer on the surface state of CDs and guides CDs to cross-arrange in an X-type stacking mode, leading to the spatially separated frontier orbitals and the through-space charge transfer (TSCT) excited state in turn. Such a self-assembled mode contributes to both the small singlet-triplet energy gap (ΔEST) and the fast inter-system crossing (ISC) process that is directly related to ultralong RTP. This work not only proposes a new strategy to prepare CDs-based CIP materials in one step but also reveals the potential for the self-assembled behavior controlled by NH4 +.

Sm-like 5 knockdown inhibits proliferation and promotes apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

BACKGROUND: The role of Sm-like 5 (LSM5) in colon cancer has not been determined. In this study, we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved. AIM: To determine the role of LSM5 in the progression of colon cancer and the potential underlying mechanism involved. METHODS: The Gene Expression Profiling Interactive Analysis database and the Human Protein Atlas website were used for LSM5 expression analysis and prognosis analysis. Real-time quantitative polymerase chain reaction and Western blotting were utilized to detect the expression of mRNAs and proteins. A lentivirus targeting LSM5 was constructed and transfected into colon cancer cells to silence LSM5 expression. Proliferation and apoptosis assays were also conducted to evaluate the growth of the colon cancer cells. Human GeneChip assay and bioinformatics analysis were performed to identify the potential underlying mechanism of LSM5 in colon cancer. RESULTS: LSM5 was highly expressed in tumor tissue and colon cancer cells. A high expression level of LSM5 was related to poor prognosis in patients with colon cancer. Knockdown of LSM5 suppressed proliferation and promoted apoptosis in colon cancer cells. Silencing of LSM5 also facilitates the expression of p53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and tumor necrosis factor receptor superfamily 10B (TNFRSF10B). The inhibitory effect of LSM5 knockdown on the growth of colon cancer cells was associated with the upregulation of p53, CDKN1A and TNFRSF10B. CONCLUSION: LSM5 knockdown inhibited the proliferation and facilitated the apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

Recurrence of Hepatocellular Carcinoma in Patients with Low Albumin-Bilirubin Grade in TACE Combined with Ablation: A Random Forest Cox Predictive Model.

Purpose: The aim of our study was to investigate the relationship between albumin-bilirubin (ALBI) grade and recurrence in patients who underwent TACE sequential ablation. We developed and validated a nomogram to predict low levels of ALBI patients' recurrence. Patients and Methods: A total of 880 patients undergoing TACE combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were retrospectively enrolled, including 415 patients with L-ALBI (≤-2.6) and 465 patients with high levels (>-2.6) of ALBI (H-ALBI). L-ALBI patients were randomized in a 7:3 ratio into the training cohort (N=289) and validation cohort (N=126). Multivariate Cox regression followed by random survival forest was carried out to identify independent risk factors for prediction nomogram construction. An examination of nomogram accuracy was performed using the C-index, receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) curves. According to the nomogram, the patients were divided into low-risk, intermediate-risk, and high-risk groups. Kaplan-Meier (KM) curves were applied to compare the difference in recurrence-free survival (RFS) among the three groups. Results: The median RFS in L-ALBI patients was significantly longer than the H-ALBI patients (40.8m vs 20.1m, HR:1.71, 95% CI:1.44-2.04, P<0.0001). The nomogram was composed of five variables, such as age, Barcelona Clinic Liver Cancer (BCLC) stage, globulin, gamma-glutamyl transferase to lymphocyte ratio (GLR), and international normalized ratio (INR). The C-index (0.722 and 0.731) and 1-, 3-, and 5-year AUCs (0.725, 0.803, 0.870, and 0.764, 0.816, 0.798) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves demonstrated good consistency and good clinical utility. There were significant differences in RFS between the low-risk, intermediate-risk, and high-risk groups (P<0.0001). Conclusion: L-ALBI Patients who underwent TACE combined ablation had better recurrence-free survival than patients with H-ALBI. The nomogram developed and validated in our study had good predictive ability in recurrence for L-ALBI patients.

Synthesis and antiproliferative activity of CBD aromatic ester derivatives.

This study involved the synthesis of a series of novel cannabidiol (CBD) aromatic ester derivatives, including CBD-8,12-diaromaticester derivatives (compounds 2a-2t) and CBD-8,12-diacetyl-21-aromaticester derivatives (compound 5a-5c). The antiproliferative activities of these compounds against human liver cancer cell lines HePG2 and HeP3B as well as human pancreatic cancer cell lines ASPC-1 and BXPC-3 were evaluated in vitro using the CCK-8 assay. The results indicated that compound 2f exhibited an IC50 value of 2.75 µM against HePG2, which is 5.32-fold higher than that of CBD. Additionally, compounds 2b and 5b demonstrated varying degrees of improved anticancer activity (IC50 5.95-9.21 µM) against HePG2.

Dual-scale shifted window attention network for medical image segmentation.

Swin Transformer is an important work among all the attempts to reduce the computational complexity of Transformers while maintaining its excellent performance in computer vision. Window-based patch self-attention can use the local connectivity of the image features, and the shifted window-based patch self-attention enables the communication of information between different patches in the entire image scope. Through in-depth research on the effects of different sizes of shifted windows on the patch information communication efficiency, this article proposes a Dual-Scale Transformer with double-sized shifted window attention method. The proposed method surpasses CNN-based methods such as U-Net, AttenU-Net, ResU-Net, CE-Net by a considerable margin (Approximately 3% ∼ 6% increase), and outperforms the Transformer based models single-scale Swin Transformer(SwinT)(Approximately 1% increase), on the datasets of the Kvasir-SEG, ISIC2017, MICCAI EndoVisSub-Instrument and CadVesSet. The experimental results verify that the proposed dual scale shifted window attention benefits the communication of patch information and can enhance the segmentation results to state of the art. We also implement an ablation study on the effect of the shifted window size on the information flow efficiency and verify that the dual-scale shifted window attention is the optimized network design. Our study highlights the significant impact of network structure design on visual performance, providing valuable insights for the design of networks based on Transformer architectures.

The TAK1/JNK axis participates in adaptive immunity by promoting lymphocyte activation in Nile tilapia.

The transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) axis is an essential MAPK upstream mediator and regulates immune signaling pathways. However, whether the TAK1/JNK axis harnesses the strength in regulation of signal transduction in early vertebrate adaptive immunity is unclear. In this study, by modeling on Nile tilapia (Oreochromis niloticus), we investigated the potential regulatory function of TAK1/JNK axis on lymphocyte-mediated adaptive immune response. Both OnTAK1 and OnJNK exhibited highly conserved sequences and structures relative to their counterparts in other vertebrates. Their mRNA was widely expressed in the immune-associated tissues, while phosphorylation levels in splenic lymphocytes were significantly enhanced on the 4th day post-infection by Edwardsiella piscicida. In addition, OnTAK1 and OnJNK were significantly up-regulated in transcriptional level after activation of lymphocytes in vitro by phorbol 12-myristate 13-acetate plus ionomycin (P + I) or PHA, accompanied by a predominant increase in phosphorylation level. More importantly, inhibition of OnTAK1 activity by specific inhibitor NG25 led to a significant decrease in the phosphorylation level of OnJNK. Furthermore, blocking the activity of OnJNK with specific inhibitor SP600125 resulted in a marked reduction in the expression of T-cell activation markers including IFN-γ, CD122, IL-2, and CD44 during PHA-induced T-cell activation. In summary, these findings indicated that the conserved TAK1/JNK axis in Nile tilapia was involved in adaptive immune responses by regulating the activation of lymphocytes. This study enriched the current knowledge of adaptive immunity in teleost and provided a new perspective for understanding the regulatory mechanism of fish immunity.

Sediment porewaters serve as a transient organic carbon pool at the land-ocean interface.

The organic carbon (OC) cycle at the land-ocean interface is an important component of the global carbon budget, yet the processes that control the transfer, transformation, and burial of OC in these regions remain poorly understood. In this work, we examined sedimentary OC (SOC) in short core sediments, dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), and chromophoric dissolved organic matter (CDOM), as well as other solutes in sediment porewaters of the Changjiang Estuary and adjacent East China Sea (ECS) shelf. The main goal of this work is to investigate the variation of the sources and composition of different forms of carbon in estuarine sediments associated with different sedimentary regimes, to further understand the role of sediment porewater in carbon sequestration at the land-ocean interface. Concentrations of Fe2+ and Mn2+ in porewaters of the muddy sediments are much higher than those in the sandy sediments, and SO42- decreases with depth in the deep sediment layer, indicating the degradation of SOC in mobile muds is mainly driven by suboxic and/or anoxic diagenetic processes (e.g., iron-manganese reduction). The accumulation of DIC in the muddy sediment is higher compared to the sandy sediment, indicating relatively complete SOC remineralization. The DOC in porewaters of the muddy areas is mainly composed of highly degraded and low molecular weight humic-like substances (C1), whereas in the sandy area, porewater DOC is mainly composed of less degraded and high molecular weight protein-like substances (C2 and C3). The average DOC stock (28.5 t/km2) in the upper 30 cm sediment porewaters is significantly higher than that of DIC (12.5 t/km2) in sandy area, but less in muddy areas (17.0 t/km2 of DOC vs. 25.4 t/km2 of DIC). The total DOC stock in sediment porewaters of the sandy area accounted for ∼61 % of DOC stock in water column of the ECS, indicating that the porewater is an important DOC pool in the ECS. However, this DOC pool is rather transient due to its high reactivity and mobility, especially in sandy area. Nevertheless, compared with other marine environments, the carbon stock of DOC (average of 43.8 t/km2) in porewaters of stable sedimentary environments is much higher than that of DIC (average of 21.7 t/km2). This work further supports the notion that sedimentary regime plays an important role in OC cycling at the land-ocean interface and highlights the significance of sediment porewaters as a vast carbon pool in marine ecosystems.

Efficacy and safety of sintilimab in combination with chemotherapy for recurrent extensive-stage small cell lung cancer: a real-world retrospective study.

Background: Immune checkpoint inhibitors (ICIs) no longer are approved for second-line or later treatment of extensive-stage small cell lung cancer (ES-SCLC), and have not been studied in combination with chemotherapy. Exploring the efficacy and safety of second-line or later immunotherapy for ES-SCLC is an urgent clinical question that needs to be addressed, and combination therapies are an important research direction. This study intended to investigate the efficacy and safety of the sintilimab in combination with chemotherapy as a second-line and beyond treatment option for ES-SCLC. Methods: Medical records of patients who received treatment with sintilimab in combination with chemotherapy or chemotherapy alone as a second-line or beyond therapy were retrospectively analyzed. The study evaluated efficacy and safety. Indicators of efficacy included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety indicators included adverse events (AEs). Results: This cohort comprised of 46 patients: 24 in the sintilimab combination chemotherapy group and 22 in the chemotherapy group. Chemotherapy received by both groups was either albumin-bound paclitaxel or irinotecan. Compared with the chemotherapy group, the sintilimab combination chemotherapy group had higher ORR and DCR (ORR: 37.5% vs. 9.1%, P=0.04; DCR: 75.0% vs. 40.9%, P=0.04), and significantly prolonged PFS and OS [median PFS (mPFS): 5.07 vs. 2.45 months, P=0.006; median OS (mOS): 14.43 vs. 10.34 months, P=0.009]. Also, there was no significant increase in the incidence of AEs in the sintilimab combination chemotherapy group, which was well tolerated by patients. Conclusions: Sintilimab in combination with chemotherapy is superior to single-agent chemotherapeutic treatment as second-line or later therapy in ES-SCLC patients who have not received prior immunotherapy. These results need to be confirmed in future clinical trials.