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Abstract As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Abstract Pancreatic cancer is a gastrointestinal tumor with a high mortality rate, and advances in surgical procedures have only resulted in limited improvements in the prognosis of patients. Solute carriers (SLCs), which rank second among membrane transport proteins in terms of abundance, regulate cellular functions, including tumor biology. An increasing number of studies focusing on the role of SLCs in tumor biology have indicated their relationship with pancreatic cancer. The mechanism of SLC transporters in tumorigenesis has been explored to identify more effective therapies and improve survival outcomes. These transporters are significant biomarkers for pancreatic cancer, the functions of which include mainly proliferative signaling, cell death, angiogenesis, tumor invasion and metastasis, energy metabolism, chemotherapy sensitivity and other functions in tumor biology. In this review, we summarize the different roles of SLCs and explain their potential applications in pancreatic cancer treatment.

Abstract Aims Emergency department (ED) providers play an important role in the management of patients with acute heart failure (AHF). We present findings from a pilot study of an electronic decision support that includes personalized risk estimates using the STRIDE‐HF risk tool and tailored recommendations for initiating guideline directed medical therapy (GDMT) among appropriate patients. Methods Among ED patients treated for AHF who were discharged from the ED or the ED‐based observation unit in two EDs from 1 January 2023 to 31 July 2023, we assess prescriptions to the four classes of GDMT at two intervals: (1) ED arrival and (2) ED discharge. Specifically, we report active prescriptions for beta‐blockers (BBs), renin–angiotensin receptor system inhibitors (RASis), sodium‐glucose transport protein 2 inhibitors (SGLT2is) and mineralocorticoid receptor antagonists (MRA) among patients with reduced ejection fraction (HFrEF) and mildly reduced (HFmrEF). Second, we describe rates of 30‐day serious adverse events (SAE) (death, cardiopulmonary resuscitation, balloon‐pump insertion, intubation, new dialysis, myocardial infarction or coronary revascularization) among patients predicted to be very low risk by STRIDE‐HF and discharged home. Results Among 234 discharged patients, 55% were female and 76% were non‐White. We found 51 (21.8%), 21 (9.0%) and 126 (53.8%) had HFrEF, HFmEF and HFpEF, respectively, while 36 (15.4%) were missing EF, and 51 (22%) were very low risk, 82 (35%) were low risk, 60 (26%) were medium risk and 41 (18%) were high risk. Among HFrEF patients, 68.6%, 66.7%, 25.5% and 19.6% were on a RASi, BB, SGLT2i and MRA, respectively, at ED arrival, while 42.9%, 66.7%, 14.3% and 4.8% of HFmrEF patients were on a RASi, BB, SGLT2i and MRA, respectively. Among patients with HFpEF, only 6 (4.8%) were on an SGLT2i at ED arrival. The most prescribed new medication at ED discharge was an SGLT2i, with a nearly 10% increase in the proportion of patients with an active prescription for SGLT2i at ED discharge among HFrEF and HFmEF patients. We observed no 30‐day SAE among the 51 patients predicted to be very low risk and discharged home. Conclusions Ongoing treatment with GDMT at ED arrival was sub‐optimal. Initiation among appropriate patients at discharge may be feasible and safe.

Abstract To enhance the capability of identifying unknown emitters in open spaces, an open‐multiscale attention kernel (MSAK)‐convolutional neural network‐long short‐term memory (CNN‐LSTM) structure is proposed. To this end, first, a MSAK module and CNN‐LSTM structure are introduced, and then, the depth and complexity of the feature extraction network are improved to enhance its representation capability. To classify unknown emitters accurately, the MSAK‐CNN‐LSTM model is improved to obtain an open‐MSAK‐CNN‐LSTM model with open‐set recognition capability. Additionally, the two preprocessing procedures are summarised, and their strengths and weaknesses are compared. Experimental results show that the proposed open‐MSAK‐CNN‐LSTM model achieves satisfactory accuracy in identifying unknown emitters in open space. In addition, it has significant advantages in low signal‐to‐noise ratio (SNR) scenarios.

ABSTRACT Microsatellites or simple sequence repeats (SSRs) are prevalent across various organisms' genomes. However, their distribution patterns and evolutionary dynamics in reptile genomes are rarely studied systematically. We herein conducted a comprehensive analysis of SSRs in the genomes of 36 reptile species. Our findings revealed that the total number of SSRs ranged from 1,840,965 to 7,664,452, accounting for 2.16%–8.19% of the genomes analyzed. The relative density ranged from 21,567.82 to 81,889.41 bp per megabase (Mbp). The abundance of different SSR categories followed the pattern of imperfect SSR (I‐SSR) > perfect SSR (P‐SSR) > compound SSR (C‐SSR). A significant positive correlation was observed between the number of SSRs and genome size (p = 0.0034), whereas SSR frequency (p = 0.013) or density (p = 0.0099) showed a negative correlation with genome size. Furthermore, no correlation was found between SSR length and genome size. Mononucleotide repeats were the most common P‐SSRs in crocodilians and turtles, whereas mononucleotides, trinucleotides, or tetranucleotides were the most common P‐SSRs in snakes, lizards, and tuatara. P‐SSRs of varying motif sizes showed nonrandom distribution across different genic regions, with AT‐rich repeats being predominant. The genomic SSR content of the squamate lineage ranked the highest in abundance and variability, whereas crocodilians and turtles showed a slowly evolving and reduced microsatellite landscape. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that genes harboring P‐SSRs in the coding DNA sequence regions were primarily involved in the regulation of transcription and translation processes. The SSR dataset generated in this study provides potential candidates for functional analysis and calls for broader‐scale analyses across the evolutionary spectrum.

Abstract The specific mechanisms underlying bacteria‐triggered cell death and osteogenic dysfunction in host bone marrow mesenchymal stem cells (BMSCs) remain unclear, posing a significant challenge to the repair of infected bone defects. This study identifies ferroptosis as the predominant cause of BMSCs death in the infected bone microenvironment. Mechanistically, the bacteria‐induced activation of the innate immune response in BMSCs leads to upregulation and phosphorylation of interferon regulatory factor 7 (IRF7), thus facilitating IRF7‐dependent ferroptosis of BMSCs through the transcriptional upregulation of acyl‐coenzyme A synthetase long‐chain family member 4 (ACSL4). Moreover, it is found that intervening in ferroptosis can partially rescue cell injuries and osteogenic dysfunction. Based on these findings, a hydrogel composite 3D‐printed scaffold is designed with reactive oxygen species (ROS)‐responsive release of antibacterial quaternized chitosan and sustained delivery of the ferroptosis inhibitor Ferrostatin‐1 (Fer‐1), capable of eradicating pathogens and promoting bone regeneration in a rat model of infected bone defects. Together, this study suggests that ferroptosis of BMSCs is a promising therapeutic target for infected bone defect repair.

Abstract The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti‐inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti‐inflammation and anti‐infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory‐microenvironment‐responsive nanomedicine is designed by using poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non‐toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus‐induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET‐based nanoparticles by simultaneously controlling infections and inflammation may be promising nano‐therapeutics for treatment of severe infectious diseases.

Abstract Scaffold‐based tissue engineering provides an efficient approach for repairing uterine tissue defects and restoring fertility. In the current study, a novel trilayer tissue engineering scaffold with high similarity to the uterine tissue in structure was designed and fabricated via 4D printing, electrospinning and 3D bioprinting for uterine regeneration. Highly stretchable poly(l‐lactide‐co‐trimethylene carbonate) (PLLA‐co‐TMC, “PTMC” in short)/thermoplastic polyurethane (TPU) polymer blend scaffolds were firstly made via 4D printing. To improve the biocompatibility, porous poly(lactic acid‐co‐glycolic acid) (PLGA)/gelatin methacryloyl (GelMA) fibers incorporated with polydopamine (PDA) particles were produced on PTMC/TPU scaffolds via electrospinning. Importantly, estradiol (E2) was encapsulated in PDA particles. The bilayer scaffolds thus produced could provide controlled and sustained release of E2. Subsequently, bone marrow derived mesenchymal stem cells (BMSCs) were mixed with gelatin methacryloyl (GelMA)‐based inks and the formulated bioinks were used to fabricate a cell‐laden hydrogel layer on the bilayer scaffolds via 3D bioprinting, forming ultimately biomimicking trilayer scaffolds for uterine tissue regeneration. The trilayer tissue engineering scaffolds thus formed exhibited a shape morphing ability by transforming from the planar shape to tubular structures when immersed in the culture medium at 37°C. The trilayer tissue engineering scaffolds under development would provide new insights for uterine tissue regeneration.

Abstract Human bocavirus (HBoV) 1 is considered an important pathogen that mainly affects infants aged 6–24 months, but preventing viral transmission in resource‐limited regions through rapid and affordable on‐site diagnosis of individuals with early infection of HBoV1 remains somewhat challenging. Herein, we present a novel faster, lower cost, reliable method for the detection of HBoV1, which integrates a recombinase polymerase amplification (RPA) assay with the CRISPR/Cas12a system, designated the RPA‐Cas12a‐fluorescence assay. The RPA‐Cas12a‐fluorescence system can specifically detect target gene levels as low as 0.5 copies of HBoV1 plasmid DNA per microliter within 40 min at 37°C without the need for sophisticated instruments. The method also demonstrates excellent specificity without cross‐reactivity to non‐target pathogens. Furthermore, the method was appraised using 28 clinical samples, and displayed high accuracy with positive and negative predictive agreement of 90.9% and 100%, respectively. Therefore, our proposed rapid and sensitive HBoV1 detection method, the RPA‐Cas12a‐fluorescence assay, shows promising potential for early on‐site diagnosis of HBoV1 infection in the fields of public health and health care. The established RPA‐Cas12a‐fluorescence assay is rapid and reliable method for human bocavirus 1 detection. The RPA‐Cas12a‐fluorescence assay can be completed within 40 min with robust specificity and sensitivity of 0.5 copies/μl.

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Abstract Metal–organic frameworks (MOFs) are a class of promising nanomaterials for atmospheric water harvesting (AWH), especially in arid remote areas. However, several challenges are still faced for practical applications because of the dissatisfied water adsorption/desorption properties in terms of the capability, kinetics, and stability. Herein, we report the facile synthesis of a nano‐sized octahedral nitrogen‐modified MOF‐801 that exhibits superior solar‐powered AWH performance using a custom‐made device, with a state‐of‐the‐art water harvesting ability up to 4.64LH2OkgMOFs−1 from air upon 12‐h test under a relative humidity (RH) of 30% and simulated sunlight irradiation. The nitrogen‐modified MOF‐801 with rapid sorption–desorption kinetics, uptakes 0.29gH2OgMOFs‐1 of water at 30% RH within 30 min and releases 90% of the captured water within 10 min under 1‐sun illumination. The success relies on N‐doping‐induced mixed‐linkers in the form of 2,3‐diaminobutanedioic acid and fumaric acid in the unique pore structures of the MOFs for rapid and high‐capacity water capture. The N‐doped MOF‐801 with water uptake capacity, fast adsorption kinetics, and cycle stability sheds light on the practical use of MOFs for effective solar‐powered water harvesting from droughty air.

Abstract Background Cancer‐related pain is one of the common priority symptoms in advanced lung cancer patients at the end‐of‐life (EOL). Alleviating pain is undoubtedly a critical component of palliative care in lung cancer. Our study was initiated to examined trends in opioid prescription‐level outcomes as potential indicators of undertreated pain in China. Methods This study used data on 1330 patients diagnosed with lung cancer of urban city medical insurance in China who died between 2014 and 2017. Opioid prescription‐level outcomes were determined by annual trends of the proportion of patients filling an opioid prescription, the total dose of opioids filled by decedents, and morphine milligram equivalents per day (MMED) at the EOL (defined as the 60 days before death). We further analyzed monthly changes in the number of opioid prescriptions filled, MMED, and mean daily dose of opioids per prescription (MDDP) of the last 60 days of life by year at death and age, respectively. Results A total of 959 patients with exact dates of death were included, with 432 cases (45.06%; 95% CI: 44.36%–45.77%) receiving at least one opioid prescription at the EOL. The declining trends were shown in the proportion of patients filling any opioid prescription, the total dose of opioids filled by decedents and MMED, with an annual decrease of 0.341% (p = 0.01), 104.23 mg (p = 0.011) and 2.84 mg (p = 0.014), respectively. Within the 31–60 days to the 0–30 days of life, the MMED declined 6.08 mg (95% CI: −7.14 to −5.03; p = 0.000351), while the number of opioid prescriptions rose 0.66 (95% CI: 0.160–1.16; p = 0.025). Like the MMED, the MDDP fell 4.11 mg (95% CI: −5.86 to −2.37; p = 0.005) within the last month before death compared to the previous month. Conclusion Terminal lung cancer populations in urban China have experienced reduced access to opioids at the EOL. The clinicians did not prescribe a satisfactory dose of opioids per prescription, while the patients suffered increasing pain in the last 30 days of life. Sufficient opioid analgesic administration should be advocated for lung cancer patients during the EOL period.

Abstract The carbon market plays a critical role in promoting the transition toward renewable energy sources and reducing greenhouse gas emissions in the electricity generation and transmission. Extant research has overlooked the dynamic bilateral causality that exists between electricity and carbon markets. Moreover, these studies have frequently treated the macroeconomic effect as exogenous. To bridge this research gap, this paper presents a holistic modeling framework that comprehensively captures the intertwined nature of electricity and carbon markets and their concomitant interactions with the overarching economy. The suggested modeling framework is an integration of three principal modules, namely, a carbon market, an electricity market, and economic system. This synergistic blend provides an exhaustive understanding of the entire market operation cycle. It offers detailed clearance rules, and most importantly, it adopts a macroeconomic systematic modeling approach for evaluating the impact emanating from the interconnected electricity and carbon markets. To illustrate the practicality and effectiveness of the proposed approach, a case study anchored on empirical data sourced from the electricity and carbon markets in China is conducted. The empirical findings underscore the fact that incorporating a green certificate market into the modeling framework can precipitate a reduction in greenhouse gas emissions. Additionally, the results indicate that expanding the scale of the green certificate market from 1.9% in 2021 to 33% by 2023 will increase the generation of green electricity by 10%.

Key Clinical Message One Kirsten Ras (KRAS) G12C mutated non‐small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first‐line KRAS‐targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8‐month median progress‐free survival (PFS) and 12.5‐month overall survival (OS) in previously treated KRAS G12C‐mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next‐generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG‐PS) with metastatic KRAS G12C‐mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first‐line treatment. Although 5‐month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG‐PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first‐line treatment with sotorasib for the advance untreated KRAS G12C‐mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C‐mutated patient may favor the immunotherapy.

Abstract Objective It has been observed that the prognosis of patients with HER2‐positive metastatic breast cancer has improved significantly with HER2‐targeted agents. However, there is still a lack of evidence regarding first‐line anti‐HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2‐positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti‐HER2 treatment in these patients. Methods Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2‐positive metastatic breast cancer were enrolled. Pyrotinib plus albumin‐bound paclitaxel were used as first‐line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. Results From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow‐up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand‐foot syndrome (3.7%). Toll‐like receptor 3 (TLR3) and Proto‐oncogene tyrosine‐protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. Conclusions This study demonstrates that pyrotinib plus albumin‐bound paclitaxel as a first‐line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2‐positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

Abstract The Gaussian noise model and estimators based on least squares (LS) are widely used in target localisation with distributed multiple‐input multiple‐output (MIMO) radar because of their computational efficiency. However, the accuracy of existing LS‐based target localisation algorithms deteriorates sharply in the presence of outliers in the measurements. Thus, a robust solution is developed based on the lp‐norm minimisation criterion and iteratively reweighted least squares (IRLS) for locating a moving target with impulse noise using the angle of arrival (AOA), time delay (TD), and Doppler shift (DS) measurements. First, the AOA, TD, and DS measurement noise models are developed based on the α‐stable distribution. Then, the localisation problem is transformed into an lp‐norm minimisation problem by linearising the AOA, TD, and DS measurement equations. Finally, the lp‐norm minimisation problem is solved using an IRLS method to obtain the target position and estimate the velocity. Moreover, the optimum of the norm order (p) and the Cramér–Rao lower bound for the target position and velocity estimation are derived under α‐stable distributed measurement noise. The simulation results demonstrate that the developed algorithm offers higher accurascy and robustness than the existing ones in the presence of measurement outliers.

Abstract Purpose The prognostic outcomes of metastasis patterns in patients with de novo metastatic breast cancer (dnMBC) of different ages are unknown. Our study used a large‐scale data to investigate the metastasis patterns and prognostic features in dnMBC of different ages. Methods Total 24,698 women with dnMBC in the Surveillance, Epidemiology and End Results database (2010–2018) were divided into three groups by age. Chi‐squared test was used to compare metastasis patterns and logistic regression was performed to investigate the risk of age and specific organ metastases. Kaplan–Meier survival curves were used to compare the overall survival. Results In three groups, young group had the largest proportion of liver metastases (35.2% vs. 28.2% vs. 21.1%, p

Abstract Passive localization using time difference of arrival (TDOA) is one of the common methods for radiated source target localization, and its localization performance depends on the accuracy of TDOA estimation. In many localization scenarios, the signals of target are intricate and often contain multiple ones, so how to effectively extract the time difference parameters from them becomes a difficult problem. This letter proposes a signal‐level fusion method for TDOA estimation to address this problem. At the receiver terminal, multiple signals are fused to obtain their cross‐ambiguity function, so as to estimate the TDOA value for target localization. The effect of fused signals on the accuracy of TDOA estimation is analyzed and the concept of frequency depression is proposed. Simulation experiments verify that the estimation method with signal‐level fusion gets a higher accuracy of the TDOA value and a smaller position error in target localization.