Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Dietary sn-2 palmitate influences cognitive behavior by increasing the transport of liver-produced lysophosphatidylcholine VLCPUFAs to the brain.

Investigations indicated that sn-2 palmitate have positive effects on brain development, although its mechanism remains largely unexamined. This research delved into how a diet abundant in sn-2 palmitate influenced the cognitive behavior of mice and elucidated the associated mechanisms using metabolomics and lipidomics. The study demonstrated that dietary sn-2 palmitate led to improved working memory and cognition in mice, as well as an increase in brain BDNF concentration when compared to those fed blend vegetable oil (BVO). This was because sn-2 palmitate feeding promoted the synthesis of very long-chain fatty acids (VLCPUFAs) for the lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) in the liver. This led to more efficient delivery of VLCPUFAs to the brain, as indicated by elevated concentration of LPC/LPE-VLCPUFAs in the liver and heightened expression of the major facilitator superfamily domain containing 2a (MFSD2A). In essence, this paper offered a potential mechanism by which sn-2 palmitate enhanced mouse neurodevelopment.

A portable micro-nanochannel bio-3D printed liver microtissue biosensor for DON detection.

We investigated a portable micro-nanochannel biosensor 3D-printed liver microtissues for rapid and sensitive deoxynivalenol (DON) detection. The screen-printed carbon electrode (SPCE) was modified with nanoporous anodic aluminum oxide (AAO), gold nanoparticles (AuNPs), and cytochrome C oxidase (COx) to enhance sensor performance. Gelatin methacrylate hydrogel, combined with hepatocellular carcinoma cells, formed the bioink for 3D printing. Liver microtissues were prepared through standardized and high-throughput techniques via bio-3D printing technology. These microtissues were immobilized onto modified electrodes to fabricate liver microtissue sensors. The peak current of this biosensor was positively correlated with DON concentration, as determined by cyclic voltammetry (CV), within a linear detection range of 2∼40 µg/mL. The standard curve equation is denoted by ICV(µA) = = 18.76956 + 0.03107CDON(µg/mL), with a correlation coefficient R2 was 0.99471(n＝3). A minimum detection limit of 1.229 µg/mL was calculated from the formula, indicating the successful construction of a portable micro-nanochannel bio-3D printed liver microtissue biosensor. It provides innovative ideas for developing rapid and convenient instrumentation to detect mycotoxin hazards after grain production. It also holds significant potential for application in the prediction and assessment of post-production quality changes in grain.

Gelatinase MMP Expression Is Correlated with Muscle Fiber Growth in Maiwa Yak Gluteus Maximus.

Yak (Bos grunniens) is the only large mammal species in the Qinghai-Tibet Plateau. The most of the studies in yak remain confined for the main contributor of meat, which requires a good understanding of muscle growth. Matrix metalloproteinases-2 (MMP-2) and MMP-9 are widely expressed in mammal tissues they mainly degrade collagen in the extracellular matrix for muscle development. However, the influence of MMPs on yak muscle remains unclear. Hence, we assessed the expression of MMP-2, MMP-9, and related factors with ages in Maiwa yak for study the correlation between MMPs expression and yak muscle growth. The mRNA expression of MMP-2, MMP-9, MMP-14, and collagen III increased with age, except collagen I by quantitative real-time PCR. Moreover, muscle fiber diameter increased with age, whereas the density decreased, which showed that fiber grew thicker with age using hematoxylin-eosin staining. Interestingly, MMP and collagen expression significantly decreased with age using western blotting. Pearson correlation method showed that both mRNA and protein expression of MMP-14 and collagen were strongly correlated with muscle fiber growth, but MMP-2 protein and MMP-9 mRNA expression were moderately correlated with muscle fiber growth. Overall, the expression of MMPs and collagen significantly changed with age, which means that MMPs and their function related genes could correlate with Maiwa yak muscle fiber growth.

Enzyme-accelerated catalytic DNA circuits enable rapid and one-pot detection of bacterial pathogens.

Catalytic DNA circuits, serving as signal amplification strategies, can enable simple and accurate detection of pathogenic bacteria in complex matrices but suffer from low reaction rates and depths. Herein, we design an enzyme-accelerated catalytic hairpin assembly (EACHA) in which duplex DNA products are converted into hairpin reactants to continue participating in the next circuit reaction with the assistance of RNase H. Profiting from the high recyclability of the reactants, EACHA exhibits an approximately 37.6-fold enhancement in the rate constant and a two-order-of-magnitude improvement in sensitivity compared to conventional catalytic hairpin assembly (CHA). By integrating an allosteric probe with EACHA, a one-pot method is developed for rapid and direct detection of S. enterica Enteritidis (S. Enteritidis). This method is capable of detecting 15 CFU mL-1 of S. Enteritidis within 20 min, which is superior to that of real-time PCR. By testing 60 milk samples, we demonstrate this method's high accuracy in discriminating contaminated samples, with an area under the curve (AUC) of 0.997. Moreover, this method can be employed to accurately diagnose early-stage infected mice, with an AUC of 1.00 for feces samples and 0.986 for serum samples. Therefore, this study offers a simple and feasible method for identifying pathogens in complex matrices.

Does Sperm DNA Fragmentation Index Continuously Decrease Over Time After Varicocelectomy in Varicocele-Induced Infertility? A Systematic Review and Meta-Analysis.

Varicocele (VC) is the most frequent and reversible cause of male infertility. One of the preferred management strategies to alleviate this problem is varicocelectomy. However, there are no researchers who have explored the relationship between better timing and postoperative sperm DNA fragmentation index (DFI) improvement in patients. We conducted this meta-analysis by enrolling published studies to find out the best waiting time after varicocelectomy to wait for better improvement of sperm DFI. A literature search was conducted using PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases. The data from the pooled analysis were presented as mean difference (MD) along with a 95% confidence interval (CI). Heterogeneity was evaluated using I2. Four studies were included after screening relevant literature. Statistical analysis revealed that after varicocelectomy, follow-up results within 3 months showed a significant improvement in sperm DFI compared with the preoperative period (MD: -3.66, 95% CI = [-5.17, -2.14], p < .00001), and follow-up results with 6 months showed a significant improvement in sperm DFI compared with the postoperative 3 months as well (MD: -1.51, 95% CI = [-2.73, -0.29], p = .02). Notably, no further improvement in sperm DFI was observed when the follow-up period reached 12 months (MD: -1.59, 95% CI = [-3.22, 0.05], p = .06). Six months after varicocelectomy may be the optimal time for sperm DFI compared with 12 months or even longer, which means it is also the preferable time for conception. However, more well-designed prospective studies are needed in the future to validate our conclusion.

Chromosome-level genome of diamondback terrapin provides insight into the genetic basis of salinity adaptation.

Diamondback terrapins (Malaclemys terrapin centrata) exhibit strong environmental adaptability and live in both freshwater and saltwater. However, the genetic basis of this adaptability has not been the focus of research. In this study, we successfully constructed a ∼2.21-Gb chromosome-level genome assembly for M. t. centrata using high-coverage and high-depth genomic sequencing data generated on multiple platforms. The M. t. centrata genome contains 25 chromosomes and the scaffold N50 of ∼143.75 Mb, demonstrating high continuity and accuracy. In total, 53.82% of the genome assembly was composed of repetitive sequences, and 22 435 protein-coding genes were predicted. Our phylogenetic analysis indicated that M. t. centrata was closely related to the red-eared slider turtle (Trachemys scripta elegans), with divergence approximately ∼23.6 million years ago (Mya) during the early Neogene period of the Cenozoic era. The population size of M. t. centrata decreased significantly over the past ∼14 Mya during the Cenozoic era. Comparative genomic analysis indicated that 36 gene families related to ion transport were expanded and several genes (AQP3, solute carrier subfamily, and potassium channel genes) underwent specific amino acid site mutations in the M. t. centrata genome. Changes to these ion transport-related genes may have contributed to the remarkable salinity adaptability of diamondback terrapin. The results of this study not only provide a high-quality reference genome for M. t. centrata but also elucidate the possible genetic basis for salinity adaptation in this species.

Synergistic Therapy of Melanoma by Co-Delivery of Dacarbazine and Ferroptosis-Inducing Ursolic Acid Using Biomimetic Nanoparticles.

Melanoma is one of the most aggressive types of cancer and is prone to metastasis, making current clinical treatment quite difficult. The usage of the first-line medication dacarbazine (DTIC) for melanoma is limited due to harsh side effects, limited water solubility, and a short half-life. To tackle these disadvantages, polylactic acid-hydroxyacetic acid copolymer nanoparticles (NPs) loaded with dacarbazine and ursolic acid (NPs) were fabricated, which were further encapsulated with a red blood cell membrane (RNPs). MTT, apoptosis assay, wound healing assay, colony formation assay, and immunohistochemistry were used to assess the antitumor effect of NPs and RNPs. Ferroptosis evaluation was implemented using GSH detection and the malondialdehyde assay. We found that RNPs exhibited stability and biosafety in vitro and in vivo and achieved superior anticancer ability against xenograft tumors compared with single agents and NPs, which indicated the synergistic and biomimetic efficacy. Furthermore, ferroptotic activity was observed in RNPs-treated tumor cells, and ferroptosis inhibition could partially rescue melanoma cells from RNPs-induced cell death. Collectively, this study evaluated the potential of RNPs as a novel biomimetic nanomedicine for synergistic melanoma therapy by eliciting ferroptosis in tumor cells with both anticancer activity and biosafety.

Pcv-aCO2/Ca-cvO2 Combined with Optic Nerve Sheath Diameter in Predicting Elevated Intracranial Pressure of Patients with Traumatic Brain Injury in Prehospital Setting.

Purpose: To investigate a correlation between the central venous minus arterial CO2 pressure to arterial minus central venous O2 content ratio (Pcv-aCO2/Ca-cvO2) combined with optic nerve sheath diameter (ONSD) in predicting prehospital elevated intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Patients and Methods: This was a prospective observational study of all adult TBI patients from the surgical intensive care unit who underwent invasive ICP monitoring between January 2023 and December 2023. Using a Delica MVU-6300 machine with 14-5 MHz linear probe to measure ONSD. We drew blood samples for arterial and central venous blood gases to measure and calculate the following indicators such as Pcv-aCO2, Ca-cvO2, and Pcv-aCO2/Ca-cvO2 ratio. ONSD and Pcv-aCO2/Ca-cvO2 were recorded during the first 3 days after admission. Simultaneous ICP values were gained from the invasive monitoring. Associations between ONSD, Pcv-aCO2/Ca-cvO2 and simultaneous ICP were explored by Spearman correlation analysis. We constructed an ROC curve to identify the ONSD and Pcv-aCO2/Ca-cvO2 cutoff for the evaluation of elevated ICP. Results: We included 54 patients aged mean 57.13 (standard deviation 4.02) years and 24 (44%) were male. A significant correlation was observed between ONSD and ICP (r = 0.74, P < 0.01). The AUC was 0.861 (95% CI: 0.727-0.951), with a best cutoff value of 5.62 mm. Using a cutoff of 5.62mm, ONSD had a sensitivity of 92.8%, specificity of 80.4%. The Pcv-aCO2/Ca-cvO2 ratio also significantly correlated with ICP (r = 0.70, P < 0.01). The AUC was 0.791 (95% CI: 0.673-0.889). The optimal Pcv-aCO2/Ca-cvO2 value for predicting elevated ICP was 1.98 mmHg/mL. Using a cutoff of 1.98 mmHg/mL, Pcv-aCO2/Ca-cvO2 had a sensitivity of 87.3%, specificity of 77.2%. The AUC for ONSD combined with Pcv-aCO2/Ca-cvO2 was 0.952 (95% CI: 0.869-0.971), which had a sensitivity of 95.1%, specificity of 93.9%. Conclusion: Pcv-aCO2/Ca-cvO2 combined with ONSD performed best in predicting elevated intracranial pressure of patients with TBI in a prehospital setting. Our findings provide a crucial tool to improve earlier management of these patients in prehospital care, where the availability and utilization of invasive monitoring is limited. It could lead to significant changes in how TBI patients are monitored and treated before reaching a hospital.

Blue light inhibits cell viability and proliferation in hair follicle stem cells and dermal papilla cells.

Hair loss is a prevalent issue worldwide, which, though not life-threatening, can result in psychological problems, low self-esteem, and social anxiety. Previous studies have shown that ultraviolet radiation can have negative effects on hair follicle cells, leading to hair loss, while the impact of blue light on hair and hair follicle has largely been overlooked. This study aimed to examine the effects of blue light on hair follicle stem cells (HFSCs) and primary dermal papilla cells (DPCs), which are essential components of hair follicles. Human HFSCs and primary DPCs were exposed to blue light (457 nm) at various intensities (1, 4, 8, and 16 mW/cm2) for 3 days. Subsequently, cell viability, cell proliferation, and intracellular reactive oxygen species (ROS) were assessed. The results showed that blue light (457 nm) significantly reduced the cell viability and proliferation of HFSCs and DPCs in vitro, with the inhibition being intensity-dependent. Additionally, blue light triggered the overproduction of ROS in the DPCs. While the exact mechanisms by which blue light affects hair follicle cells remain unclear, these findings suggest that blue light could impede the growth of these cells. This insight may offer a new approach to protecting hair by avoiding exposure to high-intensity blue light.

Azoospermia Due to Functional and Partial Ejaculatory Duct Obstruction: A Rare Case Report and Literature Review.

Ejaculatory duct obstruction (EDO) is a rare but treatable cause of male infertility. This case report describes a 28-year-old male with obstructive azoospermia. The patient came to our hospital after a fertility check-up revealed azoospermia. A subsequent semen analysis confirmed azoospermia. Transrectal ultrasonography (TRUS) and magnetic resonance imaging (MRI) revealed bilaterally enlarged seminal vesicles and thickened, calcified ejaculatory duct walls. The patient underwent transurethral seminal vesiculoscopy and transurethral resection of the ejaculatory ducts (TURED) for presumed partial EDO. Despite two transurethral seminal vesiculoscopy and TURED procedures, postoperative semen analysis still showed azoospermia. TRUS indicated non-contractile seminal vesicles and an unobstructed ejaculatory duct. The patient ultimately underwent percutaneous epididymal sperm aspiration for assisted reproductive technology and his spouse got pregnant. We identified a case of azoospermia caused by a rare combination of partial and functional ejaculatory duct obstruction. There are currently no reports of similar cases. This case report aims to provide valuable insights for diagnosing and treating EDO.

Modern agriculture and One Health.

BACKGROUND: The development of modern agriculture has significantly contributed to improving global food security and safety, alleviating poverty, and enhancing human health and livelihoods. However, the rapid advancement of modern agriculture has also brought about various challenges that limit its sustainable development. This commentary aims to discuss these issues through the One Health lens, and provide valuable insights for balancing modern agricultural activities with the need to protect and promote the health of all the sectors. MAIN TEXT: This commentary explores the multifaceted impacts of modern agriculture on social development, as well as the associated various health challenges and environmental impacts within the One Health framework. Key issues include ecosystem degradation, increased risk of interspecies disease transmission like zoonoses, reverse zoonoses, and vector-borne diseases, and the escalated threat of antimicrobial resistance due to intensified agricultural production and increased antimicrobial use. To address these challenges, this commentary outlines potential solutions anchored in the development and implementation of modern technologies and good agricultural practices, such as precision farming, integrated pest management, biosecurity measures, vaccination programs, as well as surveillance and early detection of health risks. CONCLUSIONS: Good agricultural practices supported by scientific and technological advancements are essential for aligning productivity with the One Health vision, ensuring the health and resilience of all the sectors. Enhancing stakeholder education, strengthening regulatory frameworks, and providing supportive policies and infrastructure for farmers to adopt sustainable practices are crucial for the long-term viability of agrifood systems. The Food and Agriculture Organization of the United Nations plays a pivotal role in guiding this sustainable transformation through the One Health approach.

Corneal stromal lenticule transplantation for the treatment of congenital optic disc pit maculopathy : a case report and review.

BACKGROUND: Congenital optic disc pit (ODP) is a relatively uncommon congenital anomaly of the optic disc, which seriously affects the patient's vision when combined with optic disc pit maculopathy(ODP-M). Currently, the treatment of ODP-M remains a clinical challenge and a focus of research. CASE PRESENTATION: A boy had a pit in the inferotemporal segment of the optic disc with ODP-M. Optical Coherence Tomography(OCT) showed ODP and serous retinal detachment. He was treated with pars plana vitrectomy(PPV), followed by Corneal Stromal Lenticule (CSL) sealing and C3F8 tamponade. In the end, significant anatomical improvement was achieved, and the Best Corrected Visual Acuity(BCVA) was improved. CONCLUSIONS: The CSL transplantation may be a viable therapeutic option for improving ODP-M with stable anatomical and functional result. However, more cases and longer follow-up are needed to confirm the safety and effectiveness of the technology.

Integrated multi-omics approach revealed TTNtv c.13254T>G causing dilated cardiomyopathy in mice.

Titin-truncating variant (TTNtv) is the most common genetic cause of dilated cardiomyopathy (DCM). In the previous study, we found a novel heterozygous TTNtv c.13254T>G (p.Tyr4418Ter) associated with DCM, but lacking functional evidence. The purpose of this study is to demonstrate the pathogenicity of TTNtv c.13254T>G. We constructed a mouse model with TTNtv Y4370* on exon 45 by CRISPR/Cas9-mediated genome engineering to imitate the TTNtv. c.13254T>G. Transmission electron microscope (TEM), immunohistochemistry, western blot (WB), Transcriptome sequencing (RNA-seq), and tandem Mass Tag (TMT) proteome analysis were performed on the mutant (KO) and WT mice cardiac tissue. Multi-omics association analysis was performed to observe the damages of cardiac tissue, and changes of inflammatory factors and Titin protein. TEM results showed that TTNtv Y4370* may lead to broken myofibrils, sparse myofilament structure, and broken Z-line and H-zone in many places of cardiac tissue of KO mice. Immunohistochemistry showed a significant increase in cTnT and TNF-α expression level in KO mice cardiac tissue. RNA-seq and TMT proteome enrichment analysis further strengthened that TTNtv Y4370* led to cardiac injury and inflammatory response in KO mice. In summary, TTNtv c.13254T>G contributed to the cardiac injury, inflammatory response and construct alterations in mice, that is TTNtv c.13254T>G may cause DCM in mice. These functional evidence of TTNtv c.13254T>G have important significance for follow-up genetic research of DCM in human.

Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway.

Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, with hypertension emerging as an independent risk factor. Previous literature has established associations between DNA damage response (DDR) and autophagy in relation to the pathogenesis of AF. The aim of this study was to evaluate the effect of atrial DNA damage response in persistent hypertension-induced atrial electrical and structural remodeling, and to further explore the potential therapeutic targets. Patient samples, spontaneous hypertensive rats (SHR) and angiotensin II (Ang II)-challenged HL-1 cells were employed to elucidate the detailed mechanisms. Bioinformatics analysis and investigation on human atrial samples revealed a critical role of DDR in the pathogenesis of AF. The markers of atrial DNA damage, DDR, autophagy, inflammation and fibrosis were detected by western blot, immunofluorescence, monodansyl cadaverine (MDC) assay and transmission electron microscopy. Compared with the control group, SHR exhibited significant atrial electrical and structural remodeling, abnormal increase of autophagy, inflammation, and fibrosis, which was accompanied by excessive activation of DDR mediated by the ATM/CHK2/p53 pathway. These detrimental changes were validated by in vitro experiments. Ang II-challenged HL-1 cells also exhibited significantly elevated γH2AX expression, and markers related to autophagy, inflammation as well as structural remodeling. Additionally, inhibition of ATM with KU55933 (a specific ATM inhibitor) significantly reversed these effects. Collectively, these data demonstrate that DNA damage and the subsequently overactivated ATM/CHK2/p53 pathway play critical roles in hypertension-induced atrial remodeling and the susceptibility to AF. Targeting ATM/CHK2/p53 signaling may serve as a potential therapeutic strategy against AF.

Quantitative detection of heavy metal Cd in vegetable oils: A nondestructive method based on Raman spectroscopy combined with chemometrics.

Heavy metal contaminants in vegetable oils can cause irreversible damage to human health. In this study, the quantitative detection of Cd in vegetable oils was investigated based on Raman spectroscopy combined with chemometric methods. The necessary preprocessing of the Raman signal was performed using baseline calibration and the Savitzky-Golay method. Three variable optimization methods were applied to the preprocessed Raman spectra. Namely, bootstrap soft shrinkage, multiple feature spaces ensemble strategy with least absolute shrinkage and selection operator, and competitive adaptive reweighted sampling (CARS), respectively. Partial least squares regression (PLSR) modeling for the determination of Cd in vegetable oils. The results show that three variable optimization algorithms improved the predictive performance of the model. Among them, the CARS-PLSR model has strong generalization performance and robustness. Its prediction coefficient of determination ( R P 2 $R_{\mathrm{P}}^2$ ) was 0.9995, the root mean square error of prediction was 0.3533 mg/kg, and the relative prediction deviation was 44.3748, respectively. In summary, rapid quantitative analysis of Cd contamination in vegetable oils can be realized based on Raman spectroscopy combined with chemometrics.

BMSCs-derived exosomes carrying miR-668-3p promote progression of osteoblasts in osteonecrosis of the femoral head: Expression of proteins CD63 and CD9.

Recently, exosomes that are derived from bone marrow mesenchymal stem cells (BMSCs) have garnered considerable interest due to their significant roles in the processes of bone regeneration and repair. Among the various molecular components present within these exosomes, miR-668-3p has emerged as a pivotal microRNA that may be instrumental in modulating the function and proliferation of osteoblasts, the cells responsible for bone formation. The primary objective of this research was to examine the enhancing effects of BMSC-derived exosomes that are enriched with miR-668-3p on the advancement of osteoblasts in the context of osteonecrosis of the femoral head. Furthermore, the study aimed to analyze how the expression of specific exosomal proteins, namely CD63 and CD9, influences this biological process. To conduct the investigation, BMSCs were isolated from healthy rat models, followed by the extraction of their secreted exosomes. The subsequent phase of the study involved assessing the proliferation and differentiation of osteoblasts by introducing the exosomes enriched with miR-668-3p into an experimental setup representing osteonecrosis of the femoral head. The findings revealed that exosomes derived from BMSCs, which contained miR-668-3p, significantly enhanced the proliferation of osteoblasts as well as the expression of key osteogenic marker genes. Notably, the levels of CD63 and CD9 proteins were markedly increased in the treated groups, indicating that the mechanisms underlying this promotion might involve cell adhesion and the endocytic uptake of exosomes.

The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer.

Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre;PyMT;Zeb1fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT;Zeb1cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.

Accessibility of and Barriers to Long-Term Follow-Up Care for Childhood Cancer Survivors.

Importance: Childhood cancer survivorship programs and long-term follow-up (LTFU) practices are inadequate in most regions of China. Objective: To understand the clinician and caregiver perceptions of LTFU care and to identify barriers to adherence to LTFU care in mainland China. Design, Setting, and Participants: This survey study had a 2-phase sequential mixed-methods approach, consisting of a cross-sectional survey followed by semistructured interviews. Participants included oncology clinicians recruited through an educational seminar on LTFU and caregivers recruited through convenience sampling. Data were collected from November 2022 to September 2023. Main Outcomes and Measures: The clinician survey and interview focused on the standards and resources for LTFU care at their practicing institution and barriers to the coordination of LTFU care. For caregivers, the survey and interview focused on their awareness of and participation in LTFU care and their opinions on future LTFU care visits. Results: A total of 101 clinicians (28 [27.7%] male; 73 [72.3%] female; 46 [45.6%] aged >40 to 50 years) completed the survey (response rate: 90.2%) representing 32 institutions from 22 provinces. As for the caregivers' survey, 164 eligible participants (36 [22.0%] male; 128 [78.0%] female) were recruited (response rate: 20.2%). The majority of the caregivers had received a high school or greater education (96 [56.7%]) and were parents of CCSs diagnosed with leukemia (67 [40.9%]), lymphoma or solid tumors (47 [28.7%]), or conditions requiring hematopoietic stem cell transplantation (50 [30.5%]). Most clinicians (74 [73.3%]) reported providing late effects care, yet only 10 (13.5%) had a dedicated follow-up clinic for CCSs. Two-thirds (64 [63.4%]) reported that the LTFU plan for each survivor is solely determined by their clinical judgment. In structured interviews, all doctors admitted to deviating from published guidelines due to challenges in implementing screening recommendations in their settings. Barriers to providing LTFU services included patient-related factors (76 [75.2%]), survivor knowledge deficits (61 [60.4%]), and the absence of dedicated LTFU clinics (61 [60.4%]). Among caregivers responding to the survey, 60 (36.6%) had never heard of late effects. Overall, 22 of 26 caregivers (84.6%) who participated in the interviews were not aware of potential late effects, although 17 (68.0%) could articulate existing conditions and symptoms that their children were experiencing. Conclusions: In this mixed-methods study involving clinicians and caregivers, substantial disparities in the uniformity and accessibility of LTFU in China were observed, suggesting the imperative need for a standardized approach to LTFU care for survivors. This includes advocating for establishment of dedicated clinics, alongside an emphasis on enhanced education and training for both clinicians and caregivers.

Photoinduced Radical Approach for Desulfurative Alkylation of Cysteine Derivatives to Make Unnatural Amino Acids.

Unnatural amino acids (UAAs) are highly valuable molecules in organic synthesis, pharmaceutical sciences, and material science. Herein, we present a photocatalytic radical approach for desulfurative alkylation of cysteine derivatives with arenethiol as the hydrogen atom transfer catalyst for making UAAs and peptides. The formate salt, acting as the hydrogen atom donor, in situ generates the highly reductive CO2 radical anion species, which is the key to unlocking the C-S bond cleavage process with a simple benzoyl protecting group. No photocatalyst is required for the radical initiation and propagation, which makes such a visible-light-induced process mild, efficient, and sustainable.