Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3ß/ß-catenin signaling.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers. METHODS: Bioinformatics analyses were performed to reveal EC patients' prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively. RESULTS: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3ß-mediated ß-catenin ubiquitination and degradation, thus facilitating the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/ß-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects. CONCLUSIONS: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/ß-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.

Terahertz Biosensor Engineering Based on Quasi-BIC Metasurface with Ultrasensitive Detection.

Terahertz (THz) sensors have attracted great attention in the biological field due to their nondestructive and contact-free biochemical samples. Recently, the concept of a quasi-bound state in the continuum (QBIC) has gained significant attention in designing biosensors with ultrahigh sensitivity. QBIC-based metasurfaces (MSs) achieve excellent performance in various applications, including sensing, optical switching, and laser, providing a reliable platform for biomaterial sensors with terahertz radiation. In this study, a structure-engineered THz MS consisting of a "double C" array has been designed, in which an asymmetry parameter α is introduced into the structure by changing the length of one subunit; the Q-factor of the QBIC device can be optimized by engineering the asymmetry parameter α. Theoretical calculation with coupling equations can well reproduce the THz transmission spectra of the designed THz QBIC MS obtained from the numerical simulation. Experimentally, we adopt an MS with α = 0.44 for testing arginine molecules. The experimental results show that different concentrations of arginine molecules lead to significant transmission changes near QBIC resonant frequencies, and the amplitude change is shown to be 16 times higher than that of the classical dipole resonance. The direct limit of detection for arginine molecules on the QBIC MS reaches 0.36 ng/mL. This work provides a new way to realize rapid, accurate, and nondestructive sensing of trace molecules and has potential application in biomaterial detection.

The relative contribution of PM2.5 components to the obstructive ventilatory dysfunction-insights from a large ventilatory function examination of 305,022 workers in southern China.

BACKGROUND: The new round of WHO/ILO Joint Estimates of the Work-related Burden of Disease assessment requires futher research to provide more evidence, especially on the health impact of ambient air pollution around the workplace. However, the evidence linking obstructive ventilatory dysfunction (OVD) to fine particulate matter (PM2.5) and its chemical components in workers is very limited. Evidence is even more scarce on the interactive effects between occupational factors and particle exposures. We aimed to fill these gaps based on a large ventilatory function examination of workers in southern China. METHODS: We conducted a cross-sectional study among 363,788 workers in southern China in 2020. The annual average concentration of PM2.5 and its components were evaluated around the workplace through validated spatiotemporal models. We used mixed-effect models to evaluate the risk of OVD related to PM2.5 and its components. Results were further stratified by basic characteristics and occupational factors. FINDINGS: Among the 305,022 workers, 119,936 were observed with OVD. We found for each interquartile range (IQR) increase in PM2.5 concentration, the risk of OVD increased by 27.8 (95 % confidence interval (CI): 26.5-29.2 %). The estimates were 10.9 % (95 %CI: 9.7-12.1 %), 15.8 % (95 %CI: 14.5-17.2 %), 2.6 % (95 %CI: 1.4-3.8 %), 17.1 % (95 %CI: 15.9-18.4 %), and 11 % (95 %CI: 9.9-12.2 %), respectively, for each IQR increment in sulfate, nitrate, ammonium salt, organic matter and black carbon. We observed greater effect estimates among females, younger workers, workers with a length of service of 24-45 months, and professional skill workers. Furthermore, it is particularly noteworthy that the noise-exposed workers, high-temperature-exposed workers, and less-dust-exposed workers were at a 5.7-68.2 % greater risk than others. INTERPRETATION: PM2.5 and its components were significantly associated with an increased risk of OVD, with stronger links among certain vulnerable subgroups.

Nitrogen fertilization modulates rice phyllosphere functional genes and pathogens through fungal communities.

The phyllosphere is a vital yet often neglected habitat hosting diverse microorganisms with various functions. However, studies regarding how the composition and functions of the phyllosphere microbiome respond to agricultural practices, like nitrogen fertilization, are limited. This study investigated the effects of long-term nitrogen fertilization with different levels (CK, N90, N210, N330) on the functional genes and pathogens of the rice phyllosphere microbiome. Results showed that the relative abundance of many microbial functional genes in the rice phyllosphere was significantly affected by nitrogen fertilization, especially those involved in C fixation and denitrification genes. Different nitrogen fertilization levels have greater effects on fungal communities than bacteria communities in the rice phyllosphere, and network analysis and structural equation models further elucidate that fungal communities not only changed bacterial-fungal inter-kingdom interactions in the phyllosphere but also contributed to the variation of biogeochemical cycle potential. Besides, the moderate nitrogen fertilization level (N210) was associated with an enrichment of beneficial microbes in the phyllosphere, while also resulting in the lowest abundance of pathogenic fungi (1.14 %). In contrast, the highest abundance of pathogenic fungi (1.64 %) was observed in the highest nitrogen fertilization level (N330). This enrichment of pathogen due to high nitrogen level was also regulated by the fungal communities, as revealed through SEM analysis. Together, we demonstrated that the phyllosphere fungal communities were more sensitive to the nitrogen fertilization levels and played a crucial role in influencing phyllosphere functional profiles including element cycling potential and pathogen abundance. This study expands our knowledge regarding the role of phyllosphere fungal communities in modulating the element cycling and plant health in sustainable agriculture.

Personalised graded psychological intervention on negative emotion and quality of life in patients with breast cancer.

BACKGROUND: Psychological factors are a risk factor for the incidence of breast cancer and have a significant impact on patient prognosis. OBJECTIVE: The present study aims to investigate the effects of personalised graded psychological intervention on negative emotion and quality of life in patients with breast cancer. METHODS: A total of 200 patients with breast cancer were randomly divided into two groups: an experimental group (n= 100) and control group (n= 100). Both groups received routine nursing care. The experimental group received personalised graded psychological intervention care, and the control group received routine nursing measures. After 2 months of standard treatment, the patients' quality of life and negative emotions were evaluated using the self-rating depression scale (SDS), self-rating anxiety scale (SAS), social support rating scale (SSRS) and quality of life measurement scale (FACT-B) scoring criteria. RESULTS: There were no significant differences in the general data between the two groups (p> 0.05). Furthermore, there were no significant differences in the SDS, SAS, SSRS and FACT-B scores between the two groups before personalised graded psychological intervention (p> 0.05). After the intervention, the experimental group exhibited an improved nursing effect compared with the control group. The SDS and SAS scores were lower in the experimental group than in the control group (p< 0.05); after the intervention, the SDS and SAS scores were significantly lower in the experimental group than in the control group (p< 0.05). The SSRS and FACT-B scores were higher in the experimental group than in the control group (p< 0.05), and the experimental group's post-intervention SSRS and FACT-B scores were significantly higher than before the intervention (p< 0.05). CONCLUSIONS: The use of personalised graded psychological intervention for the nursing of patients with breast cancer in clinical practice can significantly reduce patients' negative emotions as well as improve positive emotions and quality of life; thus, this method can be popularised in the nursing process.

Z-scheme Fe@Fe2O3/BiOBr heterojunction with efficient carrier separation for enhanced heterogeneous photo-Fenton activity of tetracycline degradation: Fe2+ regeneration, mechanism insight and toxicity evaluation.

The recombination of photogenerated carrier leads to inefficient Fe2+ regeneration, which limits the extensive application of heterogeneous photo-Fenton. Here, a novel Fe@Fe2O3/BiOBr catalyst with Z-scheme heterojunction structure is designed, and the establishment of the Z-scheme heterojunction facilitates the separation and transfer of photogenerated carrier and maintains the superior redox capability of the system. As-prepared Fe@Fe2O3/BiOBr catalyst exhibits outstanding catalytic performance and stability, especially for the optimum composite FFB-3, its degradation efficiency of tetracycline (TC) achieves 98.22% and the mineralization degree reaches 59.48% within 90 min under natural pH. The preeminent catalytic efficiency benefited from the synergistic of heterogeneous photo-Fenton and Z-scheme carriers transfer mechanism, where Fe2+ regeneration was achieved by photogenerated electrons, and increased hydroxyl radicals were produced with the participation of H2O2 in-situ generated. The results of free-radical scavenging experiment and ESR illustrated that •OH, •O2-, 1O2 and h+ were active species participating in TC degradation. Furthermore, the TC degradation paths were proposed according to LC-MS, and the toxicity evaluation result showed that the toxicity of TC solutions was markedly decreased after degradation. This study provides an innovative strategy for heterogeneous photo-Fenton degradation of antibiotic contaminations by constructing Z-scheme heterojunctions.

Iodine Adsorption-Desorption-Induced Structural Transformation and Improved Ag+ Turn-On Luminescent Sensing Performance of a Nonporous Eu(III) Metal-Organic Framework.

Posttreatment of pristine metal-organic frameworks (MOFs) with suitable vapor may be an effective way to regulate their structures and properties but has been less explored. Herein, we report an interesting example in which a crystalline nonporous Eu(III)-MOF was transferred to a porous amorphous MOF (aMOF) via iodine vapor adsorption-desorption posttreatment, and the resulting aMOF showed improved turn-on sensing properties with respect to Ag+ ions. The crystalline Eu-MOF, namely, Eu-IPDA, was assembled from Eu(III) and 4,4'-{4-[4-(1H-imidazol-1-yl)phenyl]pyridine-2,6-diyl}dibenzoic acid (H2IPDA) and exhibited a two-dimensional (2D) coordination network based on one-dimensional secondary building blocks. The close packing of the 2D networks gives rise to a three-dimensional supramolecular framework without any significant pores. Interestingly, the nonporous Eu-IPDA could absorb iodine molecules when Eu-IPDA crystals were placed in iodine vapor at 85 °C, and the adsorption capacity was 1.90 g/g, which is comparable to those of many MOFs with large BET surfaces. The adsorption of iodine is attributed to the strong interactions among the iodine molecule, the carboxy group, and the N-containing group and leads to the amorphization of the framework. After immersion of the iodine-loaded Eu-IPDA in EtOH, approximately 89.7% of the iodine was removed, resulting in a porous amorphous MOF, denoted as a-Eu-IPDA. In addition, the remaining iodine in the a-Eu-IPDA framework causes strong luminescent quenching in the fluorescence emission region of the Eu(III) center when compared with that in Eu-IPDA. The luminescence intensity of a-Eu-IPDA in water suspensions was significantly enhanced when Ag+ ions were added, with a detection limit of 4.76 × 10-6 M, which is 1000 times that of pristine Eu-IPDA. It also showed strong anti-interference ability over many common competitive metal ions and has the potential to sense Ag+ in natural water bodies and traditional Chinese medicine preparations. A mechanistic study showed that the interactions between Ag+ and the absorbed iodine, the carboxylate group, and the N atoms all contribute to the sensing performance of a-Eu-IPDA.

Artemisinins: Promising drug candidates for the treatment of autoimmune diseases.

Autoimmune diseases are characterized by the immune system's attack on one's own tissues which are highly diverse and diseases differ in severity, causing damage in virtually all human systems including connective tissue (e.g., rheumatoid arthritis), neurological system (e.g., multiple sclerosis) and digestive system (e.g., inflammatory bowel disease). Historically, treatments normally include pain-killing medication, anti-inflammatory drugs, corticosteroids, and immunosuppressant drugs. However, given the above characteristics, treatment of autoimmune diseases has always been a challenge. Artemisinin is a natural sesquiterpene lactone initially extracted and separated from Chinese medicine Artemisia annua L., which has a long history of curing malaria. Artemisinin's derivatives such as artesunate, dihydroartemisinin, artemether, artemisitene, and so forth, are a family of artemisinins with antimalarial activity. Over the past decades, accumulating evidence have indicated the promising therapeutic potential of artemisinins in autoimmune diseases. Herein, we systematically summarized the research regarding the immunoregulatory properties of artemisinins including artemisinin and its derivatives, discussing their potential therapeutic viability toward major autoimmune diseases and the underlying mechanisms. This review will provide new directions for basic research and clinical translational medicine of artemisinins.

Distribution, connection and function of ALDH1A1+/TH+ neurons in substantia nigra pars reticulata of mouse.

The massive cell death of dopaminergic neurons (DANs) in substantia nigra pars compacta (SNC) is associated with motor diseases, such as Parkinson's disease. Moreover, as a subtype of DANs in SNC, ALDH1A1+ neurons show better resistance to PD related neurotoxin. DANs can also be found in the substantia nigra pars reticulata (SNR), however, whether they are ALDH1A1+ neurons are rarely reported, as well as their projection, function, and reaction in the PD pathology. We studied the distribution of ALDH1A1+ neurons and track their projection by injecting pAAV. We figured out that, in SNR, 87 % neurons are ALDH1A1+/TH+ in ALDH1A1+ cluster averagely, while ALDH1A1+/TH+: TH+ is 52 % averagely. There are two enrichment regions of ALDH1A1+/TH+ neurons at brgma -3.40 mm and brgma -3.70 mm in the SNR of the nTg mice. Nevertheless, in one type of PD-liked mice model, the proportion of ALDH1A1+/TH+: ALDH1A1+ neurons are 98 % averagely, while ALHD1A1+/TH+: TH+ is 57 %. Intriguingly, neuro-tracing discovered that there may be a previously unreported connection between SNR and anterior dorsal thalamus (ADT). The mouse received MPTP stereotactic injection to destroy TH+ neurons in SNR showed depression behavior, indicated the DANs death in SNR may contribute to depression behavior.

A highly efficient liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for etomidate and etomidate acid in urine, liver and kidney.

Etomidate (ETO) is a highly-efficient drug that can induce anesthesia with increasing doses, thus subject to strict regulation. However, an accurate and efficient method for ETO intake detection is currently lacking. Therefore, this study developed a straightforward sample preparation method using LC-MS/MS to analyze ETO and its primary metabolite, etomidate acid (ETA), in urine, liver, and kidney samples. Snap frozen pig liver and kidney samples were ground into a fine powder. Then, all the biological samples, including human urine, pig liver and kidney tissues, were deproteinized using acetonitrile and filtered for analysis. The separation was achieved in 9.01 min with gradient elution. The calibration curves ranged from 0.5 to 50 ng/mL for ETO in urine and 0.5 to 50 ng/g in liver and kidney, while the curves ranged from 1 to 100 ng/mL for ETA in urine and 1 to 100 ng/g in liver and kidney. The correlation coefficients (R2) were greater than 0.9957. The Limit of detection (LOD) and limit of quantitation (LOQ) for ETO were 0.2 and 0.5 ng/mL in urine samples and 0.2 and 0.5 ng/g in liver and kidney samples, respectively. For ETA, the LOD and LOQ were 0.5 and 1 ng/mL in urine samples and 0.5 and 1 ng/g in liver and kidney samples. This method was assessed by validation parameters, including selectivity, intra- and inter-day precision and accuracy, recovery, matrix effect, dilution integrity and stability. It was successfully applied to a practical case, revealing ETO and ETA concentrations in urine of 1.01 and 5.58 µg/mL, in liver samples of 12.30 and 1.13 µg/g, and in kidney samples of 6.95 and 4.23 µg/g. This suggests that the method is suitable for routine forensic detection of illicit ETO abuse.

Seeds Act as Vectors for Antibiotic Resistance Gene Dissemination in a Soil-Plant Continuum.

Though the evidence for antibiotic resistance spread via plant microbiome is mounting, studies regarding antibiotic resistome in the plant seed, a reproductive organ and important food resource, are still in their infancy. This study investigated the effects of long-term organic fertilization on seed bacterial endophytes, resistome, and their intergenerational transfer in the microcosm. A total of 99 antibiotic resistance genes (ARGs) and 26 mobile genetic elements (MGEs) were detected by high-throughput quantitative PCR. The amount of organic fertilizer applied was positively correlated to the number and relative abundance of seed-associated ARGs and MGEs. Moreover, the transmission of ARGs from the rhizosphere to the seed was mainly mediated by the shared bacteria and MGEs. Notably, the rhizosphere of progeny seedlings derived from seeds harboring abundant ARGs was found to have a higher relative abundance of ARGs. Using structural equation models, we further revealed that seed resistome and MGEs were key factors affecting the ARGs in the progeny rhizosphere, implying the seed was a potential resistome reservoir for rhizosphere soil. This study highlights the overlooked role of seed endophytes in the dissemination of resistome in the soil-plant continuum, and more attention should be paid to plant seeds as vectors of ARGs within the "One-Health" framework.

The interfacial properties of 2D metal-monolayer blue phosphorene heterojunctions and transport properties of their field-effect transistors.

Monolayer blue phosphorene (BlueP) has attracted much interest as a potential channel material in electronic devices. Searching for suitable two-dimensional (2D) metal materials to use as electrodes is critical to fabricating high-performance nanoscale channel BlueP-based field effect transistors (FETs). In this paper, we adopted first-principles calculations to explore binding energies, phonon calculations and electronic structures of 2D metal-BlueP heterojunctions, including Ti3C2-, NbTe2-, Ga(110)- and NbS2-BlueP, and thermal stability of Ti3C2-BlueP heterojunction at room temperature. We also used density functional theory coupled with the nonequilibrium Green function method to investigate the transport properties of sub-5 nm BlueP-based FETs with Ti3C2-BlueP electrodes. Our calculated results indicate that Ti3C2-BlueP has excellent thermal stability and may be used as a candidate electrode material for BlueP-based FETs. The double-gate can more effectively improve the device performance compared with the single-gate. The estimated source leakage current of sub-5 nm transistors reaches up to 369µA µm-1, which is expected to meet the requirements of the international technology roadmap for semiconductors for LP (low-power) devices. Our results imply that 2D Ti3C2may act as an appropriate electrode material for LP BlueP-based FETs, thus providing guidance for the design of future short-gate-length BlueP-based FETs.

The role of acute normovolemic hemodilution in reducing allogeneic blood transfusion in glioblastoma surgery: a case-control study.

BACKGROUND: Acute normovolemic hemodilution (ANH) was first introduced in glioblastoma surgery, and its role in reducing allogeneic blood transfusion was investigated in this study. METHODS: This study enrolled supratentorial glioblastoma patients who received total resection. In the ANH group, the patients were required to draw blood before the operation, and the blood will be transfused back to the patient during the operation. The association between ANH and clinical features was investigated. RESULTS: Sixty supratentorial glioblastoma patients were enrolled in this study, 25 patients were allocated in the ANH group, and another 35 patients were included in the control group. ANH dramatically reduced the need for allogeneic blood transfusion (3 [12%] vs 12 [34.3%], P = 0.049), and the blood transfusion per total of patients was dramatically decreased by the application of ANH (0.40 ± 1.15 units vs 1.06 ± 1.59 units, P = 0.069). Furthermore, ANH also markedly reduced the requirement of fresh frozen plasma (FFP) transfusion (2 [8%] vs 11 [31.4%], P = 0.030) and the volume of FFP transfusion per total of patients (32.00 ± 114.46 mL vs 115.71 ± 181.00 mL, P = 0.033). The complication rate was similar between the two groups. CONCLUSIONS: ANH was a safe and effective blood conservation technique in glioblastoma surgery.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Sesamol serves as a p53 stabilizer to relieve rheumatoid arthritis progression and inhibits the growth of synovial organoids.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame (Sesamum indicum L.) with various biological activities. PURPOSE: The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment. METHODS: CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression. RESULTS: Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA. CONCLUSIONS: Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.

Basophils absence predicts poor prognosis and indicates immunosuppression of patients in intensive care units.

Immune cells and immunity are associated with the prognosis of patients with critical illness. Here, medical records retrospectively extracted from the Medical Information Mart for Intensive Care IV were used for screening an immune-related biomarker in intensive care units (ICU) patients and applied for validating the identified indicator in septic patients. In this work, the count of innate immune cells, basophils, harbored a superior role in predicting ICU patients' prognosis compared with those of other blood immune cells (OR 0.013, 95% CI 0.001, 0.118, P < 0.001). Importantly, basophils absence during ICU stay was positively correlated with the 28-day mortality of ICU patients and served as an independent predictor of ICU patients' prognosis (OR 3.425, 95% CI 3.717-3.165, P < 0.001). Moreover, the association between critical illness progression, poor outcome, and basophils absence was verified in septic patients. Subsequent investigations revealed the positive relationship between basophils absence and immunosuppression, and suggested the potential of basophils-mediated immunity in predicting the 28-day mortality of ICU patients. Collectively, we identify basophils absence during ICU stay as a novel and unfavorable indicator for evaluating the prognosis of ICU patients and recognizing a branch of ICU patients potentially suitable for intensified treatment and immunoenhancement therapy.

Arecoline hydrobromide suppresses PI3K/AKT pathway in rheumatoid arthritis synovial fibroblasts and relieves collagen-induced arthritis in mice.

OBJECTIVE: This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and collagen-induced arthritis (CIA) mice. METHODS: Immunofluorescence was used to identify RA-FLSs. Cell Counting Kit-8 (CCK-8) was used to determine the viability of RA-FLSs and the half maximal inhibitory concentration (IC50) of AH. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to detect DNA replication in RA-FLSs. Cell cycle and apoptosis were examined by flow cytometry. Migration and invasion, as well as wound healing assays, were employed to determine cell migration and invasion ability. Proteins and mRNA expression levels were investigated using Western blot, quantitative real-time PCR (RT-qPCR), and immunofluorescence. The CIA mice model was used to assess the effect of AH in vivo. RNA-sequencing (RNA-seq) was used to find the potential signaling pathways of AH against RA, and Western blot was used to verify the key signaling pathway of AH on RA-FLSs. Network pharmacology and molecular docking were used to predict drug targets. RESULTS: AH inhibited the proliferation and DNA replication of RA-FLSs, promoted cell cycle arrest by reducing the levels of cyclin-dependent kinase 1 (CDK1), cyclin A2, and cyclin B1, promoted apoptosis by suppressing B-cell lymphoma-2 (Bcl-2) expression, and suppressed migration and invasion by inhibiting vimentin expression in RA-FLSs. AH was also effective in relieving arthritis in vivo. RNA sequencing analyses suggested that AH inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs, which was also confirmed in Western blot analysis. Furthermore, network pharmacology and molecular docking suggested that F2, MAPK14, SRC, AKT1, and CTSK might be the direct targets of AH. CONCLUSION: AH can modulate the pathological process of RA-FLSs by blocking the PI3K/AKT pathway and relieve CIA in mice, making it a potential new small molecule candidate.

Efficacy and safety of trastuzumab deruxtecan in patients with solid tumors: a systematic review and meta-analysis of 3 randomized controlled trials.

Trastuzumab deruxtecan (T-DXd, DS-8201) is a targeted antibody-drug conjugate that specifically targets human epidermal growth factor receptor 2 (HER2). In 2019, it was approved by the US Food and Drug Administration for the treatment of HER2-positive breast cancer. However, ongoing research is exploring its potential efficacy in other solid tumors, such as non-small-cell lung cancer and colorectal cancer, as well as in tumors with low HER2 levels. It is important to examine the safety and effectiveness of trastuzumab deruxtecan in these various types of solid tumors, as some studies have raised concerns about potential serious adverse events associated with its use. In this meta-analysis, we conducted a comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) that evaluated the efficacy and safety of trastuzumab deruxtecan in solid tumors. We used RevMan 5.4 software to perform a meta-analysis, calculating odds ratios (OR), risk ratios (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs). After an exhaustive search, we identified three articles that met our inclusion criteria, which included a total of 1268 patients. The results of the meta-analysis showed that the treatment group had significantly higher overall survival (WMD=5.12, 95% CI (2.79, 7.44), P<0.0001), progression-free survival (WMD=3.45, 95% CI (0.8, 6.1), P=0.01), overall response rate (OR=6.49, 95% CI (4.90, 8.58), P<0.00001), and disease control rate (OR=4.68, 95% CI (2.78, 7.89), P<0.00001), TRAEs (RR=6.93, 95% CI (2.06, 23.25), P=0.002). However, there was no significant difference in TRAEs≥3 (RR=1.08, 95% CI (0.75, 1.56), P=0.68) between the trials. Based on the available evidence, trastuzumab deruxtecan appears to be an effective and safe treatment option for HER2-positive solid tumors. Although the number of studies included in this analysis is limited, ongoing trials are being conducted, further evaluating its potential in various solid tumors. The results of these trials will enhance our understanding of trastuzumab deruxtecan and potentially expand its applications, bringing hope to more patients with solid tumors.

Host traits shape virome composition and virus transmission in wild small mammals.

Bats, rodents, and shrews are the most important animal sources of human infectious diseases. However, the evolution and transmission of viruses among them remain largely unexplored. Through the meta-transcriptomic sequencing of internal organ and fecal samples from 2,443 wild bats, rodents, and shrews sampled from four Chinese habitats, we identified 669 viruses, including 534 novel viruses, thereby greatly expanding the mammalian virome. Our analysis revealed high levels of phylogenetic diversity, identified cross-species virus transmission events, elucidated virus origins, and identified cases of invertebrate viruses in mammalian hosts. Host order and sample size were the most important factors impacting virome composition and patterns of virus spillover. Shrews harbored a high richness of viruses, including many invertebrate-associated viruses with multi-organ distributions, whereas rodents carried viruses with a greater capacity for host jumping. These data highlight the remarkable diversity of mammalian viruses in local habitats and their ability to emerge in new hosts.

Molecular mechanisms of pyroptosis and its role in anti-tumor immunity.

Pyroptosis is a form of cell death that is characterized by the destruction of the cell, and it has implications in both the immune system and cancer immunotherapy. The gasdermin family is responsible for the activation of pyroptosis, which involves the formation of pores in the cellular membrane that permit the discharge of inflammatory factors. The inflammasome response is a powerful mechanism that helps to eliminate bacteria and cancer cells when cellular damage occurs. As tumor cells become more resilient to apoptosis, other treatments for cancer are becoming more popular. It is essential to gain a thorough understanding of pyroptosis in order to use it in cancer treatment, considering the intricate association between pyroptosis and the immune system's defensive reaction against tumors. This review offers an overview of the mechanisms of pyroptosis, the relationship between the gasdermin family and pyroptosis, and the interplay between pyroptosis and anti-tumor immunity. In addition, the potential implications of pyroptosis in cancer immunotherapy are discussed. Additionally, we explore future research possibilities and introduce a novel approach to tumor treatment.