TMEM147: A Promising Cancer Biomarker Associated with Immune Cell Infiltration and Prognosis in LIHC-Insights from a Comprehensive Pan-Cancer Genomic Analysis.

Previous studies have demonstrated the regulatory roles of Transmembrane protein 147 (TMEM147) in various diseases, including cancer. However, systematic pan-cancer analyses investigating the role of TMEM147 in diagnosis, prognosis, and immunological prediction are lacking. An analysis of data from The Cancer Genome Atlas (TCGA) revealed differential TMEM147 expression across various types of cancer as well as within immune and molecular cancer subtypes. Moreover, high TMEM147 expression was associated with poor disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI) across cancers, suggesting its potential as a prognostic biomarker. Our study further revealed a significant correlation between TMEM147 expression and T helper cell and Tcm cell infiltration in most cancer types. In the case of liver hepatocellular carcinoma (LIHC), the effect of TMEM147 on prognosis varied among different clinical subtypes. Additionally, functional enrichment analysis revealed an association between TMEM147 and metabolic pathways. Finally, experiments on the MIHA cell line and four LIHC cell lines confirmed the role of TMEM147 in promoting liver cancer cell proliferation, further confirming the clinical value of TMEM147 in liver cancer diagnosis. Our findings suggest that TMEM147 may serve as a diagnostic and prognostic biomarker across cancers while also playing a significant role in LIHC.

Progresses of T-cell-engaging bispecific antibodies in treatment of solid tumors.

T-cell-engaging bispecific antibody (TCB) therapies have emerged as a promising immunotherapeutic approach, effectively redirecting effector T cells to selectively eliminate tumor cells. The therapeutic potential of TCBs has been well recognized, particularly with the approval of multiple TCBs in recent years for the treatment of hematologic malignancies as well as some solid tumors. However, TCBs encounter multiple challenges in treating solid tumors, such as on-target off-tumor toxicity, cytokine release syndrome (CRS), and T cell dysfunction within the immunosuppressive tumor microenvironment, all of which may impact their therapeutic efficacy. In this review, we summarize clinical data on TCBs for solid tumor treatment, highlight the challenges faced, and discuss potential solutions based on emerging strategies from current clinical and preclinical research. These solutions include TCB structural optimization, target selection, and combination strategies. This comprehensive analysis aims to guide the development of TCBs from design to clinical application, addressing the evolving landscape of cancer immunotherapy.

Predictive value of MRI-based deep learning model for lymphovascular invasion status in node-negative invasive breast cancer.

To retrospectively assess the effectiveness of deep learning (DL) model, based on breast magnetic resonance imaging (MRI), in predicting preoperative lymphovascular invasion (LVI) status in patients diagnosed with invasive breast cancer who have negative axillary lymph nodes (LNs). Data was gathered from 280 patients, including 148 with LVI-positive and 141 with LVI-negative lesions. These patients had undergone preoperative breast MRI and were histopathologically confirmed to have invasive breast cancer without axillary LN metastasis. The cohort was randomly split into training and validation groups in a 7:3 ratio. Radiomics features for each lesion were extracted from the first post-contrast dynamic contrast-enhanced (DCE)-MRI. The Least Absolute Shrinkage and Selection Operator (LASSO) regression method and logistic regression analyses were employed to identify significant radiomic features and clinicoradiological variables. These models were established using four machine learning (ML) algorithms and one DL algorithm. The predictive performance of the models (radiomics, clinicoradiological, and combination) was assessed through discrimination and compared using the DeLong test. Four clinicoradiological parameters and 10 radiomic features were selected by LASSO for model development. The Multilayer Perceptron (MLP) model, constructed using both radiomic and clinicoradiological features, demonstrated excellent performance in predicting LVI, achieving a high area under the curve (AUC) of 0.835 for validation. The DL model (MLP-radiomic) achieved the highest accuracy (AUC = 0.896), followed by DL model (MLP-combination) with an AUC of 0.835. Both DL models were significantly superior to the ML model (RF-clinical) with an AUC of 0.720. The DL model (MLP), which integrates radiomic features with clinicoradiological information, effectively aids in the preoperative determination of LVI status in patients with invasive breast cancer and negative axillary LNs. This is beneficial for making informed clinical decisions.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

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The radial growth of trees plays a crucial role in determining forest carbon sequestration capacity. Understanding the growth dynamics of trees and their response to environmental factors is essential for predicting forest's carbon sink potential under future climate change. Coniferous forest trees are particularly sensitive to climate change, with growth dynamics responding rapidly to environmental shifts. We collected and analyzed data from 99 papers published between 1975 and 2023, and examined the effects of exogenous factors (such as temperature, water, and photoperiod) and endogenous factors (including tree age and species) on cambial activity and radial growth in conifers. We further explored the mechanisms underlying these effects. The results showed that climate warming had the potential to advance the onset while delayed the end of xylem differentiation stages in conifers in temperate and boreal regions. Water availability played a crucial role in regulating the timing of cambial phenology and wood formation by influencing water potential and cell turgor. Additionally, the photoperiod not only participated in regulating the start and end times of growth, but also influenced the timing of maximum growth rate occurrence. Future climate warming was expected to extend the growing season, leading to increase in growth of conifers in boreal regions and expanding forests to higher altitudes or latitudes. However, changes in precipitation patterns and increased evapotranspiration resulting from temperature increases might advance the end of growing season and reduce growth rate in arid areas. To gain a more comprehensive understanding of the relationship between radial growth and climatic factors, it is necessary to develop process-based models to elucidate the physiological mechanisms underlying wood formation and the response of trees to climatic factors.

The immunotoxin targeting PRLR increases tamoxifen sensitivity and enhances the efficacy of chemotherapy in breast cancer.

BACKGROUND: Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. METHODS: High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. RESULTS: PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. CONCLUSIONS: PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer.

Non-linear relationship between TSH and psychotic symptoms on first episode and drug naïve major depressive disorder patients: a large sample sized cross-sectional study in China.

INTRODUCTION: Psychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical outcomes. TSH may involve in the development of PD. This study aims to explore relationship between TSH and PD. METHODS: A total of 1718 outpatients diagnosed as FEDN MDD were recruited in this study. The relationship between PD and TSH was evaluated using multivariable binary logistic regression analysis. To assess the presence of non-linear associations, a two-piecewise linear regression model was employed. Furthermore, interaction and stratified analyses were conducted with respect to sex, education, marital status, comorbid anxiety, and suicide attempt. RESULTS: Multivariable logistic regression analysis revealed that TSH was positively associated with the risk of PD after adjusting for confounders (OR = 1.26, 95% CI: 1.11 to 1.43; p < 0.05). Smoothing plots showed a nonlinear relationship between TSH and PD, with the inflection point of TSH being 4.94 mIU/L. On the right of the inflection point, for each unit increase in serum TSH level on the right side of the inflection point, the probability of PD increased substantially by 47% (OR = 1.47, 95% CI: 1.25 to 1.73, p < 0.001), while no significant association was observed on the left side of the inflection point (OR = 0.87, 95% CI: 0.67 to 1.14, p = 0.32). CONCLUSION: Our investigation showed a nonlinear TSH-PD relationship in FEDN MDD patients, thus contributing to effective intervention strategies for psychotic symptoms in depression patients.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

Development and validation of a nomogram for suicide attempts in patients with first-episode drug-naïve major depressive disorder.

Objective: The risk of suicide can be decreased by accurately identifying high-risk suicide groups and implementing the right interventions. The aim of this study was to develop a nomogram for suicide attempts (SA) in patients with first-episode drug-naïve (FEDN) major depressive disorder (MDD). Methods: This study undertook a cross-sectional analysis of 1,718 patients diagnosed with FEDN MDD, providing comprehensive clinical data from September 2016 to December 2018. Data on anthropometric and sociodemographic factors were gathered, and the severity of depression and anxiety was evaluated using the 17-item Hamilton Depression Scale (HAMD-17) and the Hamilton Anxiety Scale (HAMA), respectively. Additionally, thyroid hormone levels, lipid profile parameters, and fasting blood glucose (FBG) were measured. Suicide attempt (SA) history was verified based on an amalgamation of medical records, patient interviews, and family interviews. Participants were randomly divided into a training group (70%, n = 1,204) and a validation group (30%, n = 514). In the training group, LASSO analysis and multivariate regression were used to identify variables associated with SA. A nomogram was then constructed using the identified risk factors to estimate the likelihood of SA within the training group. To assess the accuracy, the area under the receiver operating characteristic curve (AUC) was utilized, and calibration plots were employed to evaluate calibration. Additionally, decision curve analysis (DCA) was performed to assess the precision of the model. Finally, internal validation was carried out using the validation group. Results: A practical nomogram has been successfully constructed, incorporating HAMD, HAMA, thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and systolic blood pressure (SBP) parameters, to estimate the probability of SA in Chinese patients diagnosed with FEDN MDD. The pooled area under the ROC for SA risk in both the training and validation groups was found to be 0.802 (95% CI: 0.771 to 0.832) and 0.821 (95% CI: 0.774 to 0.868), respectively. Calibration analysis revealed a satisfactory correlation between the nomogram probabilities and the actual observed probabilities. The clinical applicability of the nomogram was confirmed through decision curve analysis. To enhance accessibility for clinicians and researchers, an online version of the nomogram can be accessed at https://doctorjunjunliu.shinyapps.io/dynnomapp/. Conclusions: We constructed and validated a nomogram for the early detection of FEDN MDD patients with a high risk of SA, thereby contributing to the implementation of effective suicide prevention programs.

Role of protein arginine methyltransferase 1 in obesity-related metabolic disorders: Research progress and implications.

Obesity has become a major global problem that significantly confers an increased risk of developing life-threatening complications, including type 2 diabetes mellitus, fatty liver disease and cardiovascular diseases. Protein arginine methyltransferases (PRMTs) are enzymes that catalyse the methylation of target proteins. They are ubiquitous in eukaryotes and regulate transcription, splicing, cell metabolism and RNA biology. As a key, epigenetically modified enzyme, protein arginine methyltransferase 1 (PRMT1) is involved in obesity-related metabolic processes, such as lipid metabolism, the insulin signalling pathway, energy balance and inflammation, and plays an important role in the pathology of obesity-related metabolic disorders. This review summarizes recent research on the role of PRMT1 in obesity-related metabolic disorders. The primary objective was to comprehensively elucidate the functional role and regulatory mechanisms of PRMT1. Moreover, this study attempts to review the pathogenesis of PRMT1-mediated obesity-related metabolic disorders, thereby offering pivotal information for further studies and clinical treatment.

Asiatic acid alleviates vascular remodeling in BAPN-induced aortic dissection through inhibiting NF-κB p65/CX3CL1 signaling.

Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on ß-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.

U-shaped association between fasting blood glucose and suicide attempts in Chinese patients with first-episode drug-naïve major depressive disorder.

BACKGROUND: Evidence regarding the relationship between fasting blood glucose (FBG) and suicide attempts (SA) in patients with major depressive disorder (MDD) was limited. Therefore, the objective of this research was to investigate whether FBG was independently related to SA in Chinese patients with first-episode drug-naïve (FEDN) MDD after adjusting for other covariates. METHODS: The present study was a cross-sectional study. A total of 1718 participants (average age: 34.9 ± 12.4 years, 65.8% females) with FEDN MDD were involved in a hospital in China from September 2016 to December 2018. Multiple logistic regression analysis and smooth curve fitting were used to estimate the association between FBG and the risk of SA. The threshold effect was examined by the two-piecewise linear regression model. Interaction and stratified analyses were conducted according to sex, education, marital status, comorbid anxiety, and psychotic symptoms. RESULTS: The prevalence of SA in patients with FEDN MDD was 20.1%. The result of fully adjusted binary logistic regression showed FBG was positively associated with the risk of SA (odds ratio (OR) = 1.62, 95% CI: 1.13-2.32). Smoothing plots also revealed a nonlinear relationship between FBG and SA, with the inflection point of FBG being 5.34 mmol/l. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 0.53 (0.32-0.88, P = 0.014) and 1.48 (1.04-2.10, P = 0.030), respectively. CONCLUSIONS: A U-shaped relationship between FBG and SA in FEDN MDD patients was found, with the lowest risk of SA at a FBG of 5.34 mmol/l, indicating that both the lower and higher FBG levels may lead to an increased risk of SA.

Ecosystem-based management approaches for watershed conservation and geosustainability.

When contributors' goals and legislative and political structures vary, as they often do in the case of worldwide fish populations, it becomes more challenging to implement ethical fishing tactics. Canada, the United States, and Mexico all fish from Pacific regions anchovies in the California Modern. Climate-driven numbers and geographic dynamics may pollute the waters of collaborative aquaculture and lead to overloading. This research expands upon prior works using a game theoretic model of Tran's boundary sardine fisheries in different climatic conditions to account for ecological links. More significant economic advantages accrue from cooperation fishing tactics that consider the mackerel's role as feed for other species in the natural system, as opposed to plans that merely take note of the worth of mackerel harvests to a particular fishing nation. The maximum environmental benefit is obtained at a fishery rate for sardines barely less than the sardine Fishery Management Safe Yield. Ecological-based control of fisheries can increase sustainability and profits, but only if investors and policy makers consider the ecology in business-applicable models. Understanding and adapting to the fast alterations in habitat distributions due to climate change and designing ways to achieve viable and lucrative fishery amidst altering environments will necessitate an increased emphasis on ecosystem-based governance.

Ultrarobust stable ABTS radical cation prepared using Spore@Cu-TMA biocomposites for antioxidant capacity assay.

Herein, spore@Cu-trimesic acid (TMA) biocomposites were prepared by self-assembling Cu-based metal-organic framework on the surface of Bacillus velezensis spores. The laccase-like activity of spore@Cu-TMA biocomposites was enhanced by 14.9 times compared with that of pure spores due to the reaction of Cu2+ ions with laccase on the spore surface and the microporous structure of Cu-TMA shell promoting material transport and increasing substrate accessibility. Spore@Cu-TMA rapidly oxidized and transformed 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) into ABTS●+ without using H2O2. Under optimum conditions, the ABTS●+ could be stored for 21 days at 4 °C and 7 days at 37 °C without the addition of any stabilizers, allowing for the large-scale preparation and long-term storage of ABTS●+. The ultrarobust stable ABTS●+ obtained with the use of Cu-TMA could effectively reduce the "back reaction" by preventing the leaching of the metabolites released by the spores. On the basis of these findings, a rapid, low-cost, and eco-friendly colorimetric platform was successfully developed for the detection of antioxidant capacity. Determination of antioxidant capacity for several antioxidants such as caffeic acid, glutathione, and Trolox revealed their corresponding limits of detection at 4.83, 8.89, and 7.39 nM, respectively, with linear ranges of 0.01-130, 0.01-140, and 0.01-180 µM, respectively. This study provides a facile way to prepare ultrarobust stable ABTS●+ and presents a potential application of spore@Cu-TMA biocomposites in food detection and bioanalysis.

A novel bispecific antibody drug conjugate targeting HER2 and HER3 with potent therapeutic efficacy against breast cancer.

Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3 mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3 mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.

The regulatory role of m6A methylation modification in metabolic syndrome pathogenesis and progression.

Metabolic syndromes are characterized by various complications caused by disrupted glucose and lipid metabolism, which are major factors affecting the health of a population. However, existing diagnostic and treatment strategies have limitations, such as the lack of early diagnostic and therapeutic approaches, variability in patient responses to treatment, and cost-effectiveness. Therefore, developing alternative solutions for metabolic syndromes is crucial. N6-methyladenosine (m6A) is one of the most abundant modifications that determine the fate of RNA. m6A modifications are closely associated with metabolic syndrome development and present novel prospects for clinical applications. Aberrant m6A modifications have been detected during inflammatory infiltration, apoptosis, autophagy, iron sagging, necrosis, and scorching during metabolic syndrome pathogenesis and progression. However, few reviews have systematically described the correlation between m6A modifications and these factors concerning metabolic syndrome pathogenesis and progression. This study summarizes the m6A methylation regulators and their roles in metabolic syndrome development, highlighting the potential of m6A modification as a biomarker in metabolic disorders.

Selenium Counteracts Tight Junction Disruption and Attenuates the NF-κB-Mediated Inflammatory Response in Staphylococcus aureus-Infected Mouse Mammary Glands.

Tight junctions (TJs) are the key determinant of barrier function in the mammary gland, with their disruption being associated with the pathogenesis and progression of mastitis, especially in the case of Staphylococcus aureus (S. aureus) infection. This study investigated whether selenium (Se) could attenuate S. aureus-induced mastitis by inhibiting inflammation and protecting mammary gland TJs in mice. The expression profiles of S. aureus-infected gland tissues derived from the gene expression omnibus dataset were analyzed. We found cytokine production, cell junctions, the nuclear transcription factor-κB (NF-κB) signalling pathway, and inflammatory responses associated with the differentially expressed genes, as revealed by Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses. Se reduced the mRNA expression and production of inflammatory cytokines, including tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and decreased phosphorylation levels of the NF-κB complex. Moreover, Se alleviated structural damage and microvillus injury in mammary glands. Immunohistochemical staining revealed that Se increased the expression of Claudin-3; Western blot analysis revealed increased protein levels of Occludin and Tricellulin in the group supplemented with dietary Se. In summary, Se counteracted TJ disruption and attenuated NF-κB-mediated inflammatory responses in S. aureus-infected mouse mammary glands.

Characterization of a novel T cell-engaging bispecific antibody for elimination of L1CAM-positive tumors.

Neural cell adhesion molecule L1 (L1CAM) is a cell-surface glycoprotein involved in cancer occurrence and migration. Up to today, L1CAM-targeted therapy appeared limited efficacy in clinical trials although quite a few attempts by monoclonal antibody (mAb) or chimeric antigen receptor T-cell therapy (CAR-T) have been reported. Therefore, the development of new effective therapies targeting L1CAM is highly desirable. It has been demonstrated that T cell-engaging bispecific antibody (TCE) plays an effective role in cancer immunotherapy by redirecting the cytotoxic activity of CD3+ T cells to tumor cells, resulting in tumor cell death. In this study, we designed and characterized a novel bispecific antibody (CE7-TCE) based on the IgG-(L)-ScFv format, which targets L1CAM and CD3 simultaneously. In vitro, CE7-TCE induced specific killing of L1CAM-positive tumor cells through T cells. In vivo, CE7-TCE inhibited tumor growth in human peripheral blood mononuclear cell/tumor cell co-grafting models. To overcome the adaptive immune resistance (AIR) that impairs the efficacy of TCEs, we conducted a combination therapy of CE7-TCE with Pembrolizumab (anti-PD1 mAb), which enhanced the anti-tumor activity of CE7-TCE. Our results confirmed the feasibility of using L1CAM as a TCE target for the treatment of solid tumors and revealed the therapeutic potential of CE7-TCE combined with immune checkpoint inhibitors.

Prevalence and related factors of first-time suicide attempts in the past 14 days in Chinese adult patients with first-episode drug-naïve major depressive disorder.

Background: This study aimed to identify socio-demographic, physiologic, and psychologic related factors of the first-time suicide attempt (FSA) in the past 14 days in Chinese adult patients with first-episode drug-naïve (FEDN) major depressive disorder (MDD). Methods: A total of 1718 adult patients with FEDN MDD were enrolled in this cross-sectional survey. Depression, anxiety symptoms, and suicide attempts were assessed. Additionally, biological samples were collected and measured, while Logistic regression analysis was employed to explore the risk factors for FSA in the past 14 days among FEDN MDD patients. Results: Among suicide attempters, 12.11% (208 out of 1718) reported experiencing FSA in the past 14 days. Logistic regression analysis showed that the risk factors for FSA included more severe anxiety symptoms (OR=1.37, 95%CI: 1.28-1.48, p<0.001), higher levels of total cholesterol (TC) (OR=1.42, 95%CI: 1.13-1.77, p=0.003), and elevated thyroid-stimulating hormone (TSH) (OR=1.13, 95%CI: 1.03-1.25, p=0.01). The regression model exhibited good discriminatory power for FSA with an area under the curve (AUC) of 0.82. Conclusion: FEDN MDD patients with more severe anxiety and higher levels of TSH and TC are more likely to develop FSA in the past 14 days. These factors are risk factors for short-term (in the past 14 days) FSA and may serve as indicators for early intervention.

Process-Based Modeling of Phenology and Radial Growth in Pinus tabuliformis in Response to Climate Factors over a Cold and Semi-Arid Region.

(1) Background: Climate change significantly impacts the phenology and dynamics of radial tree growth in alpine dryland forests. However, there remains a scarcity of reliable information on the physiological processes of tree growth and cambial phenology in response to long-term climate change in cold and semi-arid regions. (2) Methods: We employed the process-based Vaganov-Shashkin (VS) model to simulate the phenology and growth patterns of Chinese pine (Pinus tabuliformis) in the eastern Qilian Mountains, northeastern Tibetan Plateau. The model was informed by observed temperature and precipitation data to elucidate the relationships between climate factors and tree growth. (3) Results: The simulated tree-ring index closely aligned with the observed tree-ring chronology, validating the VS model's effectiveness in capturing the climatic influences on radial growth and cambial phenology of P. tabuliformis. The model outputs revealed that the average growing season spanned from mid-April to mid-October and experienced an extension post-1978 due to ongoing warming trends. However, it is important to note that an increase in the duration of the growing season did not necessarily result in a higher level of radial growth. (4) Conclusions: While the duration of the growing season was primarily determined by temperature, the growth rate was predominantly influenced by water conditions during the growing season, making it the most significant factor contributing to ring formation. Our study provides valuable insights into the potential mechanisms underlying tree growth responses to climate change in cold and semi-arid regions.