A nanobody against the V-ATPase c subunit inhibits metastasis of 4T1-12B breast tumor cells to lung in mice.

The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that functions to control the pH of intracellular compartments as well as to transport protons across the plasma membrane of various cell types, including cancer cells. We have previously shown that selective inhibition of plasma membrane V-ATPases in breast tumor cells inhibits the invasion of these cells in vitro. We have now developed a nanobody directed against an extracellular epitope of the mouse V-ATPase c subunit. We show that treatment of 4T1-12B mouse breast cancer cells with this nanobody inhibits V-ATPase-dependent acidification of the media and invasion of these cells in vitro. We further find that injection of this nanobody into mice implanted with 4T1-12B cells orthotopically in the mammary fat pad inhibits metastasis of tumor cells to lung. These results suggest that plasma membrane V-ATPases represent a novel therapeutic target to limit breast cancer metastasis.

Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8+ T cells and inhibited tumor growth.

BACKGROUND: Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects. METHODS: Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an in vivo T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice. RESULTS: TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8+ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1's antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1's CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8+ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions. CONCLUSION: Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

Pre-operative prediction of histopathological growth patterns of colorectal cancer liver metastasis using MRI-based radiomic models.

PURPOSE: Histopathological growth patterns (HGPs) of colorectal liver metastases (CRLMs) have prognostic value. However, the differentiation of HGPs relies on postoperative pathology. This study aimed to develop a magnetic resonance imaging (MRI)-based radiomic model to predict HGP pre-operatively, following the latest guidelines. METHODS: This retrospective study included 93 chemotherapy-naïve patients with CRLMs who underwent contrast-enhanced liver MRI and a partial hepatectomy between 2014 and 2022. Radiomic features were extracted from the tumor zone (RTumor), a 2-mm outer ring (RT+2), a 2-mm inner ring (RT-2), and a combined ring (R2+2) on late arterial phase MRI images. Analysis of variance method (ANOVA) and least absolute shrinkage and selection operator (LASSO) algorithms were used for feature selection. Logistic regression with five-fold cross-validation was used for model construction. Receiver operating characteristic curves, calibrated curves, and decision curve analyses were used to assess model performance. DeLong tests were used to compare different models. RESULTS: Twenty-nine desmoplastic and sixty-four non-desmoplastic CRLMs were included. The radiomic models achieved area under the curve (AUC) values of 0.736, 0.906, 0.804, and 0.794 for RTumor, RT-2, RT+2, and R2+2, respectively, in the training cohorts. The AUC values were 0.713, 0.876, 0.785, and 0.777 for RTumor, RT-2, RT+2, and R2+2, respectively, in the validation cohort. RT-2 exhibited the best performance. CONCLUSION: The MRI-based radiomic models could predict HGPs in CRLMs pre-operatively.

Safety analysis of laboratory parameters in paediatric patients with spinal muscular atrophy treated with nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder that can be treated with intrathecal nusinersen, an antisense oligonucleotide. In addition to efficacy, safety is a determining factor in the success of any therapy. Here, we aim to assess the safety of nusinersen therapy in paediatric patients with SMA. METHODS: Laboratory data of paediatric patients with SMA who received nusinersen between October 2019 and May 2022 were retrospectively analysed. RESULTS: During the observation period, 46 infants and children aged 2.9 months to 13.6 years received a total of 213 nusinersen doses without safety concerns. Inflammatory markers were stable throughout the study. International normalized ratio was increased by 0.09 per injection. Urea levels were increased by 0.108 mmol/L, and cystatin C decreased by 0.029 mg/L per injection. There were no significant changes in platelet count, activated partial thrombin time, creatinine levels or liver enzyme levels during treatment. The cerebrospinal fluid (CSF) leukocyte count remained stable, and total protein increased by 24.038 mg/L per injection. CONCLUSION: Our data showed that nusinersen therapy is generally safe in children with SMA. Laboratory monitoring did not identify any persistent or significantly abnormal findings. CSF protein should be monitored to gain more insights.

The role of reactive oxygen species in regulation of the plasma membrane H+-ATPase activity in Masson pine (Pinus massoniana Lamb.) roots responding to acid stress.

To understand the role of reactive oxygen species (ROS) in regulation of the plasma membrane (PM) H+-ATPase in acid-stressed Masson pine roots, different acidity (pH 6.6 as the control, pH 5.6 and pH 4.6) of simulated acid rain (SAR) added with and without external chemicals (H2O2, enzyme inhibitors and ROS scavenger) was prepared. After 30 days of SAR exposure, the plant morphological phenotype attributes, levels of cellular ROS and lipid peroxidation, enzymatic activities of antioxidants, PM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and PM H+-ATPase activity in pine seedlings were measured. Compared with the control, the growth of pine seedlings exposed to SAR in the presence or absence of H2O2 was well-maintained, but the application of Na3VO4, 1,3-dimethyl-2-thiourea, N, N-dimethylthiourea (DMTU) and diphenyleneiodonium chloride (DPI) caused a substantial growth inhibition. In addition, SAR exposure, SAR with H2O2 treatment, and SAR with Na3VO4 treatment increased the cellular H2O2 content, O2- content and malondialdehyde (MDA) content, while the use of DMTU and DPI lead to relatively low levels. Similarly, the enzymatic activities of antioxidants, PM NADPH oxidase and PM H+-ATPase in acid stressed pine seedlings elevated with the increasing acidity. A significant stimulation of these enzymatic activities obtained from SAR with H2O2 treatment was observed, whereas which decreased obviously with the addition of Na3VO4, DMTU and DPI (P < 0.05). Moreover, a positive correlation was found between plant morphological attributes and the PM H+-ATPase activity (P < 0.05). Besides, the PM H+-ATPase activity positively correlated with the cellular ROS contents and the enzymatic activities of antioxidants and PM NADPH oxidase (P < 0.05). Therefore, the PM H+-ATPase is instrumental in the growth of pine seedlings resisting to acid stress by enhancing its activity. The process involves the signaling transduction of cellular ROS and coordination with PM NADPH oxidase.

Building a Layer-Structured Aluminum/Graphene Composite with Significant Improvement in Electrical Conductivity.

Aluminum (Al) and its alloys are widely used in various fields due to their excellent physical properties. Although many efforts have been made to fabricate an Al-based composite, they usually results in a significant decrease in electrical conductivity. Herein, a special layer-structured Al/graphene (Gr)/Al composite was successfully designed and fabricated through a facile method using the ultrasonic spraying of graphene powder with alumina removal and a subsequent vacuum hot-pressing process. The as-obtained Al/Gr/Al composite presents a significantly enhanced electrical conductivity of 66% IACS, which is much higher than that of other reported Al-based composites, while it still maintains similar mechanical properties. This work provides a new strategy for the development of highly conductive Al-based composites, which would be very useful and important for practical applications.

Fluoxetine Successfully Treats Intracranial Enterovirus E18 Infection in a Patient with CD79a Deficiency Arising from Segmental Uniparental Disomy of Chromosome 19.

The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igß respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients.

Long-term comparison of image-guided thermal ablation vs. lobectomy for solitary papillary thyroid microcarcinoma: a multi-center retrospective cohort study.

BACKGROUND: Image-guided thermal ablation has been applied in patients with papillary thyroid microcarcinoma (PTMC) who refuse surgery or active surveillance. However, evidence to support ablation is limited by single-center designs and a lack of long-term data. The purpose of this study was to compare long-term outcomes between ablation and lobectomy for patients with solitary PTMC. MATERIALS AND METHODS: This multi-center retrospective study included 1021 consecutive patients with solitary PTMC who underwent ablation ( n =444) or lobectomy ( n =577) at the four university-affiliated hospitals. The primary outcomes were disease progression [lymph node metastasis (LNM), recurrent tumors, persistent tumors and distant metastasis] and disease-free survival (DFS). Secondary outcomes were complications, hospitalization, procedure time, estimated blood loss and cost. The two groups were compared using propensity score matching. RESULTS: After matching, no significant differences were observed in disease progression (4.7% vs. 3.4%, P =0.307), LNM (1.6% vs. 1.6%, P =1.000), recurrent tumors (2.9% vs. 1.8%, P =0.269), persistent tumors(0.2% vs. 0%, P =0.317) and DFS (95.5% vs. 97.1%, P =0.246) between the ablation and lobectomy groups during the median follow-up of 96.5 months. The ablation group had significantly lower complication rates (0.7% vs. 5.2%, P <0.001), shorter post-treatment hospitalization {median [interquartile range (IQR)], 0 vs. 4.0 [3.0] days, P <0.001}, shorter procedure time [8.5 (2.8) vs. 90.0 (43.8) min, P <0.001], reduced estimated blood loss [0 vs. 20.0 (10.0) ml, P <0.001], and lower cost [$1873.2 (254.0) vs. $2292.9 (797.8), P <0.001] than the lobectomy group. CONCLUSIONS: This study revealed comparable disease progression and survival outcomes between ablation and lobectomy for solitary PTMC. Imaged-guided thermal ablation could be effective and safe alternatives to lobectomy for properly selected patients with PTMC.

Selective oxidation behavior based on iron-doped MOF derived carbon-based catalysts: Active site regulation and degradation mechanism analysis.

Selective removal of target organic pollutants in complex water quality of municipal sewage is extremely important for the deep treatment of water quality. Here, energetic MOF and Fe-MOF are doped in electrostatic spinning process to adjust the structure and composition of the catalysts, active oxygen species (ROSs), realizing the selective removal of organic pollutants. Non-azo and azo pollutants are selected as target pollutants. Catalysts PCFe-8 with Fe nanoclusters, EPCFe-8 with Fe-Nx, and EPC-8 without Fe doping are used to activate peroxymonosulfate (PMS) for degrading pollutants. The results show that the PCFe-8/PMS system can produce the most SO4- and exhibit superior removal of azo pollutants, whereas the degradation behavior of non-azo pollutants is more inclined to occur in the EPCFe-8/PMS system and the EPC-8/PMS system. This work provides a reference for elucidating the relationship between catalyst structure and components, types of ROSs, and selective degradation of pollutants.

Protective effects of sugarcane polyphenol against UV-B-induced photoaging in Balb/c mouse skin: Antioxidant, anti-inflammatory, and anti-glycosylation Effects.

Although the benefits of sugarcane polyphenol (SP) are well documented, its function in preventing photoaging has not yet been investigated. This study aimed to investigate the protective effects of SP in preventing ultraviolet (UV)-B-induced skin photoaging in Balb/c mice, as well as the underlying mechanism. Chlorogenic acid was determined to be the primary component of SP by using high-performance liquid chromatography-mass spectrometry. SP and chlorogenic acid were orally administrated to mice for 56 days, and UV-B radiation exposure was administered 14 days after SP and chlorogenic acid administration and lasted 42 days to cause photoaging. SP and chlorogenic acid administrations significantly alleviated the UV-B-induced mouse skin photoaging, as indicated by the decrease in epidermal thickness, increase in the collagen (COL) volume fraction, and elevation in type 1 and type 3 COL contents. Notably, both SP and chlorogenic acid effectively reversed the overexpression of matrix metalloproteinase induced by UV-B exposure in the mouse skin. Furthermore, SP and chlorogenic acid reduced the expression of receptor for advanced glycosylation end products in the mice; amplified the activities of antioxidant enzymes superoxide dismutase and catalase; reduced malondialdehyde levels; and decreased inflammatory cytokines interleukin 1ß, interleukin 6, and tumor necrosis factor α levels. SP could be a prospective dietary supplement for anti-photoaging applications due to its antioxidant, anti-inflammatory, and anti-glycosylation attributes, and chlorogenic acid might play a major role in these effects. PRACTICAL APPLICATION: This study can provide a scientific basis for the practical application of sugarcane polyphenols. We expect that sugarcane polyphenols can be used in food and beverage products to provide flavor while combating skin aging.

Correlation between plasma PSGL-1 and FIGO stage, tumor metastasis, and survival in epithelial ovarian cancer.

Plasma circulating P-selectin glycoprotein ligand-1 (PSGL-1) levels and its clinical correlation in patients with epithelial ovarian cancer (EOC) are unknown. The study determined plasma PSGL-1 levels in EOC patients and investigated its relationship with clinicopathological factors and prognosis. Plasma PSGL-1 levels were measured using ELISA in 69 patients with EOC, 34 patients with benign ovarian cystadenoma, and 36 healthy controls. Subsequently, the relationship between PSGL-1 levels and clinicopathological characteristics of patients, as well as the prognosis of EOC patients, was examined. Additionally, the specificity and sensitivity of plasma PSGL-1 were assessed through ROC curve analysis. Plasma PSGL-1 was upregulated in EOC patients compared with healthy subjects and/or patients with benign ovarian cystadenoma (p < 0.01). Elevated levels of PSGL-1 in the plasma were positively associated with advanced FIGO stage (p < 0.001), tumor size (p = 0.001), tumor metastasis (p = 0.036), and tumor recurrence (p = 0.013), while was negatively correlated with residual tumor size (p < 0.001). Kaplan-Meier survival analysis showed that high plasma PSGL-1 levels were associated with progression-free survival (p = 0.0345). In univariate and multivariate Cox regression analyses, PSGL-1 (HR = 1.456, p = 0.009) was an independent prognostic marker. Plasma PSGL-1 levels distinguished EOC patients and healthy individuals (AUC = 0.905), patients at late and early FIGO stages (AUC = 0.886), and metastatic and non-metastatic EOC (AUC = 0.722). The expression of plasma PSGL-1 is significantly increased in patients with EOC, serving as a reliable biomarker to differentiate between healthy individuals and those with EOC. Furthermore, PSGL-1 in patients is correlated with prognostic indicators, such as advanced FIGO stage, tumor lymph node metastasis, and progression-free survival.

Ultrasensitive SERS quantitative detection of antioxidants via diazo derivatization reaction and deep learning for signal fluctuation mitigation.

Synthetic antioxidants serve as essential protectors against oxidation and deterioration of edible oils, however, prudent evaluation is necessary regarding potential health risks associated with excessive intake. The direct adsorption of antioxidants onto conventional surface-enhanced Raman scattering (SERS) substrates is challenging due to the presence of phenolic hydroxyl groups in their molecular structures, resulting in weak Raman scattering signals and rendering direct SERS detection difficult. In this study, a diazo derivatization reaction was employed to enhance SERS signals by converting antioxidant molecules into azo derivatives, enabling the amplification of the weak Raman scattering signals through the strong vibrational modes induced by the N = N double bond. The resulting diazo derivatives were characterized using UV-visible absorption and infrared spectroscopy, confirming the occurrence of diazo derivatization of the antioxidants. The proposed method successfully achieved the rapid detection of three commonly used synthetic antioxidants, namely butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), and propyl gallate (PG) on interfacial self-assembled gold nanoparticles. Furthermore, rapid predictions of BHA, PG, and TBHQ within the concentration range of 1 × 10-6 to 2 × 10-3 mol/L were achieved by integrating a convolutional neural network model. The predictive range of this model surpassed the traditional quantitative method of manually selecting characteristic peaks, with linear coefficients (R2) of 0.9992, 0.9997, and 0.9997, respectively. The recovery of antioxidants in real soybean oil samples ranged from 73.0 % to 126.4 %. Based on diazo derivatization, the proposed SERS method eliminates the need for complex substrates and enables the analysis and determination of synthetic antioxidants in edible oils within 20 min, providing a convenient analytical approach for quality control in the food industry.

DNA Image Cytometry for Screening the Carcinogenetic Risk of Oral Potential Malignant Disorders.

Background: Oral Submucosal Fibrosis (OSF) and Oral Leukoplakia (OLK) are well-known oral potentially malignant disorders, and cases of Oral Submucosal Fibrosis concomitant Oral Leukoplakia (OSF+OLK) are now being reported clinically. DNA image cytometry is an objective and non-invasive method for monitoring the risk of precancerous lesions in the oral cavity. Methods: A total of 111 patients with clinically characterized oral mucosal lesions underwent simultaneous and independent histopathological and DNA imaging cytometry assessments. Clinical data were also collected for each patient. Results: The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.003) for OLK. The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.035) for OSF+OLK. The differences of DNA content abnormality in age, sex, dietary habit, smoking, and alcohol intake were not observed in OLK and OSF+OLK. The study indicates an association between DNA content abnormality and pathological examination in OSF+OLK ( χ2 test, P = 0.007). OLK showed higher sensitivity and specificity than OSF, while the sensitivity and specificity of OSF+OLK are higher than OLK only and OSF only. Conclusion: DNA image cytometry can be utilized as an adjunctive device for the initial detection of oral potentially malignant disorders that require further clinical management.

Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.

Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.

Suppression of the METTL3-m6A-integrin ß1 axis by extracellular acidification impairs T cell infiltration and antitumor activity.

The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the "tumor acidity (TuAci) score" for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin ß1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.

[Inhibitory Effect of Metformin and Arsenic Trioxide on KG1a Cell Proliferation].

OBJECTIVE: To investigate the effect of metformin and arsenic trioxide on KG1a cells proliferation of acute myeloid leukemia and its possible mechanism. METHODS: CCK-8 method was used to detect the killing effect of metformin, arsenic trioxide and combined application on KG1a cells. Annexin V-FITC/PI Dual Stain Flow Cytometry was used to detect the effect of combined application on apoptosis of KG1a cells. Western blot was used to detect the expression of intracellular apoptosis-,autophagy-related protein. RESULTS: Metformin and arsenic trioxide alone or in combination could inhibit the proliferation of KG1a cells and induce apoptosis of KG1a cells, and the proliferation inhibition rate and apoptosis rate in the combined drug group were higher than those in the drug group alone(P <0.05). The combination of drugs induced upregulation of Caspase 8 protein and P62 protein expression and was higher than that in the drug group alone(P <0.05). CONCLUSION: Metformin can synergize with arsenic trioxide to kill KG1a cells, and its mechanism of action may be related to inducing apoptosis and enhancing autophagy.

A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER- cells via endoplasmic reticulum stress-induced apoptosis.

Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER-) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER- cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER- cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER- breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER- cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

HNRNPC promotes estrogen receptor-positive breast cancer cell cycle by stabilizing WDR77 mRNA in an m6A-dependent manner.

Breast cancer has become the most commonly diagnosed cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a reader of N6-methyladenosine (m6A), has been observed to be upregulated in various types of cancer. Nevertheless, the role of HNRNPC in breast cancer and whether it is regulated by m6A modification deserve further investigation. The expression of HNRNPC in breast cancer was examined by quantitative real-time polymerase chain reaction and western blot analysis. RNA immunoprecipitation was performed to validate the binding relationships between HNRNPC and WD repeat domain 77 (WDR77). The effects of HNRNPC and m6A regulators on WDR77 were investigated by actinomycin D assay. The experiments in vivo were conducted in xenograft models. In this research, we found that HNRNPC was highly expressed in breast cancer, and played a crucial role in cell growth, especially in the luminal subtype. HNRNPC could combine and stabilize WDR77 mRNA. WDR77 successively drove the G1/S phase transition in the cell cycle and promoted cell proliferation. Notably, this regulation axis was closely tied to the m6A modification status of WDR77 mRNA. Overall, a critical regulatory mechanism was identified, as well as promising targets for potential treatment strategies for luminal breast cancer.

Statistical Characterization of Food-Derived α-Amylase Inhibitory Peptides: Computer Simulation and Partial Least Squares Regression Analysis.

α-Amylase inhibitory peptides are used to treat diabetes, but few studies have statistically characterized their interaction with α-amylase. This study performed the molecular docking of α-amylase with inhibitory peptides from published papers. The key sites, side chain chargeability, and hydrogen bond distribution characteristics were analyzed. Molecular dynamics simulated the role of key sites in complex stability. Moreover, partial least squares regression (PLSR) was used to analyze the contribution of different amino acids in the peptides to inhibition. The results showed that, for the α-amylase molecule, His201 and Gln63, with the highest interaction numbers (INs, 15, 15) and hydrogen bond values (HBVs, 11.50, 10.33), are the key sites on α-amylase, and amino acids with positively charged side chains were important for inhibitory activity. For the inhibitory peptides, Asp and Arg had the highest HBVs, and amino acids with charged side chains were more likely to form hydrogen bonds and exert inhibitory activity. In molecular dynamics simulations, peptides involving key binding sites formed more stable complexes with α-amylase than α-amylase alone, suggesting enhanced inhibitory effects. Further, PLSR results showed that amino acids close to the N-terminus of the inhibitory peptide, located in the third and fifth positions, were significantly correlated with its inhibitory activity. In conclusion, this study provides a new approach to developing and screening α-amylase inhibitors.

Organophosphate Esters in Building Materials from China: Levels, Sources, Emissions, and Preliminary Assessment of Human Exposure.

Source characteristics and health risks of indoor organophosphate esters (OPEs) are limited by the lack of knowledge on emission processes. This study attempted to integrate the contents and emissions of OPEs from indoor building materials to assess human health effects. Thirteen OPEs were investigated in 80 pieces of six categories of building materials. OPEs are ubiquitous in the building materials and ∑13OPE contents varied significantly (p < 0.05) from 72.8 ng/g (seam agent) to 109,900 ng/g (wallpaper). Emission characteristics of OPEs from the building materials were examined based on a microchamber method. Depending on the sample category, the observed initial area-specific emission rates of ∑13OPEs varied from 154 ng/m2/h (carpet) to 2760 ng/m2/h (wooden floorboard). Moreover, the emission rate model was developed to predict the release levels of individual OPEs, quantify source contributions, and assess associated exposure risks. Source apportionments of indoor OPEs exhibited heterogeneities in multiple environmental media. The joint OPE contribution of wallpaper and wooden floorboard to indoor dust was up to 94.8%, while latex paint and wooden floorboard were the main OPE contributors to indoor air (54.2%) and surface (76.1%), respectively. Risk assessment showed that the carcinogenic risks of tris(2-chloroethyl) phosphate (3.35 × 10-7) were close to the acceptable level (1 × 10-6) and deserved special attention.