Forkhead box M1 mediates metabolic reprogramming in human colorectal cancer cells.

Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).

Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions.

Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

A structured iterative division approach for non-sparse regression models and applications in biological data analysis.

In this paper, we focus on the modeling problem of estimating data with non-sparse structures, specifically focusing on biological data that exhibit a high degree of relevant features. Various fields, such as biology and finance, face the challenge of non-sparse estimation. We address the problems using the proposed method, called structured iterative division. Structured iterative division effectively divides data into non-sparse and sparse structures and eliminates numerous irrelevant variables, significantly reducing the error while maintaining computational efficiency. Numerical and theoretical results demonstrate the competitive advantage of the proposed method on a wide range of problems, and the proposed method exhibits excellent statistical performance in numerical comparisons with several existing methods. We apply the proposed algorithm to two biology problems, gene microarray datasets, and chimeric protein datasets, to the prognostic risk of distant metastasis in breast cancer and Alzheimer's disease, respectively. Structured iterative division provides insights into gene identification and selection, and we also provide meaningful results in anticipating cancer risk and identifying key factors.

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis.

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

Changed nocturnal levels of stress-related hormones couple with sleep-wake states in the patients with chronic insomnia disorder: A clinical pilot study.

OBJECTIVES: To explore the relationship between nocturnal levels of stress-related hormones and different sleep-wake states in chronic insomnia disorder (CID) patients. METHODS: Thirty-three CID patients and 34 good sleepers were enrolled and completed assessment of sleep log, Pittsburgh Sleep Quality Index and Insomnia Severity Index. During a-overnight polysomnography monitoring, the patients' vein bleeds were continually collected at different time points (pre-sleep, deep-sleep, 5-min or 30-min waking, and morning waking-up). The control subjects' bleeds were collected only at 22:00 and morning waking-up. The serum hormones were detected using enzyme-linked immunosorbent assay. RESULTS: Compared with at pre-sleep, the level of cortisol was significantly higher at morning waking-up respectively in two-group subjects (Ps < 0.001), with insignificant inter-group differences in cortisol, corticotropin releasing hormone and copeptin at the two time-points. In the patients, the nocturnal secretion curves of three hormones were similar, with the highest concentration at morning waking-up, followed by 30-min waking, 5-min waking, pre-sleep, and deep-sleep. The patients' cortisol (Z = 79.192, P < 0.001) and copeptin (Z = 12.333, P = 0.015) levels were statistically different at different time-points, with higher cortisol at morning waking-up relative to deep-sleep, pre-sleep and 5-min waking (Ps < 0.05), and at 30-min waking relative to deep-sleep and pre-sleep (Ps < 0.05), and higher copeptin at morning waking-up relative to deep-sleep (P < 0.05). CONCLUSIONS: In CID, the nocturnal wakes were instantaneously accompanied by high level, and deep sleep was accompanied by the lowest levels, of stress-related hormones, especially in cortisol, supporting the insomniac hypothesis of increased nocturnal pulse-release of cortisol.

Synthesis and Selective Anticancer Activity Evaluation of 2-phenylacrylonitrile Derivatives as Tubulin Inhibitors.

OBJECTIVE: This study aimed at synthesizing 13 series of novel derivatives with 2-phenylacrylonitrile, evaluating antitumor activity both in vivo and in vitro, and obtaining novel tubulin inhibitors. METHOD: The 13 series of 2-phenylacrylonitrile derivatives were synthesized by Knoevenagel condensation and the anti-proliferative activities were determined by MTT assay. The cell cycle and apoptosis were analyzed by flow cytometer. Quantitative cell migration was performed using 24-well Boyden chambers. The proteins were detected by western blotting. in vitro kinetics of microtubule assembly was measured using ELISA kit for Human ß-tubulin (TUBB). Molecular docking was done by Discovery Studio (DS) 2017 Client online tool. RESULTS: Among the derivatives, compound 1g2a possessed strong inhibitory activity against HCT116 (IC50 = 5.9 nM) and BEL-7402 (IC50 = 7.8 nM) cells. Compound 1g2a exhibited better selective antiproliferative activities and specificities than all the positive control drugs, including taxol. Compound 1g2a inhibited proliferation of HCT116 and BEL-7402 cells by arresting them in the G2/M phase of the cell cycle, inhibited the migration of HCT116 and BEL-7402 cells and the formation of cell colonies. Compound 1g2a showed excellent tubulin polymerization inhibitory activity on HCT116 and BEL-7402 cells. The results of molecular docking analyses showed that 1g2a may inhibit tubulin to exert anticancer effects. CONCLUSION: Compound 1g2a shows outstanding antitumor activity both in vivo and in vitro and has the potential to be further developed into a highly effective antitumor agent with little toxicity to normal tissues.

Beyond diagnosis: Leveraging routine blood and urine biomarkers to predict severity and functional outcome in acute ischemic stroke.

Background: The initial severity of acute ischemic stroke (AIS) is a crucial predictor of the disease outcome. In this study, blood and urine biomarkers from patients with AIS were measured to estimate stroke severity and predict long-term stroke outcomes. Methods: The medical records of patients with AIS between October 2016 and May 2020 were retrospectively analyzed. The relationships of blood and urine biomarkers with stroke severity at admission were evaluated in patients with AIS. Predictive models for initial stroke severity and long-term prognosis were then developed using a panel of identified biomarkers. Results: A total of 2229 patients were enrolled. Univariate analysis revealed 12 biomarkers associated with the National Institutes of Health Stroke Scale scores at admission. The area under the curve values for predicting initial stroke severity and long-term prognosis on the basis of these biomarkers were 0.7465, 0.7470, and 0.8061, respectively. Among multiple tested machine-learning, eXtreme gradient boosting exhibited the highest effectiveness in predicting 90-day modified Rankin Scale scores. SHapley Additive exPlanations revealed fasting glucose, albumin, hemoglobin, prothrombin time, and urine-specific gravity to be the top five most crucial biomarkers. Conclusion: These findings demonstrate that clinically available blood and urine biomarkers can effectively estimate initial stroke severity and predict long-term prognosis in patients with AIS. Our results provide a scientific basis for developing tailored clinical treatment and management strategies for AIS, through incorporating liquid biomarkers into stroke risk assessment and patient care protocols for patients with AIS.

A structural optimized fluorescent probe for monitoring hydrogen sulfide in cells and zebrafish.

In this work, we reported a fluorescent probe Fur-SH, a derivative of benzofuranone, which was used to detect H2S in living cells and zebrafish. Based on the three structural characteristics of the probe, the effects of different structural modifications on the optical properties of the fluorophore were compared. Then, the fluorophore Fur-OH was synthesized by modifying diethylamino group with benzofuranone as the main skeleton. With 2,4-dinitrofluorobenzene as the recognition group and diethylamino as the electron donor, the push-pull electron effect occurred with nitro group, which led to fluorescence quenching, and an openable fluorescent probe Fur-SH was formed. The probe Fur-SH (λex = 510 nm; λem = 570 nm) had the advantages of smaller full width at half maxima, rapid response (5 min) and wide pH window. The quantitative properties of the probe were excellent, reaching saturation at 50 equivalents of substrate. The probe Fur-SH showed high sensitivity to H2S, with LOD of 48.9 nM and LOQ of 50 nM. At present, the probe Fur-SH had been applied to fluorescence imaging of MCF-7 cells and zebrafish. By comparing the effects of different structures on the optical properties of fluorophores, this work was expected to be helpful to the development of fluorescent probes in the future.

Patient-centered and integrated outreach care for chronic hepatitis C patients with serious mental illness in Taiwan.

Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population.

Effective Invasiveness Recognition of Imbalanced Data by Semi-Automated Segmentations of Lung Nodules.

Over the past few decades, recognition of early lung cancers was researched for effective treatments. In early lung cancers, the invasiveness is an important factor for expected survival rates. Hence, how to effectively identify the invasiveness by computed tomography (CT) images became a hot topic in the field of biomedical science. Although a number of previous works were shown to be effective on this topic, there remain some problems unsettled still. First, it needs a large amount of marked data for a better prediction, but the manual cost is high. Second, the accuracy is always limited in imbalance data. To alleviate these problems, in this paper, we propose an effective CT invasiveness recognizer by semi-automated segmentation. In terms of semi-automated segmentation, it is easy for doctors to mark the nodules. Just based on one clicked pixel, a nodule object in a CT image can be marked by fusing two proposed segmentation methods, including thresholding-based morphology and deep learning-based mask region-based convolutional neural network (Mask-RCNN). For thresholding-based morphology, an initial segmentation is derived by adaptive pixel connections. Then, a mathematical morphology is performed to achieve a better segmentation. For deep learning-based mask-RCNN, the anchor is fixed by the clicked pixel to reduce the computational complexity. To incorporate advantages of both, the segmentation is switched between these two sub-methods. After segmenting the nodules, a boosting ensemble classification model with feature selection is executed to identify the invasiveness by equalized down-sampling. The extensive experimental results on a real dataset reveal that the proposed segmentation method performs better than the traditional segmentation ones, which can reach an average dice improvement of 392.3%. Additionally, the proposed ensemble classification model infers better performances than the compared method, which can reach an area under curve (AUC) improvement of 5.3% and a specificity improvement of 14.3%. Moreover, in comparison with the models with imbalance data, the improvements of AUC and specificity can reach 10.4% and 33.3%, respectively.

Near-infrared imaging of hepatocellular carcinoma and its medicinal treatment with a γ-glutamyl transpeptidase-monitoring fluorescence probe.

Herein, the Near-infrared imaging of hepatocellular carcinoma (HCC) and its medicinal treatment was achieved with a γ-glutamyl transpeptidase (GGT)-monitoring fluorescence probe KYZ-GGT which consisted of the typical recognition group γ-glutamyl and the structurally modified signal reporting group hemicyanine-thioxanthene. Compared with the recently reported probes, KYZ-GGT suggested practical and steady capability for monitoring the GGT level in the cellular, xenograft, induced as well as medicinal treatment HCC models. It realized the mitochondrial targeting intracellular imaging to reflect the GGT dynamics in the induction or medicinal treatment of HCC. In the xenograft and induced model mice with multiple factors, KYZ-GGT showed stable performance for visualizing the HCC status. In the medicinal treatment of the long-period-induced HCC model mice verified by the serum indexes and histopathological analysis, KYZ-GGT successfully imaged the medicinal treatment process of HCC with two marketed drugs (Sorafenib and Lenvatinib) respectively, with an applicative penetration depth. The information here was meaningful for investigating effective medicinal strategies for overcoming HCC.

Maintenance of adult stem cells from human minor salivary glands via the Wnt signaling pathway.

BACKGROUND: Xerostomia is a salivary gland dysfunction that negatively impacts the life quality of patients; however, there is no effective treatment for xerostomia. Bioengineered organs, generated using stem cells obtained from newborn salivary glands and ligated injury models, are a new organ transplantation strategy that could be feasible for xerostomia treatment. Reconstruction of salivary gland organoids by seed cells obtained from human minor salivary glands will offer theoretical fundaments and technology support for clinical application and organ regeneration research. Herein, we aimed to propose a new method for culturing and enriching adult human minor salivary gland stem cells in vitro in a three-dimensional (3D) environment via Wnt signaling activation. METHODS: Obtained and characterized human minor salivary gland stem cells (hMSGSCs) with self-organization ability were 3D-cultured to generate organoids. We examined hMSGSCs proliferation and colony formation using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Telomerase reverse transcriptase staining, flow cytometry, immunofluorescence assay, RNA isolation, RT-PCR, and qPCR were performed to assess hMSGSCs structure and the function of reconstructive organoids in vitro. RESULTS: hMSGSCs showed typical epithelial-like characteristics, such as positive for CD49f and cell KRT expression. hMSGSCs served as adult stem cells in salivary glands and could differentiate into acinar and duct cells. Upon the addition of Noggin, CHIR99021, and Wnt3A to the 3D culture system, hMSGSCs showed higher LGR5 expression and decreased AMY1B and MUC5B expression. Therefore, the Wnt and bone morphogenetic protein (BMP) pathways are important in regulating hMSGSCs self-organization and differentiation. CONCLUSIONS: We showed that the stem cell properties of hMSGSCs in a 3D culture system can be maintained by activating the Wnt signaling pathway and inhibiting the BMP signaling pathway. Our findings contribute new insights on salivary gland organoid generation in vitro.

Imaging Investigation of Hepatocellular Carcinoma Progress via Monitoring γ-Glutamyltranspeptidase Level with a Near-Infrared Fluorescence/Photoacoustic Bimodal Probe.

Hepatocellular carcinoma (HCC) is one of the main principal causes of cancer death, and the late definite diagnosis limits therapeutic approaches in time. The early diagnosis of HCC is essential, and the previous investigations on the biomarkers inferred that the γ-glutamyltranspeptidase (GGT) level could indicate the HCC process. Herein, a near-infrared fluorescence/photoacoustic (NIRF/PA) bimodal probe, CySO3-GGT, was developed for monitoring the GGT level and thus to image the HCC process. After the in-solution tests, the bimodal response was convinced. The various HCC processes were imaged by CySO3-GGT at the cellular level. Then, the CCl4-induced HCC (both induction and treatment) and the subcutaneous and orthotopic xenograft mice models were selected. All throughout the tests, CySO3-GGT achieved NIRF and PA bimodal imaging of the HCC process. In particular, CySO3-GGT could effectively realize 3D imaging of the HCC nodule by visualizing the boundary between the tumor and the normal tissue. The information here might offer significant guidance for the dynamic monitoring of HCC in the near future.

Multi-b-values-fitting readout-segmentation of long variable echo-trains diffusion-weighted imaging (RESOLVE DWI) in evaluation of disease activity and curative effect of axial spondyloarthritis (axSpA).

Background: Disease activity is relevant to the treatment and prognosis of axSpA, and methods to quantitatively assess disease activity and efficacy of axSpA are still being explored. Objective: The purpose of this study was to find an optimal quantitative indicator for evaluating disease activity and curative effect of axSpA, using multi-b-values-fitting RESOLVE DWI. Methods: The prospective study included 106 patients divided into axSpA group (n=89) and no-axSpA group (n=17) by Assessment of Spondyloarthritis international Society (ASAS) criteria. The axSpA group were divided into active group and inactive group according to ASDAS-CRP. The active group treated with systematic tumour necrosis factor inhibitors (TNFi) was selected as treatment group (n=20). All patients underwent MRI examination of sacroiliac joints (SIJs), including RESOLVE DWI. The ADC values of subchondral bone marrow in SIJs were measured (ADC50,500 was b=50,500s/mm2 fitting, ADC50,700 was b=50,700s/mm2 fitting, and ADC50,500,700 was b=50,500,700s/mm2 fitting). By comparing the ADC values between different groups, a relatively optimal b-values-fitting sequence was obtained, further evaluating curative effect of the treatment group. Resultd: The ADC values of axSpA group, inactive group and active group SIJs were all higher than those of no-axSpA group. The ADC values of active group SIJs were all higher than those of inactive group. ADC50,500,700 had the largest AUC, relative higher sensitivity and specificity while taking account of the image quality than ADC50,700 and ADC50,500 between different groups. In the treatment group, there was no significant difference in ADC values between pre-treatment and 3 weeks, 3 weeks and 6 weeks, 6 weeks and 12 weeks (all P>0.0083, Bonferroni-corrected threshold), while the decreased ADC values in the interval of 6 weeks or more were statistically significant (all P<0.0083, Bonferroni-corrected threshold). Conclusion: Multi-b-values-fitting (b=50,500,700s/mm2) RESOLVE DWI has a certain advantage in evaluating disease activity of axSpA. It was worth noting that short-term review (3 weeks or less) of RESOLVE DWI was unsatisfactory and review at 6 weeks or later would help to evaluate curative effect of axSpA.

Multiomics reveals new biomarkers and mechanistic insights into the combined toxicity effects of 2,2',4,4',5,5'-hexachlorobiphenyl and atrazine exposures in MCF-7 cells.

Humans are constantly exposed to complicated chemical mixtures from the environment and food rather than being exposed to a single pollutant. The underlying mechanisms of the complicated combined toxicity of endocrine disrupting chemicals (EDCs) are still mainly unexplored. In this study, two representative EDCs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and atrazine (ATZ), were selected to explore their combined effects on MCF-7 cell proliferation at environmental exposure concentrations by an integrated analysis of metabolomics and transcriptomics. The results showed that 1 µM ATZ and PCB153 combined exposure significantly accelerated MCF-7 cell growth by 18.2%. More than 400 metabolites detected by UHPLC-QTOF/MS were used to observe metabolism differences induced by binary mixtures. Metabolomics analysis verified that ATZ and PCB153 exposure alone or in combination could have an additive effect on metabolism and induce significant disruption to glycolysis, purine metabolism and the TCA cycle, which provide energy demand and biosynthetic substrates for cell proliferation. Compared to PCB153 and ATZ exposure alone, a combined effect was observed in purine and pyrimidine metabolic pathways. Hexokinase 3 (HK3) and cytochrome P450 19 subfamily A1 (CYP19A1) were identified as differentially expressed genes based on transcriptomic analysis. By integrating metabolome and transcriptome analysis, the proliferation effects of ATZ and PCB153 were induced at low doses in MCF-7 cells through potential interference with the downstream transcription signaling of CYP19A1. Furthermore, molecular docking indicated that PCB153 and ATZ directly affected CYP19A1. Altogether, the regulation of pivotal metabolites and differentially expressed genes could provide helpful information to reveal the mechanism by which PCB153 and ATZ affect MCF-7 cell proliferation.

American ginseng with different processing methods ameliorate immunosuppression induced by cyclophosphamide in mice via the MAPK signaling pathways.

This study aimed to clarify the effects of two processed forms of American ginseng (Panax quinquefolius L.) on immunosuppression caused by cyclophosphamide (CTX) in mice. In the CTX-induced immunosuppressive model, mice were given either steamed American ginseng (American ginseng red, AGR) or raw American ginseng (American ginseng soft branch, AGS) by intragastric administration. Serum and spleen tissues were collected, and the pathological changes in mice spleens were observed by conventional HE staining. The expression levels of cytokines were detected by ELISA, and the apoptosis of splenic cells was determined by western blotting. The results showed that AGR and AGS could relieve CTX-induced immunosuppression through the enhanced immune organ index, improved cell-mediated immune response, increased serum levels of cytokines (TNF-α, IFN-γ, and IL-2) and immunoglobulins (IgG, IgA, and IgM), as well as macrophage activities including carbon clearance and phagocytic index. AGR and AGS downregulated the expression of BAX and elevated the expression of Bcl-2, p-P38, p-JNK, and p-ERK in the spleens of CTX-injected animals. Compared to AGS, AGR significantly improved the number of CD4+CD8-T lymphocytes, the spleen index, and serum levels of IgA, IgG, TNF-α, and IFN-γ. The expression of the ERK/MAPK pathway was markedly increased. These findings support the hypothesis that AGR and AGS are effective immunomodulatory agents capable of preventing immune system hypofunction. Future research may investigate the exact mechanism to rule out any unforeseen effects of AGR and AGS.

Discovery of the cysteine dynamics during the development and treatment of diabetic process by fluorescent imaging.

Herein, a novel fluorescent probe RhoDCM was developed for monitoring the cysteine (Cys) dynamics. For the first time, the Cys-triggered implement was applied in relatively complete diabetic mice models. The response of RhoDCM towards Cys suggested advantages including practical sensitivity, high selectivity, rapid reaction, and steadiness in various pH and temperature conditions. RhoDCM could basically monitor the intracellular Cys level, both exogenous and endogenous. It could further monitor the glucose level via detecting consumed Cys. Furthermore, the diabetic mice models including the no diabetic control group, the induced model groups by streptozocin (STZ) or alloxan, and the treatment groups induced by STZ and treated with vildagliptin (Vil), dapagliflozin (DA), or metformin (Metf) were constructed. The models were checked by oral glucose tolerance test and significant liver-related serum indexes. Based on the models, the in vivo imaging and penetrating depth fluorescence imaging both indicated that RhoDCM could characterize the status of the development and treatment in the diabetic process via monitoring the Cys dynamics. Consequently, RhoDCM seemed beneficial for inferring the order of severity in the diabetic process and evaluating the potency of therapeutic schedules, which might be informatic for correlated investigations.

[Effects of staged acupuncture on endometrial receptivity and anxiety in patients with recurrent implantation failure of thin endometrium based on "thoroughfare vessel is the sea of blood" theory].

OBJECTIVE: To compare the clinical efficacy between staged acupuncture based on "thoroughfare vessel is the sea of blood" theory combined with routine hormone replacement cycle treatment and routine hormone replacement cycle treatment for patients with recurrent implantation failure (RIF) of thin endometrium. METHODS: A total of 72 RIF patients with thin endometrium were randomly divided into an observation group and a control group, 36 cases in each group. The patients in the control group were treated with routine hormone replacement cycle treatment. Based on the treatment of the control group, the patients in the observation group were treated with staged acupuncture based on "thoroughfare vessel is the sea of blood" theory. The main acupoints were Neiguan (PC 6) and Gongsun (SP 4), and the supplementary acupoints were selected according to the menstrual cycle and syndrome differentiation; the acupuncture was given once every other day, 3 times a week, for 3 consecutive menstrual cycles. The thickness and shape of endometrium, and Hamilton anxiety scale (HAMA) score were observed at implantation window before and after treatment; the clinical pregnancy rate, live birth rate and cycle cancellation rate were compared between the two groups; the correlation between endometrial thickness and HAMA score was analyzed. RESULTS: Compared before treatment, the endometrial thickness in the two groups and the proportion of type A+B endometrium in the observation group were increased (P<0.05), and the HAMA scores in the two groups were decreased (P<0.05) after treatment. The above indexes in the observation group were superior to those in the control group (P<0.05). The clinical pregnancy rate and live birth rate in the observation group were higher than those in the control group (P<0.05), and the cycle cancellation rate was lower than that in the control group (P<0.05). There was a negative correlation between endometrial thickness and HAMA score (P<0.05). CONCLUSION: Based on the routine hormone replacement cycle treatment, the addition use of staged acupuncture based on "thoroughfare vessel is the sea of blood" theory could improve the thickness and shape of endometrium, relieve anxiety, increase the clinical pregnancy rate and live birth rate, and reduce the cycle cancellation rate in RIF patients with thin endometrium. The curative effect is superior to the routine hormone replacement cycle treatment alone.

Private Payer-Negotiated Rates for FDA-Approved Head and Neck Cancer Immunotherapy and Chemotherapy Agents.

OBJECTIVE: To quantify the price that private payers pay hospitals for head and neck squamous cell carcinoma (HNSCC) treatments and identify hospital-level factors associated with price variation. STUDY DESIGN: Cross-sectional study. SETTING: Price transparency files. METHODS: Files from the top 50 hospitals in otolaryngology according to the US News and World Report were analyzed between December 2021 and June 2022. This study analyzed the following Food and Drug Administration-approved HNSCC therapies: pembrolizumab, nivolumab, cetuximab, cisplatin, carboplatin, and paclitaxel. RESULTS: Twenty-four (48%) hospitals reported prices for at least 1 medication in our sample. Newer biologics were significantly more expensive than traditional chemotherapeutic agents. Given approved medication regimens, all biologics in our sample have similar annual costs. Price markups over acquisition costs ranged between 109% (pembrolizumab, nivolumab) and 530% for carboplatin. Across hospitals, prices varied the most for paclitaxel, the cheapest medication in our sample, and prices varied the least for pembrolizumab the most expensive medication in our sample. Hospital 340B status and geographic location in the northeast/west are associated with lower price markups. CONCLUSION: Price nondisclosure remains a significant problem among hospitals. Newer biological medications are more expensive when compared to traditional chemotherapeutic agents. Prices vary significantly across hospitals, with lower price markups observed in 340B hospitals as well as hospitals located in the geographic northeast and west. It remains to be seen if price transparency will lead to more uniform pricing or lower costs of treatments.