Symbiotic combination of Akkermansia muciniphila and inosine alleviates alcohol-induced liver injury by modulating gut dysbiosis and immune responses.

Background: Alcoholic liver disease (ALD) is exacerbated by disruptions in intestinal microecology and immune imbalances within the gut-liver axis. The present study assesses the therapeutic potential of combining Akkermansia muciniphila (A. muciniphila) with inosine in alleviating alcohol-induced liver injury. Methods: Male C57BL/6 mice, subjected to a Lieber-DeCarli diet with 5% alcohol for 4 weeks, served as the alcoholic liver injury model. Various analyzes, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), ELISA, immunochemistry, 16S rRNA gene sequencing, and flow cytometry, were employed to evaluate liver injury parameters, intestinal barrier function, microbiota composition, and immune responses. Results: Compared to the model group, the A. muciniphila and inosine groups exhibited significantly decreased alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide (LPS) levels, reduced hepatic fat deposition and neutrophil infiltration, alleviated oxidative stress and inflammation, and increased expression of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1). These effects were further pronounced in the A. muciniphila and inosine combination group compared to individual treatments. While alcohol feeding induced intestinal dysbiosis and gut barrier disruption, the combined treatment reduced the abundance of harmful bacteria (Oscillibacter, Escherichia/Shigella, and Alistipes) induced by alcohol consumption, promoting the growth of butyrate-producing bacteria (Akkermansia, Lactobacillus, and Clostridium IV). Flow cytometry revealed that alcohol consumption reduced T regulatory (Treg) populations while increasing those of T-helper (Th) 1 and Th17, which were restored by A. muciniphila combined with inosine treatment. Moreover, A. muciniphila and inosine combination increased the expression levels of intestinal CD39, CD73, and adenosine A2A receptor (A2AR) along with enhanced proportions of CD4+CD39+Treg and CD4+CD73+Treg cells in the liver and spleen. The A2AR antagonist KW6002, blocked the beneficial effects of the A. muciniphila and inosine combination on liver injury in ALD mice. Conclusion: This study reveals that the combination of A. muciniphila and inosine holds promise for ameliorating ALD by enhancing the gut ecosystem, improving intestinal barrier function, upregulating A2AR, CD73, and CD39 expression, modulating Treg cells functionality, and regulating the imbalance of Treg/Th17/Th1 cells, and these beneficial effects are partly A2AR-dependent.

Potential Mechanism of Tibetan Medicine Liuwei Muxiang Pills against Colorectal Cancer: Network Pharmacology and Bioinformatics Analyses.

This study aimed to explore the mechanism through which Tibetan medicine Liuwei Muxiang (LWMX) pills acts against colorectal cancer (CRC). We firstly retrieved the active ingredients and the correlated targets of LWMX pills from public databases. The CRC-related targets were determined through bioinformatic analysis of a public CRC dataset. By computing the intersection of the drug-specific and disease-related targets, LWMX pill-CRC interaction networks were constructed using the protein-protein interaction (PPI) method and functional enrichment analysis. Subsequently, we determined the hub genes using machine learning tools and further verified their critical roles in CRC treatment via immune infiltration analysis and molecular docking studies. We identified 81 active ingredients in LWMX pills with 614 correlated targets, 1877 differentially expressed genes, and 9534 coexpression module genes related to CRC. A total of 5 target hub genes were identified among the 108 intersecting genes using machine learning algorithms. The immune infiltration analysis results suggested that LWMX pills could affect the CRC immune infiltration microenvironment by regulating the expression of the target hub genes. Finally, the molecular docking outcomes revealed stable binding affinity between all target hub proteins and the primary active ingredients of LWMX pills. Our findings illustrate the anti-CRC potential and the mechanism of action of LWMX pills and provide novel insights into multitarget medication for CRC treatment.

Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.

Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.

A Novel Lipid Metabolism and Endoplasmic Reticulum Stress-Related Risk Model for Predicting Immune Infiltration and Prognosis in Colorectal Cancer.

Lipid metabolism and endoplasmic reticulum stress exhibit crosstalk in various cancer types, which are closely associated with the progression of colorectal cancer (CRC). This study constructs a prognostic signature based on lipid metabolism and endoplasmic reticulum stress-related genes (LERGs) for CRC patients, aiming to predict the prognosis and immune response. RNA sequencing and clinical data from the TCGA and GEO databases were analyzed to identify differentially expressed LERGs with prognostic relevance using univariate Cox regression. Subsequently, a risk model was developed using the LASSO regression. CRC patients were stratified into low-risk and high-risk groups based on risk scores, with the high-risk cohort demonstrating a poorer clinical prognosis in multiple databases. The risk model showed robust correlations with clinical features, gene mutations, and treatment sensitivity. Significant differences in immune cell infiltration and the expression of immune-related factors were also detected between risk groups, and elevated scores of cytokines and failure factors were detected in single-cell RNA sequencing analysis. This research indicates that lipid metabolism and endoplasmic reticulum stress in CRC are correlated with tumor progression, an immunosuppressive landscape, and alterations of drug sensitivity. The developed risk model can serve as a powerful prognostic tool, offering critical insights for refining clinical management and optimizing treatment in CRC patients.

Prognostic Significance of mRNA Expression RBBP8 or Its Methylation in Gliomas.

Retinoblastoma-binding protein 8 (RBBP8) affects the prognosis of patients with malignancies through various mechanisms. However, its function in gliomas is unknown. Our study explored the effects of RBBP8 on the prognosis of glioma patients, as well as its regulatory role in the glioma immune microenvironment. We used various bioinformatics methods to analyze the transcriptional profiles and methylation data of RBBP8 in gliomas from multiple databases. Our results showed that the mRNA and protein expression of RBBP8 in gliomas was higher than that in normal tissues and positively correlated with malignant clinical features such as age and WHO grade. A Kaplan-Meier analysis showed that patients with high RBBP8 expression had a poor prognosis. Cox regression demonstrated that RBBP8 was an independent risk indicator and had good diagnostic value for the poor prognosis of glioma. Importantly, RBBP8 was positively correlated with many well-known immune checkpoints (e.g., CTLA4 and PDL-1). Finally, a gene set enrichment analysis revealed that RBBP8 was remarkably enriched in cancer-related pathways such as cell cycle, DNA replication and so on. In conclusion, this study is the first to elaborate on the value of RBBP8 in the pathological process of glioma for anti-tumor immunotherapy. In addition, the expression of RBBP8 and its methylation site, cg05513509, may provide potential targets for glioma therapy.

Toward Wearable Healthcare: A Miniaturized 3D Imager With Coherent Frequency-Domain Photoacoustics.

Medical monitoring is undergoing a translation from the hospital-based system to the personalized home-based system. With the aim of wearable application of photoacoustic technique, we propose a miniaturized photoacoustic 3D imager for superficial medical imaging. By employing the compact continuous-wave laser diode based optical irradiation and an ultrathin 2D matrix array based photoacoustic detection in the coherent frequency domain, a wearable imaging probe with a size of about 80 × 25 × 24 mm3 and a weight of 21 g is developed. At the backend, an FPGA controlled Howland current source drives the laser diodes to excite linear frequency modulated optical irradiation. Recorded by a portable multichannel data acquisition system, the generated photoacoustic responses are firstly compressed with the coherent frequency domain photoacoustic method and then extrapolated in the wavenumber-frequency domain for fast image reconstruction. With three-wavelength (450 nm, 638 nm, and 808 nm) laser irradiation, photoacoustic imaging can be operated multispectrally, endowing the developed imager with functional imaging capability in 3D space. With the imager worn on the human forearm, hemoglobin oxygen saturation level in superficial arm vasculature can be long-term monitored with high stability. When the imager is applied for imaging in a relatively large area (e.g., early melanoma detection in the human breast), flexible scanning in a handheld manner can be performed. This work opens the application potential of photoacoustic technique in a broad range of areas, including personalized healthcare, home health monitoring, and long-term physiologic monitoring.

Handheld Photoacoustic Imager for Theranostics in 3D.

A handheld approach to 3D photoacoustic imaging is essential in clinical applications. To this end, we develop a 3D handheld photoacoustic imager for dynamic (temporally and spatially) volumetric visualization. In this 3D imager, the optically transmitting part and the acoustically receiving part are integrated into a single handheld probe with a compact size about 160 mm ×64 mm ×40 mm. Besides, a dedicated imaging reconstruction algorithm for the heterogeneous medium is developed based on the phase-shift migration method in the frequency domain, which deals well with the stratified condition in the designed system. Dynamic 3D imaging supporting flexible handheld operation is demonstrated with needle biopsy and in vitro temperature measurement for photothermal therapy. The development of such a 3D handheld photoacoustic system paves the way for compact and handheld-operating implementations, and its further clinical exploration is promising.

[Influence of previous abdominopelvic surgery on gynecological laparoscopic operation].

OBJECTIVE: To investigate the influence of previous abdominopelvic surgery on gynecological laparoscopic operation. METHODS: A retrospective analysis of 3 283 cases of gynecological diseases by laparoscopic operation patients in Peking University First Hospital from 2007 January to 2012 December, among them, 719 (21.90%) patients with previous abdominopelvic surgery history (study Group), 2 564 (78.10%)patients have no history of abdominopelvic surgery (control group). Study group 719 patients, previous operation times: one time in 525 cases, 194 cases were multiple; previous operation: 185 cases of gynecological surgery, 305 cases of obstetric surgery, 108 cases of general surgery, and 121 complex surgery (include at least two kinds of surgery); previous operative approach: 650 cases laparotomy and 69 cases laparoscopy. Compared two groups of patients with abdominopelvic adhesion and the gynecologic laparoscopic operation situation, analyzed the influence of previous abdominopelvic surgery on abdominopelvic adhesion on and gynecological laparoscopic operation. RESULTS: The incidence of abdominopelvic adhesion in the patients with previous abdominopelvic surgery was 51.2% (368/719), which was significantly higher than that of 8.2% (211/2 564)in patients without previous abdominopelvic surgery (P < 0.01). But the study group score (median 3) and the degree of abdominopelvic adhesion [mild 49.7% (183/368), moderate 36.1% (133/368), severe 14.1% (52 /368)] compared with the control group score (median 2) and degree [mild 55.0% (116/211), moderate 25.6% (54/211), and severe 19.4% (41/211)] were no statistical difference (P = 0.930, P = 0.684). Super-umbilical primary trocar site were chosen more common in patients with previous abdominopelvic surgery (23.1%, 166/719) was significantly higher than that in the control group (3.3% , 85/2 564;P < 0.01). And the rate of conversion to laparotomy was 0.6% (4/719) significantly more than the control groups (0.1%, 2/2 564; P = 0.023). Compared with other groups, patients with gynecological or complex surgery or multiple operation history presented more severe abdominopelvic adhesion both in the score and degree (P < 0.01). The rate of super-umbilical primary trocar site, hospitalization time, operation time and bleeding during operation in patients with multiple operation history were significantly higher than those with single operation history (P < 0.05); the rate of blood transfusion, postoperative complication and conversion to laparotomy showed no statistical difference between the two groups (P > 0.05). CONCLUSION: The laparoscopic operation could be carried out successfully and safely in patients with a history of various abdominopelvic operations, but the conversion rate increases, for patients with a history of multiple operation because of pelvic adhesion increases the difficulty of the laparoscopic operation.

[Analysis of the complications of gynecological laparoscopic operation within 10 years].

OBJECTIVE: To investigate on the incidence of gynecological laparoscopic operation complications within ten years. METHODS: From January 2003 to December 2012, clinical data and the complications of 4 897 cases undergoing gynecological laparoscopic operation in First Hospital of Peking University were studied retrospectively. Those surgeries included 876 cases with hysterectomy, 662 cases with myoectomy, 3 266 cases with adnexa surgery, 93 cases of diagnostic laparoscopy operation. RESULTS: The complications occurred in 29 cases, the incidence rate was 0.59% ( 29/4 897). The Incidence rate in Hysterectomy group was 1.83% (16/876), which was significantly higher than 0.60% (4/662) in myoectomy group and 0.28% (9/3 266) in adnexa surgery group. Twenty nine cases of complications were 14 cases with organ injures (48%, 14/29), 5 cases with hemorrhage complications (17%, 5/29), 8 cases with infectious complications (28%, 8/29), 2 cases with incisional hernia (7%, 2/29). CONCLUSION: The major complication of gynecological laparoscopic operation complication was organs injuries, which was associated with difficulty and scope of the operation.

Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations.

BACKGROUND: We tested our ability to approximate the dose (38 Gy), fractionation (four fractions), and distribution of high-dose-rate (HDR) brachytherapy for prostate cancer with CyberKnife (CK) stereotactic body radiotherapy (SBRT) plans. We also report early clinical observations of CK SBRT treatment. METHODS AND MATERIALS: Ten patients were treated with CK. For each CK SBRT plan, an HDR plan was designed using common contour sets and simulated HDR catheters. Planning target volume coverage, intraprostatic dose escalation, and urethra, rectum, and bladder exposure were compared. RESULTS: Planning target volume coverage by the prescription dose was similar for CK SBRT and HDR plans, whereas percent of volume of interest receiving 125% of prescribed radiation dose (V125) and V150 values were higher for HDR, reflecting higher doses near HDR source dwell positions. Urethra dose comparisons were lower for CK SBRT in 9 of 10 cases, suggesting that CK SBRT may more effectively limit urethra dose. Bladder maximum point doses were higher with HDR, but bladder dose falloff beyond the maximum dose region was more rapid with HDR. Maximum rectal wall doses were similar, but CK SBRT created sharper rectal dose falloff beyond the maximum dose region. Second CK SBRT plans, constructed by equating urethra radiation dose received by point of maximum exposure of volume of interest to the HDR plan, significantly increased V125 and V150. Clinically, 4-month post-CK SBRT median prostate-specific antigen levels decreased 86% from baseline. Acute toxicity was primarily urologic and returned to baseline by 2 months. Acute rectal morbidity was minimal and transient. CONCLUSIONS: It is possible to construct CK SBRT plans that closely recapitulate HDR dosimetry and deliver the plans noninvasively.

Computed tomography-ultrasound fusion brachytherapy: description and evolution of the technique.

PURPOSE: In this manuscript, we describe our computed tomography (CT)-ultrasound (US) fusion prostate brachytherapy method and report the updated dosimetry result and trend. METHODS AND MATERIALS: This cohort of 132 consecutive patients received CT-US fusion prostate brachytherapy from the first author (DBF) from December 2002 to August 2006. The technique consists of a hybrid preplanned and intraoperative dynamic dosimetry method, which initially delivers a standard preplanned source distribution, and then uses interval CT-based source identification dosimetry, fused to an identically spaced intraoperative US volume study series, to direct remedial sources that correct initial dosimetry deficiencies. RESULTS: The median and minimum prostate Day 0 prostate volume of interest receiving 100% of prescribed dose (V(100)) results in this patient cohort measured 98.26% and 92.61%, respectively, with all Day 0 prostate dose received by 90% of the volume of interest (D(90)) results exceeding 100% of the prescribed dose, and the maximum Day 0 prostate D(90) value measuring 128% of the prescribed dose. During the period of this analysis, a trend to the decreased quantity of dynamic remedial millicuries per case was identified, with the total sources decreasing from 116% to 106% of the preplanned level, resulting in minimal V(100) and D(90) decreases, while continuing to exceed the minimum Day 0 dosimetry requirements. CONCLUSIONS: CT-US fusion dynamic prostate brachytherapy represents a consistent prostate brachytherapy dosimetry delivery mechanism, creating a tight lower and upper bound to the final Day 0 prostate V(100) and D(90) parameters. The practice and pitfalls of this technique are discussed in detail.

CT-ultrasound fusion prostate brachytherapy: a dynamic dosimetry feedback and improvement method. A report of 54 consecutive cases.

PURPOSE: The authors describe a prostate brachytherapy technique with dynamic dosimetry feedback, using coregistered CT and ultrasound (US) images, to map initial dosimetry deficiencies and guide remedial source placement. METHODS AND MATERIALS: Fifty-four consecutive patients treated with this method were analyzed for coregistration accuracy and dosimetry outcomes by evaluating the prostate V100, V150, D90, and urethral D50 and D10. Dosimetric improvements created by remedial source placement and preplan/postplan prostate D90 agreement were evaluated. RESULTS: Median CT-US coregistration discrepancy with this technique ranged from 0 to 4mm, with the posterior midline prostate and base prostate providing the least consistent and the urethra providing the most consistent coregistration agreement. Final prostate V100 values ranged from 96.1% to 99.8% for all patients. The addition of remedial sources directed by CT-US fusion produced V100 and D90 improvements whose magnitude inversely correlated with the initial result and exceeded the effect of adding quantitatively identical randomly distributed increased millicuries. The final prostate D90 result agreed within (-) 5% to (+) 10% of the preplan result in 98% of all patients. CONCLUSIONS: CT-US fusion prostate brachytherapy represents a dynamic dosimetry feedback and remediation method that consistently produced high prostate V100 and D90 values with acceptably low urethra D50 and D10 values in our study. The degree of prostate V100 and D90 dosimetry improvement created by remedial source placement effectively matched the degree of initial dosimetry deficiency. This method produced a high level of correlation between the preplan and final prostate D90 values.