Deciphering the pancreatic cancer microbiome in Mainland China: Impact of Exiguobacterium/Bacillus ratio on tumor progression and prognostic significance.

The existing body of research underscores the critical impact of intratumoral microbiomes on the progression of pancreatic ductal adenocarcinoma (PDAC), particularly in reshaping the tumor microenvironment and influencing gemcitabine resistance. However, peritumoral tissues' microbiome, distinct from PDAC tumors, remain understudied, and Western-centric analyses overlooking potential variations in dietary-influenced microbiomes. Our study addresses this gap by 16 S rRNA sequencing of PDAC tumors and matched peritumoral tissues from Chinese Mainland patients. Our research has uncovered that the microbiome composition within tumors and paired peritumoral tissues exhibits a high degree of similarity, albeit with certain discrepancies. Notably, Exiguobacterium is found to be more abundant within the tumor tissues. Further investigations have revealed that a lower Exiguobacterium/Bacillus ratio in both the tumor and peritumoral tissues of PDAC patients is indicative of a more favorable prognosis. Further exploration utilizing an orthotopic tumor model demonstrates that the probiotic Bacillus Coagulans impedes PDAC progression, accompanied by an increased infiltration of inflammatory neutrophils in tumors. Additionally, in the subgroup with a low Exiguobacterium/Bacillus ratio, whole-exome sequencing reveals elevated missense mutations in ABL2 and MSH2. The elevated expression of ABL2 and MSH2 has been correlated with poorer prognostic outcomes in PDAC patients. Together, these insights shed light on risk factors influencing PDAC progression and unveil potential therapeutic targets, alongside probiotic intervention strategies.

Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis. METHODS: Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays. RESULTS: Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression. CONCLUSION: In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.

Prognostic predictive value of urothelial carcinoma of the bladder after TURBT based on multiphase CT radiomics.

OBJECTIVE: To investigate multiphase computed tomography (CT) radiomics-based combined with clinical factors to predict overall survival (OS) in patients with bladder urothelial carcinoma (BLCA) who underwent transurethral resection of bladder tumor (TURBT). METHODS: Data were retrospectively collected from 114 patients with primary BLCA from February 2016 to February 2018. The regions of interest (ROIs) of the plain, arterial, and venous phase images were manually segmented. The Cox regression algorithm was used to establish 3 basic models for the plain phase (PP), arterial phase (AP), and venous phase (VP) and 2 combination models (AP + VP and PP + AP + VP). The highest-performing radiomics model was selected to calculate the radiomics score (Rad-score), and independent risk factors affecting patients' OS were analyzed using Cox regression. The Rad-score and clinical risk factors were combined to construct a joint model and draw a visualized nomogram. RESULTS: The combined model of PP + AP + VP showed the best performance with the Akaike Information Criterion (AIC) and Consistency Index (C-index) in the test group of 130.48 and 0.779, respectively. A combined model constructed with two independent risk factors (age and Ki-67 expression status) in combination with the Rad-score outperformed the radiomics model alone; AIC and C-index in the test group were 115.74 and 0.840, respectively. The calibration curves showed good agreement between the predicted probabilities of the joint model and the actual (p < 0.05). The decision curve showed that the joint model had good clinical application value within a large range of threshold probabilities. CONCLUSION: This new model can be used to predict the OS of patients with BLCA who underwent TURBT.

Injectable Dynamic ROS-Responsive COF-Modified Microalgae Gels for In Vivo bFGF Delivery to Treat Diabetic Wounds.

Hypoxia, chronic inflammation, and elevated reactive oxygen species (ROS) production induced by hyperglycemia pose formidable challenges to the healing of diabetic chronic wounds, often resulting in impaired recovery. Currently, sustainable and eco-friendly therapeutic approaches targeting this multifaceted problem remain uncharted. Herein, we develop a unique three-functional covalent organic framework (COF)-modified microalgae gel designed for the preparation and treatment of chronic diabetic wounds. The gel comprises an oxygen-releasing basic fibroblast growth factor (bFGF) microalgae matrix, augmented by an ROS-responsive COF. Although two of these components have been reported to be used in wound healing, the combination of all three functions represents an innovative approach to synergize the treatment of chronic diabetic wounds. Therefore, we propose a new concept of "ligand interlocking" with three functional synergistic effects. Specifically, the COF has a similar effect to the "double Excalibur", which binds bFGF to promote angiogenesis and proliferation and inhibit the inflammatory response of chronic wounds and binds live microalgae to eliminate ROS and release dissolved oxygen to alleviate the hypoxia of wounds. Moreover, in vivo experiments and RNA sequencing analyses similarly demonstrated that the COF-modified microalgae gel reduced the inflammatory cascade cycle in the wound site and promoted vascular and tissue regeneration. We posit that the COF-modified microalgae gel represents a promising strategy for the active in vivo delivery of therapeutics to the wound body in intensive care unit settings.

Enzymatic Preparation, In-Depth Molecular Analysis, and In Vitro Digestion Simulation of Palmitoleic Acid (ω-7)-Enriched Fish Oil Triacylglycerols.

In this study, an enzymatic reaction was developed for synthesizing pure triacylglycerols (TAG) with a high content of palmitoleic acid (POA) using fish byproduct oil. The characteristics of synthesized structural TAGs rich in POA (POA-TAG) were analyzed in detail through ultrahigh-performance liquid chromatography Q Exactive orbitrap mass spectrometry. Optimal conditions were thoroughly investigated and determined for reaction systems, including the use of Lipozyme TL IM and Novozym 435, 15 wt % lipase loading, substrate mass ratio of 1:3, and water content of 2.5 and 0.5 wt %, respectively, resulting in yields of 67.50 and 67.45% for POA-TAG, respectively. Multivariate statistical analysis revealed that TAG 16:1/16:1/20:4, TAG 16:1/16:1/16:1, TAG 16:1/16:1/18:1, and TAG 16:0/16:1/18:1 were the main variables in Lipozyme TL IM and Novozym 435 enzyme-catalyzed products under different water content conditions. Finally, the fate of POA-TAG across the gastrointestinal tract was simulated using an in vitro digestion model. The results showed that the maximum release of free fatty acids and apparent rate constants were 71.44% and 0.0347 s-1, respectively, for POA-TAG lipids, and the physical and structural characteristics during digestion depended on their microenvironments. These findings provide a theoretical basis for studying the rational design of POA-structural lipids and exploring the nutritional and functional benefits of POA products.

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Saponins from Allium macrostemon Bulbs Attenuate Endothelial Inflammation and Acute Lung Injury via the NF-κB/VCAM-1 Pathway.

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.

Skeletal Editing of Benzene Motif: Photopromoted Transannulation for Synthesis of DNA-Encoded Seven-Membered Rings.

In this report, we present a photopromoted, metal-free transannulation of phenyl azides for the synthesis of DNA-encoded seven-membered rings. The transformation is efficiently achieved through a skeletal editing strategy targeting the benzene motif coupled with a Reversible Adsorption to Solid Support (RASS) strategy. A variety of valuable DNA-encoded seven-membered ring compounds, including DNA-encoded 3H-azepines, azepinones, and unnatural amino acids, are now accessible. Crucially, this DNA-compatible protocol can also be applied for the introduction of complex molecules, as exemplified by Lorcaserin and Betahistine. The selective conversion of readily available phenyl rings into high-value seven-membered rings offers a promising avenue for the construction of diversified and drug-like DNA-encoded library.

Intratumoral and peritumoral CT-based radiomics for predicting the microsatellite instability in gastric cancer.

PURPOSE: To investigate the value of intratumoral and peritumoral radiomics based on contrast-enhanced computer tomography (CECT) to preoperatively predict microsatellite instability (MSI) status in gastric cancer (GC) patients. METHODS: A total of 189 GC patients, including 63 patients with MSI-high (MSI-H) and 126 patients with MSI-low/stable (MSI-L/S), were randomly divided into the training cohort and validation cohort. Intratumoral and 5-mm peritumoral regions' radiomics features were extracted from CECT images. The features were standardized by Z-score, and the Inter- and intraclass correlation coefficient, univariate logistic regression analysis, and least absolute shrinkage and selection operator (LASSO) were applied to select the optimal radiomics features. Radiomics scores (Rad-score) based on intratumoral regions, peritumoral regions, and intratumoral + 5-mm peritumoral regions were calculated by weighting the linear combination of the selected features with their respective coefficients to construct the intratumoral model, peritumoral model, and intratumoral + peritumoral model. Logistic regression was used to establish a combined model by combining clinical characteristics, CT semantic features, and Rad-score of intratumoral and peritumoral regions. RESULTS: Eleven radiomics features were selected to establish a radiomics intratumoral + peritumoral model. CT-measured tumor length and tumor location were independent risk factors for MSI status. The established combined model obtained the highest area under the receiver operating characteristic (ROC) curve (AUC) of 0.830 (95% CI, 0.727-0.906) in the validation cohort. The calibration curve and decision curve demonstrated its good model fitness and clinical application value. CONCLUSION: The combined model based on intratumoral and peritumoral CECT radiomics features and clinical factors can predict the MSI status of GS with moderate accuracy before surgery, which helps formulate personalized treatment strategies.

Quantitative detection and prognostic value of antibodies against M-type phospholipase A2 receptor and its cysteine-rich ricin domain and C-type lectin domains 1 and 6-7-8 in patients with idiopathic membranous nephropathy.

BACKGROUND: M-type phospholipase A2 receptor (PLA2R) is the major autoantigen in adult idiopathic membranous nephropathy (IMN). Although reactive epitopes in the PLA2R domains have been identified, the clinical value of these domains recognized by anti-PLA2R antibodies remains controversial. Accordingly, this study aimed to quantitatively detect changes in the concentrations of different antibodies against epitopes of PLA2R in patients with IMN before and after treatment to evaluate the clinical value of epitope spreading. METHODS: Highly sensitive time-resolved fluorescence immunoassay was used to quantitatively analyze the concentrations of specific IgG and IgG4 antibodies against PLA2R and its epitopes (CysR, CTLD1, CTLD6-7-8) in a cohort of 25 patients with PLA2R-associated membranous nephropathy (13 and 12 in the remission and non-remission groups, respectively) before and after treatment, and the results were analyzed in conjunction with clinical biochemical indicators. RESULTS: The concentration of specific IgG (IgG4) antibodies against PLA2R and its epitopes (CysR, CTLD1 and CTLD6-7-8) in non-remission group was higher than that in remission group. The multipliers of elevation of IgG (IgG4) antibody were 5.6(6.2) fold, 3.0(24.3) fold, 1.6(9.0) fold, and 4.2(2.6) fold in the non-remission/remission group, respectively. However, the difference in antibody concentrations between the two groups at the end of follow-up was 5.6 (85.2), 1.7 (13.1), 1.0 (5.1), and 1.5 (22.3) times higher, respectively. When detecting concentrations of specific IgG antibodies against PLA2R and its different epitopes, the remission rate was 66.67% for only one epitope at M0 and 36.36% for three epitopes at M0. When detecting concentrations of specific IgG4 antibodies against PLA2R and its different epitopes, the remission rate was 100.00% for only one epitope at M0 and 50.00% for three epitopes at M0. A trivariate logistic regression model for the combined detection of eGFR, anti-CTLD678 IgG4, and urinary protein had an AUC of 100.00%. CONCLUSION: Low concentrations of anti-CysR-IgG4, anti-CTLD1-IgG4, and anti-CTLD6-7-8-IgG4 at initial diagnosis predict rapid remission after treatment. The use of specific IgG4 against PLA2R and its different epitopes combined with eGFR and urinary protein provides a better assessment of the prognostic outcome of IMN.

The impact of lymphadenectomy on ovarian clear cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) shares treatment strategies with epithelial ovarian cancer (EOC). Due to OCCC's rarity, there's a lack of prospective studies on its surgery, resulting in heterogeneous and limited existing data. This study aims to clarify the prognostic significance of lymphadenectomy in OCCC patients. METHODS: We systematically searched Web of Science, Scopus, PubMed, and Google Scholar until July 2023 for studies investigating lymphadenectomy's effects on OCCC patients. We calculated pooled hazard ratios (HR) with 95% confidence intervals (CI). This study is registered in PROSPERO (CRD42021270460). RESULTS: Among 444 screened articles, seven studies (2883 women) met inclusion criteria. Our analysis revealed that lymphadenectomy significantly improved disease-specific survival (DSS) (HR = 0.76, 95%CI = 0.60-0.95, P = 0.02) and disease-free survival (DFS) (HR = 0.58, 95%CI = 0.34-0.99, P = 0.05). However, it did not significantly affect overall survival (OS) (HR = 0.80, 95%CI = 0.60-1.06, P = 0.12) or progression-free survival (PFS) (HR = 0.95, 95%CI = 0.64-1.42, P = 0.79). Notably, some earlier studies reported no survival benefit, warranting cautious interpretation. CONCLUSION: Lymphadenectomy does not significantly enhance OS and PFS for OCCC but does improve DFS and DSS. Tailoring treatment to individual patient profiles is imperative for optimal outcomes. Precise preoperative or intraoperative lymph node metastasis detection is essential for identifying candidates benefiting from lymphadenectomy. Collaborative international efforts and an OCCC database are pivotal for refining future treatment strategies.

Glia-derived adenosine in the ventral hippocampus drives pain-related anxiodepression in a mouse model resembling trigeminal neuralgia.

Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.

Antiproliferative polycyclic polyprenylated acylphloroglucinols from Garcinia paucinervis.

Bioassay-guided isolation of the stems of Garcinia paucinervis led to one new adamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), (-)-garpauvinin A (1), and four known analogues (2-5). The structure and absolute configuration of 1 was established via spectroscopic techniques and ECD method. All the isolates displayed moderate antiproliferative activity against HL-60, PC-3 and Caco-2 human cancer cell lines with IC50 values ranging from 0.81 to 19.92 µM, and exhibited low toxicity on WPMY-1 normal human cells, showing selectivity between normal and malignant prostate cells. The biosynthetic pathways of the isolated PPAPs were proposed.

Oncogenic KRAS triggers metabolic reprogramming in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely high lethality rate. Oncogenic KRAS activation has been proven to be a key driver of PDAC initiation and progression. There is increasing evidence that PDAC cells undergo extensive metabolic reprogramming to adapt to their extreme energy and biomass demands. Cell-intrinsic factors, such as KRAS mutations, are able to trigger metabolic rewriting. Here, we update recent advances in KRAS-driven metabolic reprogramming and the associated metabolic therapeutic potential in PDAC.

Preoperative Noninvasive Evaluation of Tumor Budding in Rectal Cancer Using Multiparameter MRI Radiomics.

RATIONALE AND OBJECTIVES: To assess the value of a multiparametric magnetic resonance imaging (MRI)-based model integrating radiomics features with clinical and MRI semantic features for preoperative evaluation of tumor budding (TB) in rectal cancer. MATERIALS AND METHODS: A total of 120 patients with pathologically confirmed rectal cancer were retrospectively analyzed. The patients were randomized into training and validation cohorts in a 6:4 ratio. Radiomics features were extracted and selected from preoperative T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1-weighted imaging (T1CE) sequences, after which the corresponding radiomics score (RS) was calculated, and the radiomics models (T2WI model, DWI model, and T1CE model) were constructed. Logistic regression analysis was selected to develop a combined model integrated RST2WI, RSDWI, RST1CE, and clinical and MRI semantic features. The efficacy of each model in diagnosing TB grade was observed by the receiver operating characteristic (ROC) curve. Decision curve analysis (DCA) was used to assess the clinical benefits of the models. RESULTS: Seven features were extracted and selected from each T2WI, DWI, and T1CE sequence to calculate the corresponding RS and construct the corresponding radiomics model. MRI reported N stage was an independent risk factor for TB. The area under the ROC curve of the combined model was 0.961 and 0.891 in the training and validation cohorts, respectively. The combined model showed better performance than the other models. DCA showed that the net benefit of the combined model was better than that of the other models in the vast majority of threshold probabilities. CONCLUSION: A combined model integrating radiomics features and MRI semantic features allows for noninvasive preoperative evaluation of TB grading in patients with rectal cancer.

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

BACKGROUND: Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. AIM: To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. METHODS: Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. RESULTS: The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. CONCLUSION: Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

Inhibition of Galectin-1 attenuates lung fibroblast activation and proliferation in lung fibrosis.

The purpose of this study was to investigate the parenchymal changes in idiopathic pulmonary fibrosis (IPF) caused by massive fibroblastic infiltration and proliferation in lung tissue. Galectin-1 (Gal-1) has been reported to be involved in angiogenesis and fibrosis via modification of TGF-b receptor signaling pathways. However, it remains unknown whether Galectin-1 plays a critical role in IPF. In the current study, we aimed to identify Gal-1 as a crucial fibrotic protein in IPF process. Murine lung fibroblast was pre-treated using Gal-1 inhibitor OTX-008 or overexpression of Gal-1 and then activated using transforming growth factor-beta (TGF-ß). Adult male C57BL/6J mice were conducted intratracheal injection of bleomycin (BLM) for lung fibrosis. Mice were conducted OTX-008 administration. Gal-1 expression, fibroblast activation and proliferation, extracellular matrix (ECM), lung fibrosis, lung histology and pulmonary function were investigated respectively. We demonstrated that Gal-1, as a positive pro-fibrotic marker, could promote lung fibroblast activation and proliferation. Inhibition of Gal-1 reduced fibroblast activation and proliferation through negative regulation of TGF-ß/Erk1/2 and AKT pathway. In vivo, Gal-1 inhibition ameliorates lung fibroblast accumulation and protects lung histology and function. Gal-1 is verified to be a pro-fibrotic gene in IPF pathogenesis, which promotes fibroblast activation and proliferation via TGF-ß/Erk1/2 and AKT pathway. Moreover, inhibition of Gal-1 in lung fibrosis model attenuates lung fibroblast bioactivity and reduces ECM, leading to improved pulmonary histology and function. Hence, knockdown of Gal-1 in IPF may be a promising target therapy.

Knowledge Distillation Meets Label Noise Learning: Ambiguity-Guided Mutual Label Refinery.

Knowledge distillation (KD), which aims at transferring the knowledge from a complex network (a teacher) to a simpler and smaller network (a student), has received considerable attention in recent years. Typically, most existing KD methods work on well-labeled data. Unfortunately, real-world data often inevitably involve noisy labels, thus leading to performance deterioration of these methods. In this article, we study a little-explored but important issue, i.e., KD with noisy labels. To this end, we propose a novel KD method, called ambiguity-guided mutual label refinery KD (AML-KD), to train the student model in the presence of noisy labels. Specifically, based on the pretrained teacher model, a two-stage label refinery framework is innovatively introduced to refine labels gradually. In the first stage, we perform label propagation (LP) with small-loss selection guided by the teacher model, improving the learning capability of the student model. In the second stage, we perform mutual LP between the teacher and student models in a mutual-benefit way. During the label refinery, an ambiguity-aware weight estimation (AWE) module is developed to address the problem of ambiguous samples, avoiding overfitting these samples. One distinct advantage of AML-KD is that it is capable of learning a high-accuracy and low-cost student model with label noise. The experimental results on synthetic and real-world noisy datasets show the effectiveness of our AML-KD against state-of-the-art KD methods and label noise learning (LNL) methods. Code is available at https://github.com/Runqing-forMost/ AML-KD.

Pan-cancer analysis of the prognostic significance and oncogenic role of GXYLT2.

Growing evidence supports an oncogenic role for glucoside xylosyltransferase 2 (GXYLT2) in a number of malignancies. To evaluate the prognostic value and oncogenic function of GXYLT2 in diverse cancer types, we analyzed sequencing data from public databases on 33 tumor tissues and their corresponding normal tissues. We found that GXYLT2 was overexpressed in a number of tumors, and that its expression was positively correlated with disease progression and mortality in several major cancer types including stomach adenocarcinoma (STAD). GXYLT2 was also linked to tumor size, grade, and the immune and molecular subtypes of STAD. GO and KEGG pathway analyses of GXYLT2 co-expressed genes in STAD suggested that GXYLT2 possibly plays a role in epithelial-mesenchymal transition, extracellular matrix production and degradation, angiogenesis, apoptosis, as well as in tumor inflammation, such as cytokine production and T cell activation. Finally, prognostic nomograms were created and validated for predicting 1, 3, and 5-year survival of patients with STAD. Our findings indicate that GXYLT2 may play a role in tumorigenesis and tumor immunity, and it may serve as a prognostic marker and potential immunotherapeutic target for STAD and some other types of cancer.

Effect of neoadjuvant chemotherapy on the immune microenvironment of gynaecological tumours.

Purpose: To assess the impact of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment (TIME) in gynaecological tumors, with a focus on understanding the potential for enhanced combination therapies.Methods: We systematically queried the PubMed, Embase, and Cochrane databases, encompassing reviews, clinical trials, and case studies, to undertake a thorough analysis of the impact of NACT on the TIME of gynaecological tumors.Results: NACT induces diverse immune microenvironment changes in gynaecological tumors. In cervical cancer, NACT boosts immune-promoting cells, enhancing tumor clearance. Ovarian cancer studies yield variable outcomes, influenced by patient-specific factors and treatment regimens. Limited research exists on NACT's impact on endometrial cancer's immune microenvironment, warranting further exploration. In summary, NACT-induced immune microenvironment changes display variability. Clinical trials highlight personalized immunotherapy's positive impact on gynaecological tumor prognosis, suggesting potential avenues for future cancer treatments. However, rigorous investigation is needed to determine the exact efficacy and safety of combining NACT with immunotherapy.Conclusion: This review provides a solid foundation for the development of late-stage immunotherapy and highlights the importance of therapeutic strategies targeting immune cells in TIME in anti-tumor therapy.

The abnormal tumour microenvironment in gynaecological tumours can impede the penetration and accumulation of chemotherapeutic drugs, leading to poorer drug therapy efficacy.Neoadjuvant chemotherapy can improve the surgical resection rate of patients while regulating the ratio of each immune cell subpopulation to achieve the regulation of the tumour microenvironment, thus achieving anti-tumour effects.Based on the immune variability of patients after neoadjuvant chemotherapy, selecting the most suitable individualized immunotherapy will become a promising new therapy.