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Cancer Innovation Aug 2024Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether...
BACKGROUND
Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether a subset of lactate-responsive genes (LRGs) could be used to classify TNBC subtypes and predict patient outcomes.
METHODS
Lactate levels were initially measured in different breast cancer (BC) cell types. Subsequently, MDA-MB-231 cells treated with 2-Deoxy-d-glucose or l-lactate were subjected to RNA sequencing (RNA-seq). The gene set variation analysis algorithm was utilized to calculate the lactate-responsive score, conduct a differential analysis, and establish an association with the extent of immune infiltration. Consensus clustering was then employed to classify TNBC patients. Tumor immune dysfunction and exclusion, cibersort, single-sample gene set enrichment analysis, and EPIC, were used to compare the tumor-infiltrating immune cells between TNBC subtypes and predict the response to immunotherapy. Furthermore, a prognostic model was developed by combining 98 machine learning algorithms, to assess the predictive significance of the LRG signature. The predictive value of immune infiltration and the immunotherapy response was also assessed. Finally, the association between lactate and various anticancer drugs was examined based on expression profile similarity principles.
RESULTS
We found that the lactate levels of TNBC cells were significantly higher than those of other BC cell lines. Through RNA-seq, we identified 14 differentially expressed LRGs in TNBC cells under varying lactate levels. Notably, this LRG signature was associated with interleukin-17 signaling pathway dysregulation, suggesting a link between lactate metabolism and immune impairment. Furthermore, the LRG signature was used to categorize TNBC into two distinct subtypes, whereby Subtype A was characterized by immunosuppression, whereas Subtype B was characterized by immune activation.
CONCLUSION
We identified an LRG signature in TNBC, which could be used to predict the prognosis of patients with TNBC and gauge their response to immunotherapy. Our findings may help guide the precision treatment of patients with TNBC.
PubMed: 38948251
DOI: 10.1002/cai2.124 -
Cancer Innovation Aug 2024Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are...
BACKGROUND
Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to collagen gene expression to indicate their prognosis and treatment response.
METHODS
We collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA-STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform-independent collagen-subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.
RESULTS
We identified two subtypes of gastric adenocarcinoma: a high-expression collagen subtype (CS-H) and a low-expression collagen subtype (CS-L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS-L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3-kinase (PI3K)/Akt pathways were transcriptionally active in the CS-H subtype, while DNA repair activity was significantly greater in the CS-L subtype. was frequently amplified in the CS-H subtype, while , , and were frequently deleted in the CS-L subtype. CS-H subtype tumors were more sensitive to fluorouracil, while CS-L subtype tumors were more sensitive to immune checkpoint blockade. CS-L subtype was predicted to be more sensitive to HER2-targeted drugs, and CS-H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway-targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.
CONCLUSIONS
We classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transcriptome, and genetic alterations. The subtypes were closely related to patient responses to chemotherapy, immunotherapy, and targeted therapy.
PubMed: 38948250
DOI: 10.1002/cai2.125 -
Cancer Innovation Aug 2024Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene...
BACKGROUND
Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.
METHODS
We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.
RESULTS
Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix-receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.
CONCLUSIONS
Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.
PubMed: 38948248
DOI: 10.1002/cai2.128 -
Cancer Innovation Aug 2024The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as...
BACKGROUND
The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons.
METHODS
A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety.
RESULTS
Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22-0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43-0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%.
CONCLUSIONS
Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.
PubMed: 38948247
DOI: 10.1002/cai2.126 -
PeerJ 2024Gastric cancer (GC), one of the highest venous thromboembolism (VTE) incidence rates in cancer, contributes to considerable morbidity, mortality, and, prominently, extra...
OBJECTIVE
Gastric cancer (GC), one of the highest venous thromboembolism (VTE) incidence rates in cancer, contributes to considerable morbidity, mortality, and, prominently, extra cost. However, up to now, there is not a high-quality VTE model to steadily predict the risk for VTE in China. Consequently, setting up a prediction model to predict the VTE risk is imperative.
METHODS
Data from 3,092 patients from December 15, 2017, to December 31, 2022, were retrospectively analyzed. Multiple logistic regression analysis was performed to assess risk factors for GC, and a nomogram was constructed based on screened risk factors. A receiver operating curve (ROC) and calibration plot was created to evaluate the accuracy of the nomogram.
RESULTS
The risk factors of suffering from VTE were older age (OR = 1.02, 95% CI [1.00-1.04]), Karnofsky Performance Status (KPS) ≥ 70 (OR = 0.45, 95% CI [0.25-0.83]), Blood transfusion (OR = 2.37, 95% CI [1.47-3.84]), advanced clinical stage (OR = 3.98, 95% CI [1.59-9.99]), central venous catheterization (CVC) (OR = 4.27, 95% CI [2.03-8.99]), operation (OR = 2.72, 95% CI [1.55-4.77]), fibrinogen degradation product (FDP) >5 µg/mL (OR = 1.92, 95% CI [1.13-3.25]), and D-dimer > 0.5 mg/L (OR = 2.50, 95% CI [1.19-5.28]). The area under the ROC curve (AUC) was 0.82 in the training set and 0.85 in the validation set.
CONCLUSION
Our prediction model can accurately predict the risk of the appearance of VTE in gastric cancer patients and can be used as a robust and efficient tool for evaluating the possibility of VTE.
Topics: Humans; Nomograms; Venous Thromboembolism; Stomach Neoplasms; Retrospective Studies; Male; Female; Middle Aged; Risk Factors; Aged; China; Risk Assessment; ROC Curve; Fibrin Fibrinogen Degradation Products; Adult
PubMed: 38948205
DOI: 10.7717/peerj.17527 -
Journal of Inflammation Research 2024Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell...
PURPOSE
Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The tumour suppressor p53 plays a pivotal role in preventing aGVHD development. However, whether P53 pathway which contains p53 family members and other related genes participates in aGVHD development remains an unsolved question.
PATIENTS AND METHODS
Transcriptomic data was obtained from Gene Expression Omnibus (GEO) database. Gene set enrichment analysis was applied to determine the enrichment degree of signaling pathways. CIBERSORT and ssGSVA were used to evaluate immune cell compositions. Univariate and multivariate logistic regression analysis were performed to examine the independent diagnostic variables. qRT-PCR was utilized to validate the genes expression levels in our cohort.
RESULTS
A total number of 102 patients (42 aGVHD patients vs 60 non-aGVHD patients) were obtained after integrating two datasets in GEO database (GSE73809 and GSE4624). P53 pathway was remarkably suppressed in T cells from aGVHD patients and negatively associated with activated T cells as well as T cells activation related signaling pathways, including T-cell receptor (TCR), mTORC1, MYC and E2F target pathways. A risk model for aGVHD built by four genes (DDIT3, FBXW7, TPRKB and TOB1) in P53 pathway, exhibiting high differentiate and predictive value. DDIT3 and FBXW7 mRNA expression levels significantly decreased in peripheral blood mononuclear cells (PBMCs) from aGVHD patients compared with non-aGVHD group in our patient cohort, consisting with bioinformatics analysis.
CONCLUSION
P53 pathway plays a potential role in impeding T cell activation through suppressing its related signaling pathways, thereby preventing aGVHD development. P53 pathway may emerge as a promising therapeutic target in aGVHD treatment.
PubMed: 38948198
DOI: 10.2147/JIR.S458860 -
Imaging Science in Dentistry Jun 2024Patients with head and neck cancer (HNC) who undergo dental procedures during radiotherapy (RT) face an increased risk of developing osteoradionecrosis (ORN)....
PURPOSE
Patients with head and neck cancer (HNC) who undergo dental procedures during radiotherapy (RT) face an increased risk of developing osteoradionecrosis (ORN). Accordingly, new tools must be developed to extract critical information regarding the dose delivered to the teeth and mandible. This article proposes a novel approach for visualizing 3-dimensional planned dose distributions on panoramic reconstruction computed tomography (pCT) images.
MATERIALS AND METHODS
Four patients with HNC who underwent volumetric modulated arc therapy were included. One patient experienced ORN and required the extraction of teeth after RT. In the study approach, the dental arch curve (DAC) was defined using an open-source platform. Subsequently, pCT images and dose distributions were generated based on the new coordinate system. All teeth and mandibles were delineated on both the original CT and pCT images. To evaluate the consistency of dose metrics, the Mann-Whitney test and Student -test were employed.
RESULTS
A total of 61 teeth and 4 mandibles were evaluated. The correlation coefficient between the 2 methods was 0.999, and no statistically significant difference was observed (>0.05). This method facilitated a straightforward and intuitive understanding of the delivered dose. In 1 patient, ORN corresponded to the region of the root and the gum receiving a high dosage (approximately 70 Gy).
CONCLUSION
The proposed method particularly benefits dentists involved in the management of patients with HNC. It enables the visualization of a 3-dimensional dose distribution in the teeth and mandible on pCT, enhancing the understanding of the dose delivered during RT.
PubMed: 38948189
DOI: 10.5624/isd.20230230 -
Npj Imaging 2024Patient-derived tumor organoids have emerged as a crucial tool for assessing the efficacy of chemotherapy and conducting preclinical drug screenings. However, the...
Patient-derived tumor organoids have emerged as a crucial tool for assessing the efficacy of chemotherapy and conducting preclinical drug screenings. However, the conventional histological investigation of these organoids necessitates their devitalization through fixation and slicing, limiting their utility to a single-time analysis. Here, we use stimulated Raman histology (SRH) to demonstrate non-destructive, label-free virtual staining of 3D organoids, while preserving their viability and growth. This novel approach provides contrast similar to conventional staining methods, allowing for the continuous monitoring of organoids over time. Our results demonstrate that SRH transforms organoids from one-time use products into repeatable models, facilitating the efficient selection of effective drug combinations. This advancement holds promise for personalized cancer treatment, allowing for the dynamic assessment and optimization of chemotherapy treatments in patient-specific contexts.
PubMed: 38948153
DOI: 10.1038/s44303-024-00019-1 -
Endoscopic Ultrasound 2023Intraductal papillary neoplasm of the bile ducts is a rare tumor. Characteristic features include bile duct dilatation, cystic lesions with communication to the bile... (Review)
Review
Intraductal papillary neoplasm of the bile ducts is a rare tumor. Characteristic features include bile duct dilatation, cystic lesions with communication to the bile ducts, and intraluminal solid nodules arising from the bile duct wall. As in pancreatic intraductal papillary mucinous neoplasia, intestinal, pancreaticobiliary, gastric, and oncocytic types are described. Intraductal papillary neoplasm of the bile ducts has a high potential for malignancy, and patients should be surgically resected when possible. In this review, the complex imaging diagnosis is presented. The main focus is on contrast-enhanced ultrasound, an established method for many other indications whose potential on the biliary system should be better exploited. In the present article, typical contrast-enhanced ultrasound findings in intraductal papillary neoplasm of the bile ducts are demonstrated.
PubMed: 38948129
DOI: 10.1097/eus.0000000000000040 -
MedComm Jul 2024The etiology of gastrointestinal (GI) diseases is intricate and multifactorial, encompassing complex interactions between genetic predisposition and gut microbiota. The... (Review)
Review
The etiology of gastrointestinal (GI) diseases is intricate and multifactorial, encompassing complex interactions between genetic predisposition and gut microbiota. The cell fate change, immune function regulation, and microenvironment composition in diseased tissues are governed by microorganisms and mutated genes either independently or through synergistic interactions. A comprehensive understanding of GI disease etiology is imperative for developing precise prevention and treatment strategies. However, the existing models used for studying the microenvironment in GI diseases-whether cancer cell lines or mouse models-exhibit significant limitations, which leads to the prosperity of organoids models. This review first describes the development history of organoids models, followed by a detailed demonstration of organoids application from bench to clinic. As for bench utilization, we present a layer-by-layer elucidation of organoid simulation on host-microbial interactions, as well as the application in molecular mechanism analysis. As for clinical adhibition, we provide a generalized interpretation of organoid application in GI disease simulation from inflammatory disorders to malignancy diseases, as well as in GI disease treatment including drug screening, immunotherapy, and microbial-targeting and screening treatment. This review draws a comprehensive and systematical depiction of organoids models, providing a novel insight into the utilization of organoids models from bench to clinic.
PubMed: 38948115
DOI: 10.1002/mco2.574