The complex interplay of tumor-infiltrating cells in driving therapeutic resistance pathways.

Drug resistance remains a significant challenge in cancer treatment. Recently, the interactions among various cell types within the tumor microenvironment (TME) have deepened our understanding of the mechanisms behind treatment resistance. Therefore, this review aims to synthesize current research focusing on infiltrating cells and drug resistance suggesting that targeting the TME could be a viable strategy to combat this issue. Numerous factors, including inflammation, metabolism, senescence, hypoxia, and angiogenesis, contribute to drug resistance could be a viable strategy to combat this issue. Overexpression of STAT3 is commonly associated with drug-resistant cancer cells or stromal cells. Current research often generalizes the impact of stromal cells on resistance, lacking specificity and statistical robustness. Thus, future research should take notice of this issue and aim to provide high-quality evidence. Despite the existing limitations, targeting the TME to overcome therapy resistance hold promising and valuable potential.

Robotic versus laparoscopic liver resection for posterosuperior segments: a systematic review and meta-analysis.

BACKGROUND: Minimally invasive hepatectomy for difficult lesions located in posterosuperior segments (segments I, IVa, VII and VIII) remains challenging. The value of robotic liver resection (RLR) compared with laparoscopic liver resection (LLR) for posterosuperior segments is controversial. Therefore, we performed this meta-analysis to validate the safety and efficacy of RLR in posterosuperior segments. METHODS: The Medline, Embase, Web of Science, and Cochrane Library electronic databases were searched to identify available research published up to October 2023. Statistical analysis was performed with RevMan software version 5.3. RESULTS: Six studies with a total of 2289 patients (RLR: n = 749; LLR: n = 1540) were included in this meta-analysis. The RLR group had less intraoperative blood loss (WMD = -119.54 ml, 95% CI: -178.89 to -60.19, P < 0.0001), fewer blood transfusions (OR = 0.56, 95% CI: 0.39 to 0.80, P = 0.001), a lower conversion rate (OR = 0.37, 95% CI: 0.23 to 0.61, P < 0.0001), and a shorter operative time (WMD = -27.16 min, 95% CI: -35.95 to -18.36, P < 0.00001). DISCUSSION: Compared with LLR, RLR for lesions in the posterosuperior segments could be safe and effective, and it has superior surgical outcomes.

Relationship between clonal evolution and drug resistance in bladder cancer: A genomic research review.

Bladder cancer stands as a prevalent global malignancy, exhibiting notable sex-based variations in both incidence and prognosis. Despite substantial strides in therapeutic approaches, the formidable challenge of drug resistance persists. The genomic landscape of bladder cancer, characterized by intricate clonal heterogeneity, emerges as a pivotal determinant in fostering this resistance. Clonal evolution, encapsulating the dynamic transformations within subpopulations of tumor cells over time, is implicated in the emergence of drug-resistant traits. Within this review, we illuminate contemporary insights into the role of clonal evolution in bladder cancer, elucidating its influence as a driver in tumor initiation, disease progression, and the formidable obstacle of therapy resistance.

Unraveling links between aging, circadian rhythm and cancer: Insights from evidence-based analysis.

Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

Changes in Polyphenols and Antioxidant Activity in Fermentation Substrate during Maotai-Flavored Liquor Processing.

To investigate the changes in phenols and antioxidant capacity in fermented grains during different stages of the fermentation process (Xiasha, Zaosha, and single-round stages) of Maotai-flavored liquor, the total phenolic contents of 61 samples, collected in different stages, were analyzed via the Folin-Ciocalteu method, and the phenolic compounds were then identified by high-performance liquid chromatography (HPLC). Subsequently, the antioxidant activities were determined using the DPPH free radical scavenging rate and ABTS and FRAP antioxidant capacities. The correlations among the total phenolic contents, individual phenolics, and three antioxidant activities of the samples were analyzed. The results show that the total phenolic contents of the fermented samples did not change significantly in the Xiasha and Zaosha stages but showed an upward trend in the single-round stage. A total of 12 phenol acids were identified in the fermented grains, including 5 phenolic acids (e.g., ferulic acid and caffeic acid), 4 flavonoids (e.g., luteolin and apigenin), and 3 proanthocyanidins (e.g., apigeninidin), for which the DPPH free radical scavenging rates and ABTS and FRAP antioxidant capacities of all of the fermented grain samples ranged from 78.91 ± 4.09 to 98.57 ± 1.52%, 3.23 ± 0.72 to 13.69 ± 1.40 mM Trolox, and 5.06 ± 0.36 to 14.10 ± 0.69 mM FeSO4, respectively. The total phenolic contents of the fermented grain samples were significantly and positively correlated with the ABTS and FRAP (p ≤ 0.05), while no significant correlations were found between total phenolic content and DPPH. In general, the total phenolic content, phenolic substances, and antioxidant capacity of the fermented grains exhibited changes during the fermentation process in liquor production, and the phenolic components contributed more to the antioxidant properties of the fermented grains. The present study provides a theoretical reference for analyzing the dynamic changes and antioxidant properties of functional phenolic components in fermented grains.

Caudo-dorsal approach combined with the occlusion of right hepatic vein and Pringle maneuver in laparoscopic anatomical resection of segment 7.

BACKGROUND: Laparoscopic anatomical resection of segment 7 (LARS7) remains a technically challenging procedure due to the deep anatomical location and the potential risk of injury to the right hepatic vein (RHV). Herein, we initiated an innovative technique of caudo-dorsal approach combined with the occlusion of the RHV and Pringle maneuver for LARS7 and presented the outcomes of our initial series. METHOD: Since January 2021, the patients who underwent LARS7 by using this novel technique were enrolled in this study. The critical aspect of this technique was the interruption of communication between the RHV and the inferior vena cava. Meanwhile, the Pringle maneuver was adopted to control the hepatic inflow. RESULT: A total of 11 patients underwent LARS7 by using this novel technique, which included 8 hepatocellular carcinoma, 2 bile duct adenocarcinoma and one focal nodular hyperplasia. The median operative time was 199 min (range of 151-318 min) and the median blood loss was 150 ml (range of 50-200 ml). The main trunk of the RHV was fully exposed on the cutting surface in all cases and no patient received perioperative blood transfusion. No procedure was converted to open surgery. Of note, no indications of CO2 gas embolism were observed in these cases after the introduction of double occlusion. Only one patient suffered from postoperative complications and healed after treatment. The median postoperative stay was 5 days (range of 4-7 days). The 90-day mortality was nil. At a median follow-up period of 19 months, all of the patients were alive without any evidence of tumor recurrence. CONCLUSION: The caudo-dorsal approach combined with the occlusion of RHV and the Pringle maneuver may be a feasible and expected technique for safe exposure of RHV in LARS7. Further validation of the feasibility and efficacy of this technique is needed.

Chronobiology of the Tumor Microenvironment: Implications for Therapeutic Strategies and Circadian-Based Interventions.

Numerous research works have emphasized the critical role that circadian rhythm plays in the tumor microenvironment (TME). The goal of clarifying chrono-pharmacological strategies for improving cancer treatment in clinical settings is a continuous endeavor. Consequently, to enhance the use of time-based pharmaceutical therapies in oncology, combining existing knowledge on circadian rhythms' roles within the TME is essential. This perspective elucidates the functions of circadian rhythms in the TME across various stages of cancer development, progression, and metastasis. Specifically, aging, angiogenesis, and inflammation are implicated in modulating circadian rhythm within the TME. Furthermore, circadian rhythm exerts a profound influence on current cancer treatments and thereby generates chronotheray to manage tumors. From a TME perspective, circadian rhythm offers promising opportunities for cancer prevention and treatment; nevertheless, further study is needed to address unanswered scientific problems.

Establishment of novel ferroptosis-related prognostic subtypes correlating with immune dysfunction in prostate cancer patients.

Background: We aimed to identify two new prognostic subtypes and create a predictive index for prostate cancer (PCa) patients based on ferroptosis database. Methods: The nonnegative matrix factorization approach was used to identify molecular subtypes. We investigate the differences between cluster 1 and cluster 2 in terms of clinical features, functional pathways, tumour stemness, tumour heterogeneity, gene mutation and tumour immune microenvironment score after identifying the two molecular subtypes. Colony formation assay and flow cytometry assay were performed. Results: The stratification of two clusters was closely connected to BCR-free survival using the nonnegative matrix factorization method, which was validated in the other three datasets. Furthermore, multivariate Cox regression analysis revealed that this classification was an independent risk factor for patients with PCa. Ribosome, aminoacyl tRNA production, oxidative phosphorylation, and Parkinson's disease-related pathways were shown to be highly enriched in cluster 1. In comparison to cluster 2, patients in cluster 1 exhibited significantly reduced CD4+ T cells, CD8+ T cells, neutrophils, dendritic cells and tumor immune microenvironment scores. Only HHLA2 was more abundant in cluster 1. Moreover, we found that P4HB downregulation could significantly inhibit the colony formation ability and contributed to cell apoptosis of C4-2B and DU145 cell lines. Conclusions: We discovered two new prognostic subtypes associated with immunological dysfunction in PCa patients based on ferroptosis-related genes and found that P4HB downregulation could significantly inhibit the colony formation ability and contributed to cell apoptosis of PCa cell lines.

Moutai Distiller's grains Polyphenol extracts and rutin alleviate DSS-induced colitis in mice: Modulation of gut microbiota and intestinal barrier function （R2）.

Distiller's grains, byproducts of the brewing process, represent a valuable resource for extracting natural phenolic compounds due to their significant global production. This study presents the first evidence of the protective effects of Moutai distiller's grain polyphenol extract (MDGP) on dextran sulfate sodium (DSS)-induced colitis in mice. These protective effects manifest predominantly through the amelioration of general colitis indices and histopathological improvements. Utilizing liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS), the main components of MDGP were identified as rutin, quercetin, naringenin, and dihydroquercetin. Moreover, a novel mechanism was elucidated by which rutin, the primary active component of MDGP, alleviates DSS-induced colitis. Assessment of intestinal barrier function, microbial sequencing, fecal transplantation, and antibiotic depletion experiments revealed that rutin suppresses the abundance of pathogenic bacteria (Helicobacter, Klebsiella, and Veillonella) while promoting the proliferation of beneficial bacteria (Ruminococcus_torques_group, Lachnoclostridium, and norank_f__Muribaculaceae). This modulation culminates in elevated butyric acid concentrations within short-chain fatty acids (SCFAs), amplified integrity of tight (ZO-1, occludin) and adherent (E-cadherin, ß-catenin) junctional complexes, fortified intestinal barrier function, and diminished intestinal inflammation.This investigation accentuates the innovative therapeutic potential of MDGP and its main active component, rutin, in assuaging DSS-induced intestinal inflammation and fortifying the intestinal barrier through a mechanism predominantly mediated by the intestinal microbiota. Such insights potentially elevate the prominence of distiller's grains in the realm of functional food development.

Effects of Fermentation on Bioactivity and the Composition of Polyphenols Contained in Polyphenol-Rich Foods: A Review.

Polyphenols, as common components with various functional activities in plants, have become a research hotspot. However, researchers have found that the bioavailability and bioactivity of plant polyphenols is generally low because they are usually in the form of tannins, anthocyanins and glycosides. Polyphenol-rich fermented foods (PFFs) are reported to have better bioavailability and bioactivity than polyphenol-rich foods, because polyphenols are used as substrates during food fermentation and are hydrolyzed into smaller phenolic compounds (such as quercetin, kaempferol, gallic acid, ellagic acid, etc.) with higher bioactivity and bioavailability by polyphenol-associated enzymes (PAEs, e.g., tannases, esterases, phenolic acid decarboxylases and glycosidases). Biotransformation pathways of different polyphenols by PAEs secreted by different microorganisms are different. Meanwhile, polyphenols could also promote the growth of beneficial bacteria during the fermentation process while inhibiting the growth of pathogenic bacteria. Therefore, during the fermentation of PFFs, there must be an interactive relationship between polyphenols and microorganisms. The present study is an integration and analysis of the interaction mechanism between PFFs and microorganisms and is systematically elaborated. The present study will provide some new insights to explore the bioavailability and bioactivity of polyphenol-rich foods and greater exploitation of the availability of functional components (such as polyphenols) in plant-derived foods.

Glycan Node Analysis Detects Varying Glycosaminoglycan Levels in Melanoma-Derived Extracellular Vesicles.

Extracellular vesicles (EVs) play important roles in (patho)physiological processes by mediating cell communication. Although EVs contain glycans and glycosaminoglycans (GAGs), these biomolecules have been overlooked due to technical challenges in comprehensive glycome analysis coupled with EV isolation. Conventional mass spectrometry (MS)-based methods are restricted to the assessment of N-linked glycans. Therefore, methods to comprehensively analyze all glyco-polymer classes on EVs are urgently needed. In this study, tangential flow filtration-based EV isolation was coupled with glycan node analysis (GNA) as an innovative and robust approach to characterize most major glyco-polymer features of EVs. GNA is a molecularly bottom-up gas chromatography-MS technique that provides unique information that is unobtainable with conventional methods. The results indicate that GNA can identify EV-associated glyco-polymers that would remain undetected with conventional MS methods. Specifically, predictions based on GNA identified a GAG (hyaluronan) with varying abundance on EVs from two different melanoma cell lines. Enzyme-linked immunosorbent assays and enzymatic stripping protocols confirmed the differential abundance of EV-associated hyaluronan. These results lay the framework to explore GNA as a tool to assess major glycan classes on EVs, unveiling the EV glycocode and its biological functions.

Clock gene NR1D1 might be a novel target for the treatment of bladder cancer.

PURPOSE: To explore the role of circadian clock gene NR1D1 (REV-erbα) in bladder cancer (BC). METHODS: Firstly, the association of NR1D1 level with clinical characteristics and prognosis was investigated among patients diagnosed with BC. Secondly, CCK-8, transwell, and colony formation experiments were performed among BC cells treated with Rev-erbα agonist (SR9009), as well as lentivirus and siRNA, for which NR1D1 were overexpressed (OE) and knocked down (KD), respectively. Thirdly, cell cycle and apoptosis were tested by flowcytometry. PI3K/AKT/mTOR pathway proteins were determined in OE-NR1D1 cells. Finally, OE-NR1D1 and OE-Control BC cells were subcutaneously implanted in BALB/c nude mice. The tumor size and protein levels were compared between groups. A P < 0.05 was considered as statistically significant. RESULTS: Patients with NR1D1 positive status had a longer disease-free survival than those with negative expression. The cell viability, migration, and colony formation of BC cells after treated with SR9009 were significantly suppressed. OE-NR1D1 cells had obviously inhibited cell viability, migration, and colony formation, while those were found strengthened in KD-NR1D1 cells. Besides, KD-NR1D1 cells were observed with a lower proportion of dead cells and G0/G1 cells, but a higher ratio of G2/M. The changes of p-AKT, p-S6, p-4EBP1, and FASN involved in PI3K/AKT/mTOR pathway were detected in OE- and KD-NR1D1 BC cells. Finally, in vivo data demonstrated that overexpression of NR1D1 suppressed the tumorigenicity of BC cells. CONCLUSION: NR1D1 played a role of tumor suppressor and it might become a novel target for the treatment of BC.

Hemihepatic versus total hepatic inflow occlusion for laparoscopic hepatectomy: A randomized controlled trial.

BACKGROUND: An appropriate bleeding control technique for laparoscopic liver resection (LLR) is needed to decrease intraoperative blood loss and avoid large hemorrhages. To date, hemihepatic inflow occlusion (HIO) versus total hepatic inflow occlusion (TIO) for LLR is still controversial. Thus, we performed this randomized controlled trial (ChiCTR-IOR-17013866) to compare the perioperative outcomes between HIO and TIO for LLR. METHODS: From December 2017 to August 2019, patients met the criteria via surgical exploration in the operation room and were randomly assigned to both groups. Perioperative data between both groups were recorded and compared, and subgroup analysis was further performed. RESULTS: 258 patients were allocated to the TIO (n = 129) and HIO (n = 129) groups, respectively. There was no significant difference between the two groups in terms of intraoperative blood loss, operative time, postoperative complications, changes in postoperative liver function or early mortality. However, for patients whose transection plane was located on the liver Cantlie's plane, subgroup analysis results indicated that TIO had a shorter operative time (median, 220 vs. 240 min, P = 0.030) and occlusion time (median, 45 vs. 60 min, P = 0.011) and less intraoperative blood loss (median, 200 vs. 300 ml, P = 0.002) than HIO, whereas the morbidity and mortality of the two groups were comparable. CONCLUSION: Both the TIO and HIO approaches could be safely performed for LLR in selected patients when performed by experienced surgeons. The TIO technique for LLR had the advantage of being easier to master than the HIO approach. Additionally, when the transection plane was located on the liver Cantlie's plane, TIO seems to have some superior perioperative outcomes.

Laparoscopic liver resection with "ultrasonic scalpel mimic CUSA" technique.

BACKGROUND: Liver parenchymal transection is the most critical step for laparoscopic liver resection (LLR). Ultrasonic scalpel (Harmonic) is a common used energy instrument in LLR; however, it is only recommended for superficial layer transection and the Cavitron Ultrasonic Surgical Aspirator (CUSA) is recommended for deep layer dissection. We herein introduce the "Harmonic mimic CUSA" technique for LLR. METHODS: We retrospectively reviewed the medical records of the patients who underwent LLR using CUSA or the "Harmonic mimic CUSA" for parenchymal transection between July 2018 and October 2020 at West China Hospital of Sichuan University. Observation indicators included general demographic information, operative time, intraoperative blood loss, blood transfusion volume, complication rate, hospital stay, and the costs. Perioperative data was compared between the two groups by propensity score matching analysis (PSM). RESULTS: A total of 298 patients, including 192 in Harmonic group and 106 in CUSA group, were enrolled in this study. After a 1:1 PSM, 99 patients using "Harmonic mimic CUSA" were matched with 99 patients via CUSA for parenchymal transection in LLRs. The Harmonic group had significantly less intraoperative blood loss (mean, 150 ml vs. 250 ml, P < 0.001), shorter operative time (mean 170 min vs. 250 min, P < 0.001) and less costs (mean 6723$ vs. 8307$, P < 0.001). The conversion to laparotomy, length of postoperative hospital stay, complications were comparable between the two groups. There perioperative mortality was nil. CONCLUSION: The "Harmonic mimic CUSA" technique is safe, simple and feasible for LLR, which may be an alternative to CUSA for LLR.

Prognostic value of preoperative neutrophil-to-lymphocyte ratio in histological variants of non-muscle-invasive bladder cancer.

PURPOSE: Many studies identified that the preoperative neutrophil-to-lymphocyte ratio (PNLR) was associated with patient prognosis in non-muscle-invasive bladder cancer (NMIBC). We hypothesized that PNLR could be prognostic in patients with histological variants of NMIBC (VH-NMIBC). MATERIALS AND METHODS: This retrospective study included patients with VH-NMIBC admitted at our center between January 2009 and May 2019. The best cut-off value of NLR was measured by the receiver operating characteristic curve and Youden index. The Kaplan-Meier method and Cox proportional hazard regression models were employed to evaluate the association between PNLR and disease prognosis, including recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: A total of 243 patients with VH-NMIBC were enrolled in our study. According to the Kaplan-Meier method results, patients with PNLR ≥2.2 were associated with poor RFS (p<0.001), PFS (p<0.001), CSS (p<0.001), and OS (p<0.001). Multivariable analyses indicated that PNLR ≥ 2.2 was an independent prognostic factor of RFS (hazard ratio [HR], 2.11; 95% confidence interval [CI, 1.57-1.83; p<0.001), PFS (HR, 2.34; 95% CI, 1.70-3.21; p<0.001), CCS (HR, 2.87; 95% CI, 1.96-4.18; p< 0.001), and OS (HR, 2.83; 95% CI, 1.96-4.07; p<0.001). CONCLUSIONS: This study identified that PNLR ≥2.2 was usually associated with a poor prognosis for patients with VH-NMIBC.

A hypoxia related long non-coding RNA signature could accurately predict survival outcomes in patients with bladder cancer.

Hypoxia plays a significant role in tumor progression. This study aimed to develop a hypoxia-related long noncoding RNA (lncRNA) signature for predicting survival outcomes of patients with bladder cancer (BC). The transcriptome and clinicopathologic data were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis and Lasso regression analysis were used to screened lncRNAs. Ten lncRNAs were screened out and included into the hypoxia lncRNA signature. The risk score based on hypoxia lncRNA signature could accurately predict the survival outcomes of BC patients. Immune infiltration analysis showed that six types of immune cells had significant different infiltration. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, FGFR3, and RB1 were significantly different. Gene Set Enrichment Analysis (GSEA) showed that cancer-associated pathways belonged to the high risk groups and immune-related signal pathways were enriched into the low risk group. Then, we constructed a predictive model with the risk score, age, and clinical stage, which showed a robust prognostic performance. An lncRNA-mRNA coexpression network was constructed, which contained 62 lncRNA-mRNA links among 10 lncRNAs and 40 related mRNAs. In summary, the hypoxia lncRNA signature could accurately predict prognosis, chemotherapy and immunotherapy response in patients with BC and was relevant to clinicopathologic parameters and immune cell infiltration.

Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer.

OBJECTIVES: This study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer. METHODS: We downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer. RESULTS: Eight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets. CONCLUSION: We successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients' prognosis.