LIM domain only 7 negatively controls nonalcoholic steatohepatitis in the setting of hyperlipidemia.

BACKGROUND AND AIMS: Hyperlipidemia has been extensively recognized as a high-risk factor for NASH; however, clinical susceptibility to NASH is highly heterogeneous. The key controller(s) of NASH susceptibility in patients with hyperlipidemia has not yet been elucidated. Here, we aimed to reveal the key regulators of NASH in patients with hyperlipidemia and to explore its role and underlying mechanisms. APPROACH AND RESULTS: To identify the predominant suppressors of NASH in the setting of hyperlipidemia, we collected liver biopsy samples from patients with hyperlipidemia, with or without NASH, and performed RNA-sequencing analysis. Notably, decreased Lineage specific Interacting Motif domain only 7 (LMO7) expression robustly correlated with the occurrence and severity of NASH. Although overexpression of LMO7 effectively blocked hepatic lipid accumulation and inflammation, LMO7 deficiency in hepatocytes greatly exacerbated diet-induced NASH progression. Mechanistically, lysine 48 (K48)-linked ubiquitin-mediated proteasomal degradation of tripartite motif-containing 47 (TRIM47) and subsequent inactivation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) cascade are required for the protective function of LMO7 in NASH. CONCLUSIONS: These findings provide proof-of-concept evidence supporting LMO7 as a robust suppressor of NASH in the context of hyperlipidemia, indicating that targeting the LMO7-TRIM47 axis is a promising therapeutic strategy for NASH.

Cavin1 activates the Wnt/ß-catenin pathway to influence the proliferation and migration of hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Cavin1 is a cell membrane caveolin, with controversial function in different tumors. Meanwhile, the role of Cavin1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, we attempted to elucidate the significance of Cavin1 in HCC occurrence and progression. MATERIALS AND METHODS: Cavin1 content was examined in HCC tissues and paired adjacent normal liver tissues by qRT-PCR and IHC among 81 HCC patients. The Cavin1-mediated regulation of HCC proliferation and metastasis was assessed through in vitro and in vivo experiments. Finally, using GSEA, we found out Cavin1 could be a potential regulator of the Wnt pathway. The alterations of the Wnt pathway-related proteins were identified by Western Blot analysis. RESULTS: Cavin1 was lower expressed in HCC, which implied poor survival outcomes in HCC patients. Phenotypic experiments revealed that Cavin1 strongly suppressed HCC proliferation and migration in vitro and in vivo. Besides, altered epithelial-mesenchymal transition (EMT)-related protein expressions were detected. Based on our GSEA analysis, Cavin1 activated the Wnt pathway, and Western Blot analysis revealed diminished ß-catenin, c-Myc, and MMP9 contents upon Cavin1 overexpression. CONCLUSIONS: Cavin1 suppresses HCC progression by modulating HCC proliferation and migration via inhibiting the Wnt/ß-catenin axis activation.

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer.

Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.

Short- and Long-Term Outcomes of Indocyanine Green Fluorescence Navigation- Versus Conventional-Laparoscopic Hepatectomy for Hepatocellular Carcinoma: A Propensity Score-Matched, Retrospective, Cohort Study.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging technology is increasingly widely used in laparoscopic hepatectomy. However, whether it can provide long-term survival benefits to patients with liver malignancies remains unclear. This study investigated the clinical effect of laparoscopic hepatectomy for hepatocellular carcinoma (HCC) using ICG imaging technology. METHODS: We retrospectively analyzed HCC patients who underwent laparoscopic hepatectomy at Zhongnan Hospital of Wuhan University from January 2016 to December 2020. Propensity score matching (PSM) was used to match patients undergoing ICG fluorescence navigation laparoscopic hepatectomy (ICG-FNLH) with those undergoing conventional laparoscopic hepatectomy (CLH) in a 1:1 ratio to minimize the influence of confounding factors. We compared perioperative status and long-term prognosis between the two groups and performed multivariate analysis to identify risk factors associated with overall survival and recurrence-free survival. RESULTS: The original cohort consisted of 141 patients, with 50 patients in each group (100 patients in total) after PSM. The anatomical liver resection rate, R0 resection rate, and resection margin distance in the ICG-FNLH group were higher than those in the CLH group. The intraoperative blood loss was lower than that in the CLH group. The recurrence-free survival and overall survival of the ICG-FNLH group were better than those of the CLH group. ICG-FNLH improved the recurrence-free survival of HCC patients (hazard ratio [HR] = 2.165, 95% confidence interval [CI]: 1.136-4.127, P = 0.024). CONCLUSIONS: Compared with CLH, ICG-FNLH can improve the recurrence-free survival rate of patients with hepatocellular carcinoma and may help to improve the long-term prognosis of patients.

PRAME expression in cutaneous melanoma does not correlate with disease-specific survival.

BACKGROUND: Immunohistochemistry-based protein biomarkers can provide useful prognostic information in cutaneous melanoma. The independent prognostic value of Ki-67 has been studied with variable results. PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is a useful new ancillary tool for distinguishing cutaneous nevi from melanoma; however, its prognostic value has not been well studied. We evaluated PRAME as a prognostic marker in cutaneous melanoma, compared to Ki-67. METHODS: We analyzed the immunohistochemical expression of PRAME and Ki-67 in 165 melanocytic lesions, including 92 primary melanomas, 19 metastatic melanomas, and 54 melanocytic nevi using tissue microarrays. PRAME immunostaining was scored based on the percentage of positive nuclei: 0 <1%, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+ >75%. The percentage of Ki-67-positive tumor nuclei was used to calculate the proliferation index. RESULTS: PRAME and Ki-67 both showed significantly increased expression in melanomas compared to nevi (p < 0.0001 and p < 0.001, respectively). There was no significant difference in PRAME expression in primary versus metastatic melanomas. By contrast, the Ki-67 proliferation index was higher in metastatic melanoma than in primary melanoma (p = 0.013). Increased Ki-67 index correlated with ulceration (p < 0.001), increased Breslow depth (p = 0.001), and higher mitotic rate (p < 0.0001), whereas increased PRAME expression correlated with higher mitotic rate (p = 0.047) and Ki-67 index (p = 0.007). Increased Ki-67 index correlated with worse disease-specific survival in patients with primary melanoma (p < 0.001), but PRAME expression did not show prognostic significance in disease-specific survival (p = 0.63). In a multivariable analysis of patients with primary melanoma, tumor Breslow depth, ulceration, mitotic rate, and Ki-67 index were each independent predictors of disease-specific survival (p = 0.006, 0.02, 0.001, and 0.04, respectively); however, PRAME expression was not predictive of disease-specific survival (p = 0.64). CONCLUSION: Ki-67 is an independent prognostic marker; although increased PRAME expression correlates with the Ki-67 proliferation index and mitotic rate, PRAME is not an independent prognostic marker for cutaneous melanoma. PRAME and Ki-67 are useful ancillary tools for distinguishing benign from malignant melanocytic lesions.

Comparative effectiveness of hybrid and laparoscopic techniques for repairing complex incisional ventral hernias: a systematic review and meta-analysis.

BACKGROUND: The recently developed Hybrid Hernia Repair technique (HHR), an adaptation of the laparoscopic method, has been proposed as a potential alternative for the treatment of complex Incisional Ventral Hernias (IVH). While single-arm studies have reported promising outcomes, a comprehensive meta-analysis affirming these benefits is lacking. This meta-analysis aims to compare the clinical outcomes of HHR and Laparoscopic Hernia Repair (LHR) in the management of IVH. METHODS: An exhaustive search of the literature was conducted, targeting publications in both English and Chinese that compare HHR and LHR up to March 31, 2023. The primary outcomes examined were operation time, blood loss, and intestinal injury. Secondary outcomes included rates of seroma, wound infection, post-operative acute/chronic pain, recurrence, and mesh bulging. The RevMan 5.0 software facilitated the statistical meta-analysis. RESULTS: The final analysis incorporated data from 14 studies, encompassing a total of 1158 patients, with 555 undergoing HHR and 603 treated with LHR. Follow-up data, ranging from 12 to 88 months, were available in 12 out of the 14 identified studies. The HHR method was associated with a significantly lower risk of seroma (OR = 0.29, P = 0.0004), but a higher risk of wound infection (OR = 2.10, P = 0.04). No significant differences were observed between the two techniques regarding operation time, blood loss, intestinal injury, intestinal obstruction, post-operative pain, mesh bulging, and recurrence. CONCLUSIONS: The HHR technique did not demonstrate a clear advantage over LHR in reducing surgical complications, apart from a lower incidence of postoperative seroma. Surgeons with substantial expertise may choose to avoid incidental conversion or intentional hybrid procedures. Further research is needed to clarify the optimal surgical approach for IVH.

Prognostic value of CSN5 in patients with digestive system cancers: a systematic review and meta-analysis.

BACKGROUND: Despite the understanding of the COP9 signalosome subunit 5 (CSN5) in tumor genesis, there is no conclusive evidence on its value to predict the survival and prognosis of digestive system tumor patients. Hence this study aimed to evaluate the impact of CSN5 levels on the survival and clinicopathological parameters of digestive system neoplasm patients. METHODS: First, a comprehensive search was conducted in four databases. We utilized the Hazard Ratio (HR) with a 95% confidence interval (CI) to evaluate the prognostic value of CSN5 for the overall survival (OS) and recurrence-free survival (RFS) of patients. Then, we estimated the connection between CSN5 and the clinicopathological parameters based on the Odds Ratio (OR) with the corresponding 95% CI. RESULTS: This meta-analysis included 22 studies and 2193 patients diagnosed with digestive system tumors. High expression of CSN5 was correlated to poorer OS (HR = 2.28, 95% CI: 1.71-3.03; p < 0.00001). Additionally, high CSN5 levels were correlated with worse invasion depth (OR = 0.49, 95% CI: 0.25-0.96, p = 0.04), positive lymphatic metastasis (OR = 0.28, 95% CI: 0.16-0.47, p = 0.00001), positive distant metastasis (OR = 0.32, 95% CI: 0.13-0.76, p = 0.01) and poorer differentiation degree (OR = 0.34, 95% CI: 0.19-0.60, p = 0.0003). However, we did not detect a correlation between CSN5 expression and age, gender, tumor stage, tumor size or vascular invasion. Furthermore, no significant publication bias was detected. CONCLUSION: This meta-analysis demonstrated that the overexpression of CSN5 level might foresee poorer OS in digestive system cancer patients. Additionally, CSN5 levels might be related to the prognosis of digestive system tumors.

Endoscopy for the diagnosis and treatment of gastrointestinal bleeding caused by malignancy.

BACKGROUND AND AIM: The diagnosis and treatment of gastrointestinal (GI) bleeding secondary to malignancy can be challenging. Endoscopy is the gold standard to diagnose and treat gastrointestinal bleeding but clinical characteristics and outcomes of patients with malignancy-related bleeding are not well understood. This study aims to look at clinical characteristics, endoscopic findings, safety and clinical outcomes of endoscopic interventions for GI malignancy-related bleeding. METHODS: We retrospectively reviewed outcomes of patients with confirmed GI malignancies who underwent endoscopy for GI bleeding at MD Anderson Cancer Center between 2010 and 2019. Cox hazard analysis was conducted to identify factors associated with survival. RESULTS: A total of 313 patients were included, with median age of 59 years; 74.8% were male. The stomach (30.0%) was the most common tumor location. Active bleeding was evident endoscopically in 47.3% of patients. Most patients (77.3%) did not receive endoscopic treatment. Of the patients who received endoscopic treatment, 57.7% had hemostasis. No endoscopy-related adverse events were recorded. Endoscopic treatment was associated with hemostasis (P < 0.001), but not decreased recurrent bleeding or mortality. Absence of active bleeding on endoscopy, stable hemodynamic status at presentation, lower cancer stage, and surgical intervention were associated with improved survival. CONCLUSIONS: This study indicates that endoscopy is a safe diagnostic tool in this patient population; while endoscopic treatments may help achieve hemostasis, it may not decrease the risk of recurrent bleeding or improve survival.

Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring.

BACKGROUND: Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA. METHODS: We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients. RESULTS: The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively). CONCLUSIONS: The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

Clinical Characteristics and Outcomes of Oral Mucositis Associated With Immune Checkpoint Inhibitors in Patients With Cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy predisposes patients to immune-related adverse events (irAEs). Data are limited regarding the incidence, management, and outcomes of one such irAE: mucositis. In this study, we evaluated the clinical characteristics, disease course, treatment, and outcomes of ICI-mediated mucositis. METHODS: This was a retrospective, single-center study of patients who received ICI therapy and developed oral mucositis at The University of Texas MD Anderson Cancer Center from January 2009 to September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents. RESULTS: We identified 152 patients with a mean age of 60 years, 51% of whom were men. Of the sample patients, 73% had stage IV cancer, with melanoma the most common (28%). Median time from ICI initiation to mucositis was 91 days. The most common clinical presentation of mucositis was odynophagia and/or oral pain (89%), 91% developed CTCAE grade 1-2 mucositis, and 78% received anti-PD-1/L1 monotherapy. Compared with anti-PD-1/L1-based therapy, anti-CTLA-4-based therapy was more frequently associated with earlier onset of mucositis (73 vs 96 days; P=.077) and a lower rate of symptom resolution (76% vs 92%; P=.029); 24% of patients required immunosuppressive therapy, which was associated with longer symptom duration (84 vs 34 days; P=.002) and higher mucositis recurrence rate (61% vs 32%; P=.006). ICI interruption was associated with worse survival (P=.037). Mucositis recurrence, immunosuppressant use, and presence of other irAEs did not affect survival. CONCLUSIONS: For ICI-mediated mucositis, a diagnosis of exclusion has not been well recognized and is understudied. Although the clinical symptoms of mucositis are mostly mild, approximately 25% of patients require immunosuppression. Mucositis recurrence can occur in approximately 39% patients. Our results showed that ICI interruption compromises overall survival.

Long noncoding RNA SPRY4-IT1 promotes proliferation and metastasis of hepatocellular carcinoma via mediating TNF signaling pathway.

Our previous studies have indicated that long noncoding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4-IT1) was highly expressed in hepatocellular carcinoma (HCC). However, it still remained unclear how SPRY4-IT1 worked in tumorgenesis in HCC. In this study, we tested the overexpression of SPRY4-IT1 in HCC tissues and cells through a quantitative real-time polymerase chain reaction. Statistical analyses showed that the upregulation had an association with the tumor node metastasis stage, thrombin time, and alkaline phosphatase. Furthermore, SPRY4-IT1 could be involved in cell proliferation, metastasis, and the epithelial-to-mesenchymal transition (EMT) process in HCC in vitro and in vivo. RNA-sequencing and transcriptome analysis were carried out to explore the mechanism of SPRY4-IT1 in HCC. With SPRY4-IT1 being knocked down or overexpressed, the level of proteins in the tumor necrosis factor (TNF) signaling pathway changed. We detected the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a SPRY4-IT1 interacting protein through RNA pull-down assay and liquid chromatography-mass spectrometry, then verified through RNA immunoprecipitation. Downregulation of HNRNPL induced the change of proteins observed on SPRY4-IT1 downregulation revealing the SPRY4-IT1: HNRNPL complex in the TNF signaling pathway and EMT process in HCC. In general, our experimental data and analysis demonstrated the role of SPRY4-IT1 in promoting progress and metastasis of HCC by the TNF signaling pathway.

Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.

BACKGROUND: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. METHODS: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. RESULTS: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). CONCLUSIONS: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

Translational Biomarkers and Rationale Strategies to Overcome Resistance to Immune Checkpoint Inhibitors in Solid Tumors.

Immune checkpoint inhibitors (ICIs) targeting the programed cell-death protein 1 (PD-1) or its ligand PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have improved the survival for patients with solid tumors. Unfortunately, durable clinical responses are seen in only 10-40% of patients at the cost of potential immune-related adverse events. In the tumor microenvironment (TME), tumor cells can influence the microenvironment by releasing extracellular signals and generating peripheral immune tolerance, while the immune cells can affect the initiation, growth, proliferation, and evolution of cancer cells. Currently, translational biomarkers that predict responses to ICIs include high PD-L1 tumor proportion score, defective DNA mismatch repair, high microsatellite instability, and possibly high tumor mutational burden. Characterization of immune cells in the TME, such as tumor-infiltrating lymphocytes, T-cell gene expression profile, T-cell receptor sequencing, and peripheral blood biomarkers are being explored as promising biomarkers. Recent neoadjuvant studies have integrated the real-time assessment of both molecular and immune biomarkers using the tissue and blood specimens simultaneously and longitudinally. This review summarizes the current knowledge and progress in developing translational biomarkers and rational combinational strategies to improve the efficacy of ICIs tailored to individual cancer patients.

Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors.

Histologic transformation from adenocarcinoma to squamous cell carcinoma in lung cancer has not been reported as a mechanism of resistance to ALK inhibition. This report describes the clinical course of a female former light smoker with metastatic lung adenocarcinoma whose tumor underwent histologic transformation from a well-differentiated lung adenocarcinoma to a well-differentiated lung squamous cell carcinoma in the same location at the left mainstem bronchus while maintaining the ALK fusion oncogene without any resistance mutations. After experiencing disease progression while on crizotinib, the patient participated in clinical trials that provided early access to the novel ALK inhibitors ceritinib and alectinib before they were commercially available. Tumor recurrence occurred at the primary and metastatic central nervous system sites (ie, brain and spine). At tumor progression, liquid biopsy and tumor genomic profiling of plasma cell-free DNA next-generation sequencing (NGS) provided an accurate diagnosis with a short turnaround time compared with the tissue-based targeted capture NGS. The patient received several courses of radiation primarily to the brain and spine during her disease course. Her disease did not respond to the immune checkpoint inhibitor nivolumab, and she died on home hospice approximately 4 years after diagnosis. This case supports the importance of both histopathologic assessment and comprehensive genomic profiling in selecting appropriate treatment for patients with refractory, metastatic, ALK oncogene-driven non-small cell lung cancer. Use of symptom-directed radiation in tandem with ALK inhibitors contributed to the disease and symptomatic control and prolonged survival in this patient.

Analysis of Streamflow Complexity Based on Entropies in the Weihe River Basin, China.

The study on the complexity of streamflow has guiding significance for hydrologic simulation, hydrologic prediction, water resources planning and management. Utilizing monthly streamflow data from four hydrologic control stations in the mainstream of the Weihe River in China, the methods of approximate entropy, sample entropy, two-dimensional entropy and fuzzy entropy are introduced into hydrology research to investigate the spatial distribution and dynamic change in streamflow complexity. The results indicate that the complexity of the streamflow has spatial differences in the Weihe River watershed, exhibiting an increasing tendency along the Weihe mainstream, except at the Linjiacun station, which may be attributed to the elevated anthropogenic influence. Employing sliding entropies, the variation points of the streamflow time series at the Weijiabu station were identified in 1968, 1993 and 2003, and those at the Linjiacun station, Xianyang station and Huaxian station occurred in 1971, 1993 and 2003. In the verification of the above points, the minimum value of t-test is 3.7514, and that of Brown-Forsythe is 7.0307, far exceeding the significance level of 95%. Also, the cumulative anomaly can detect two variation points. The t-test, Brown-Forsythe test and cumulative anomaly test strengthen the conclusion regarding the availability of entropies for identifying the streamflow variability. The results lead us to conclude that four entropies have good application effects in the complexity analysis of the streamflow time series. Moreover, two-dimensional entropy and fuzzy entropy, which have been rarely used in hydrology research before, demonstrate better continuity and relative consistency, are more suitable for short and noisy hydrologic time series and more effectively identify the streamflow complexity. The results could be very useful in identifying variation points in the streamflow time series.

T Cell-Associated Immunotherapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide with limited therapeutic options. Accumulating evidences suggest that immunotherapy could be a promising option for treating HCC. T cell-associated immunotherapy lights up the hope for the improvement of complementary approach to conventional HCC treatments, which needs further research to consummate the clinical consequences. The present work reviewed several T cells associated cellular immunotherapies for HCC, including immune checkpoint blockade, gene-engineered T cells, bispecific T cell engagers, and so on. We also analyzed how these immunotherapies can mediate tumor cell eradication and evaluated their superiority or insufficiency.

Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma is third leading cause of cancer-related death globally. Long non-coding RNA plasmacytoma variant translocation 1 has been reported to be dysregulated and plays a crucial role in various cancers. In this study, we investigated the interactions between plasmacytoma variant translocation 1 and miR-186-5p in the progression of hepatocellular carcinoma and explored the functional significance of plasmacytoma variant translocation 1. It was determined that plasmacytoma variant translocation 1 was significantly higher, while miR-186-5p was statistically lower in the hepatocellular carcinoma tissues than that in the adjacent normal tissues. Using gain-of-function and loss-of-function methods, our results revealed that plasmacytoma variant translocation 1 affected hepatocellular carcinoma cells proliferation, invasion, and migration. It was found that there was direct interaction between miR-186-5p and the binding site of plasmacytoma variant translocation 1 by performing dual-luciferase assay and RNA immunoprecipitation assay. Furthermore, it was identified that plasmacytoma variant translocation 1 regulated the expression of the miR-186-5p target gene, yes-associated protein 1. Taken together, plasmacytoma variant translocation 1 served as an endogenous sponge for miR-186-5p to reduce its inhibiting effect on yes-associated protein 1 and thus promoted the tumorigenesis of hepatocellular carcinoma.

Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models.

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3ß1, αvß3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.