Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

Hypoxia-treated adipose mesenchymal stem cell-derived exosomes attenuate lumbar facet joint osteoarthritis.

BACKGROUND: Lumbar facet joint osteoarthritis (LFJ OA) is a common disease, and there is still a lack of effective disease-modifying therapies. Our aim was to determine the therapeutic effect of hypoxia-treated adipose mesenchymal stem cell (ADSC)-derived exosomes (Hypo-ADSC-Exos) on the protective effect against LFJ OA. METHODS: The protective effect of Hypo-ADSC-Exos against LFJ OA was examined in lumbar spinal instability (LSI)-induced LFJ OA models. Spinal pain behavioural assessments and CGRP (Calcitonin Gene-Related Peptide positive) immunofluorescence were evaluated. Cartilage degradation and subchondral bone remodelling were assessed by histological methods, immunohistochemistry, synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR), and 3D X-ray microscope scanning. RESULTS: Hypoxia enhanced the protective effect of ADSC-Exos on LFJ OA. Specifically, tail vein injection of Hypo-ADSC-Exos protected articular cartilage from degradation, as demonstrated by lower FJ OA scores of articular cartilage and less proteoglycan loss in lumbar facet joint (LFJ) cartilage than in the ADSC-Exo group, and these parameters were significantly improved compared to those in the PBS group. In addition, the levels and distribution of collagen and proteoglycan in LFJ cartilage were increased in the Hypo-ADSC-Exo group compared to the ADSC-Exo or PBS group by SR-FTIR. Furthermore, Hypo-ADSC-Exos normalized uncoupled bone remodelling and aberrant H-type vessel formation in subchondral bone and effectively reduced symptomatic spinal pain caused by LFJ OA in mice compared with those in the ADSC-Exo or PBS group. CONCLUSIONS: Our results show that hypoxia is an effective method to improve the therapeutic effect of ADSC-Exos on ameliorating spinal pain and LFJ OA progression.

Comparison of clinical outcomes of laparoscopic versus open surgery for recurrent hepatocellular carcinoma: a meta-analysis.

BACKGROUND: The purpose of this study is to compare the clinical outcomes of laparoscopic liver resection versus open liver resection for recurrent hepatocellular carcinoma (RHCC). METHODS: Published studies which investigated laparoscopic versus open liver resection for RHCC were identified, and meta-analysis was used for statistical analysis. RESULTS: Six studies were analyzed by meta-analysis method, and cumulative 335 cases were included in this study. Laparoscopic liver resection was performed in 145 cases, and open liver resection was performed in 190 cases. Meta-analysis showed that there was no difference in operative time and 90-day mortality between the laparoscopic group and the open group (p = 0.06 and p = 0.06 respectively); Nevertheless, compared with the open group, the laparoscopic group resulted in significantly lower rate of in-hospital complication (p < 0.0001), much less blood loss (p < 0.0001) and shorter postoperative hospital stay (p = 0.002). CONCLUSION: Laparoscopic liver resection for RHCC offers a benefit of lower in-hospital complication rate, less blood loss, shorter postoperative hospital stay, while similar operative time and 90-day mortality as the open liver resection. Laparoscopic liver resection is feasible with satisfactory postoperative outcomes and can be a safe alternative treatment strategy to open procedure for RHCC.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance.

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy.

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.

Platelet-Derived Growth Factor C Facilitates Malignant Behavior of Pancreatic Ductal Adenocarcinoma by Regulating SREBP1 Mediated Lipid Metabolism.

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

Analysis of Degenerative and Isthmic Lumbar Spondylolisthesis from the Difference of Pelvic Parameters and the Degree of Degeneration through Imaging Data.

BACKGROUND: In previous studies, many imaging analyses have been conducted to explore the changes in the intervertebral disc degeneration (DD), facet joint osteoarthritis (FJOA), L4 inclination angle (L4IA), pelvis-related parameters, lumbar lordosis (LL), and paravertebral muscle (PVM) in the occurrence and development of degenerative spinal diseases via measuring the X-ray, CT, and MRI data of clinical patients. However, few studies have quantitatively investigated the pelvic parameters and the degree of spine degeneration in patients with degenerative lumbar spondylolisthesis (DLS) and isthmic lumbar spondylolisthesis (ILS). This study discusses the changes in the imaging parameters of DLS, ILS, and a control group; explores the correlation between different measurement parameters; and discusses their risk factors. METHODS: We evaluated 164 patients with single L4-L5 grade 1 level degenerative lumbar spondylolisthesis (DLS group), 161 patients with single L4-L5 grade 1 level isthmic lumbar spondylolisthesis (ILS group), and 164 patients with non-specific back pain (control group). The grades of DD and FJOA as well as the percentage of the fat infiltration area (%FIA) of multifidus muscle (MM) at the L4-L5 level were measured via CT and MRI. Lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), the L4 inclination angle (L4IA), and sacral slope (SS) were measured via X-ray film, and the differences among the DLS group, ILS group, and control group were analyzed. Furthermore, the risk factors related to the incidences of the DLS and ILS groups were discussed. RESULTS: First, the pelvis-related parameters of DLS and ILS patients were 51.91 ± 12.23 and 53.28 ± 11.12, respectively, while those of the control group were 40.13 ± 8.72 (p1 < 0.001, p2 < 0.001). Lumbar lordosis (LL) in DLS patients (39.34 ± 8.57) was significantly lower than in the control group (44.40 ± 11.79, p < 0.001). On the contrary, lumbar lordosis (LL) in the ILS group (55.16 ± 12.31) was significantly higher than in the control group (44.40 ± 11.79, p < 0.001). Secondly, the three groups of patients were characterized by significant variations in the L4 inclination angle (L4IA), disc degeneration (DD), facet joint osteoarthritis (FJOA), pelvis-related parameters, and paravertebral muscle (PVM) (p < 0.05). Finally, logistic regression suggests that the L4IA, FJOA, and PT may be risk factors for the occurrence of DLS, and the occurrence of ILS is correlated with the L4IA, FJOA, DD, PT, and LL. CONCLUSIONS: Compared with the control group, there are changes in pelvic parameters, the L4IA, LL, DD, FJOA, and PVM in DLS and ILS patients, and the degree is different. The parameters within the same group are related to each other, and DLS and ILS have different risk factors. The mechanical stability of the spine is affected by the parameter and angle changes, which may be of great significance for explaining the cause of spondylolisthesis, evaluating the health of the lumbar spine, and guiding the lifestyles of patients.

Mechanical overloading-induced miR-325-3p reduction promoted chondrocyte senescence and exacerbated facet joint degeneration.

OBJECTIVE: Lumbar facet joint (LFJ) degeneration is one of the main causes of low back pain (LBP). Mechanical stress leads to the exacerbation of LFJ degeneration, but the underlying mechanism remains unknown. This study was intended to investigate the mechanism of LFJ degeneration induced by mechanical stress. METHODS: Here, mice primary chondrocytes were used to screen for key microRNAs induced by mechanical overloading. SA-ß-gal staining, qRT-PCR, western blot, and histochemical staining were applied to detect chondrocyte senescence in vitro and in vivo. We also used a dual-luciferase report assay to examine the targeting relationship of miRNA-325-3p (miR-325-3p) and Trp53. By using NSC-207895, a p53 activator, we investigated whether miR-325-3p down-regulated trp53 expression to reduce chondrocyte senescence. A mice bipedal standing model was performed to induce LFJ osteoarthritis. Adeno-associated virus (AAV) was intraarticularly injected to evaluate the effect of miR-325-3p on facet joint degeneration. RESULTS: We observed chondrocyte senescence both in human LFJ osteoarthritis tissues and mice LFJ after bipedally standing for 10 weeks. Mechanical overloading could promote chondrocyte senescence and senescence-associated secretory phenotype (SASP) expression. MicroRNA-array analysis identified that miR-325-3p was obviously decreased after mechanical overloading, which was further validated by fluorescence in situ hybridization (FISH) in vivo. Dual-luciferase report assay showed that miR-325-3p directly targeted Trp53 to down-regulated its expression. MiR-325-3p rescued chondrocyte senescence in vitro, however, NSC-207895 reduced this effect by activating the p53/p21 pathway. Intraarticular injection of AAV expressing miR-325-3p decreased chondrocyte senescence and alleviated LFJ degeneration in vivo. CONCLUSION: Our findings suggested that mechanical overloading could reduce the expression of miR-325-3p, which in turn activated the p53/p21 pathway to promote chondrocyte senescence and deteriorated LFJ degeneration, which may provide a promising therapeutic strategy for LFJ degeneration.

Grafting of CNTs onto the surface of PBO fibers at high-density for enhancing interfacial adhesion, mechanical properties and stability of composites.

To improve the interfacial adhesion and mechanical performance of PBO fiber composites, CNTs were uniformly grafted onto them at a high-density. The grafting of CNTs with massive reactive groups can improve the surface wettability and interfacial interaction of PBO fibers with epoxy resin. The IFSS and ILSS values of themodified composites (PBO-CNT-3) increased by 103.09 and 62.73%, respectively. As CNTs can strengthen interfacial regions of the composites, the mechanical properties (hardness and modulus) of the interphase were enhanced significantly. This led to the effective transfer of interfacial load, elimination of stress concentration, and improvement in the structural stability of the composites. As a result, the impact strength of the modified composites (PBO-CNT-3) was up to 103.76 kJ/m2 (an increase of 56.24%) compared to the original composites. The surface morphology and deformation behavior of the fractured composites indicate that the interfacial failure mode of the composites grafted with CNTs changes from adhesive failure to both cohesive and substrate failure. This strategy of grafting CNTs at a high-density opens a new avenue for the interfacial regulation of structural composites, ultra-capacitor, sensor, and catalytic materials.

Expression and inhibitory effects of p53-upregulated modulator of apoptosis in gallbladder carcinoma.

The p53-upregulated modulator of apoptosis (PUMA) has been reported to be involved in various types of cancer. However, its potential biological role in gallbladder carcinoma (GBC) has not been fully elucidated. The present study aimed to determine the expression levels of PUMA and its biological effects on GBC. The mRNA and protein expression levels of PUMA in GBC tissues and cell lines were measured using reverse transcription-quantitative PCR and western blotting, respectively. The effects of PUMA overexpression on cell viability, proliferation and invasive ability were determined in vitro using the MTT, colony formation and Transwell invasion assays, respectively. The apoptotic rates were detected using the Annexin V-FITC apoptosis detection kit. Furthermore, follow-up of patients with GBC was performed to identify the association between PUMA expression levels and GBC prognosis. The results of the present study demonstrated that the expression levels of PUMA were significantly lower in the GBC tissues and cell lines compared with those in adjacent normal gallbladder tissues and normal gallbladder cells, respectively. Further experiments indicated that overexpression of PUMA inhibited the viability, proliferation and invasive ability of GBC cells compared with those in the control-transfected GBC cells. In addition, overexpression of PUMA significantly promoted apoptosis in GBC cells. Furthermore, overexpression of PUMA inhibited epithelial-mesenchymal transition, and promoted Bax upregulation and Bcl-2 downregulation compared with those in the control group. Low PUMA expression levels were associated with a short overall survival time in patients with GBC. In conclusions, PUMA may act as a tumor suppressor in GBC and may serve as a potential novel treatment target for human GBC.

The incidence trends of liver cirrhosis caused by nonalcoholic steatohepatitis via the GBD study 2017.

Nonalcoholic steatohepatitis (NASH) has rapidly become the most common cause of chronic liver diseases. We aimed to explore the incidence and distribution characteristics of NASH by sex, region and sociodemographic index (SDI). We collected data, including sex and region, on NASH-related liver cirrhosis from the 2017 GBD study. The age-standardized incidence rates (ASRs) and estimated annual percentage changes (EAPCs) were used to estimate the incidence trend and distribution characteristics. Globally, the incidence of liver cirrhosis caused by NASH increased from 178,430 cases in 1990 to 367,780 cases in 2017, an increase of approximately 105.56%. The ASR of NASH increased by an average of 1.35% per year (95% CI 1.28-1.42). Meanwhile, large differences in the ASR and the EAPC were observed across regions. The middle-high SDI region had the highest increase among all five SDI regions, followed by middle SDI region. In addition, Eastern Europe, Andean Latin America and Central Asia showed a more significant growth trend of ASR. In contrast, the high SDI region demonstrated the slowest increasing trend of ASR, and the high-income Asia Pacific demonstrated a decreasing trend among the 21 regions. Liver cirrhosis has caused a huge and rising health burden in many countries and regions. In addition, with the growth of obesity, population and aging, NASH might replace viral hepatitis as the most important cause of liver cirrhosis in the near future. Therefore, appropriate interventions are needed in coming decades to realize early diagnosis and prevention of NASH-related liver cirrhosis.

EphA10 and EphB3 are prognostic markers in gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas.

AIMS: Squamous cell/adenosquamous carcinomas (SC/ASC) are rare subtypes of gallbladder cancers (GBCs). Clinical characteristics of SC/ASC have not been well documented, and no biological markers of GBC carcinogenesis, progression and prognosis are available. METHODS: We detected EphA10 and EphB3 expression in 69 SC/ASCs and 146 adenocarcinomas (ACs) with EnVision immunohistochemistry. RESULTS: The percentage of cases with a patient age of > 45 years, lymph node metastasis and invasion was significantly higher in the SCs/ASCs compared with the ACs (P < 0.05). The positive expression of EphA10 and negative expression of EphB3 were significantly higher in the cases of SC/ASC and AC than in chronic cholecystitis (P < 0.01). The positive expressions of EphA10 and negative expression of EphB3 were significantly higher in the cases of poorly differentiation, large tumor size, high TNM stage, lymph node metastasis, invasion and no resection (only biopsy) of SC/ASC and AC. The negative correlation was found between EphA10 and EphB3 expression in SC/ASC and AC (P < 0.01). The univariate Kaplan-Meier analysis showed that positive EphA10 and negative EphB3, differentiation, tumor size, TNM stage, lymph node metastasis, invasion and surgical curability, is closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). The multivariate Cox regression analysis identified that positive EphA10 and negative EphB3 expression are independent factors for a poor-prognosis in SC/ASC and AC patients. The AUC for EphA10 and EphB3 showed might have role for carcinogenesis and progression of SC/ASC and AC. CONCLUSIONS: The present study indicates that positive EphA10 and negative EphB3 expression are closely associated with the pathogenesis, clinical, pathological and biological behaviors, and poor prognosis in gallbladder cancer.