Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear ...factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment.
The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI.
The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI.
These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Few biomarkers can predict the efficiency of PD-1 blockade in patients with hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic role of AFP and PIVKA-II in HCC ...patients receiving anti-PD-1 immunotherapy. Methods A total of 235 HCC patients treated with PD-1 blockade were enrolled. Serum AFP and PIVKA-II levels were collected before and after treatments. The patients were divided into groups based on the reduction in AFP and PIVKA-II: AFP reduction less than or equai to50% vs AFP reduction > 50% and PIVKA-II reduction less than or equai to50% vs PIVKA-II reduction > 50%. The primary endpoints included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Binary logistic regression analyses were used to explore the related factors of ORR. A Cox proportional hazards model was employed to identify the potential prognostic factors of PFS and OS. Results Among all the patients, 34.9% (82/235) achieved a complete or partial response. There was a positive correlation between AFP reduction > 50% or PIVKA-II reduction> 50% and the ORR of PD-1 blockade (P < 0.001 and = 0.003). PFS was significantly improved in patients with AFP reduction > 50% and PIVKA-II reduction > 50% (p < 0.001 and = 0.021). In addition, AFP reduction > 50% and PIVKA-II reduction> 50% were positively correlated with longer OS (p = 0.003 and 0.006). Conclusion Early reductions in AFP and PIVKA-II can be predictors of the efficacy of PD-1 blockade in HCC patients. Keywords: Hepatocellular carcinoma, AFP, PIVKA-II, Immunotherapy, Survival
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a lack of effective treatment to improve the prognosis of intrahepatic cholangiocarcinoma (ICC). Programmed cell death protein-1 (PD-1)-targeted immunotherapy has shown promising results in ...a variety of malignant tumours. However, in patients with advanced ICC, the safety and efficacy of anti-PD-1 agents remain unclear.
Forty-two advanced ICC patients treated with anti-PD-1 agents from August 2018 to December 2020 were retrospectively analyzed. Tumour response, overall survival (OS), progression-free survival (PFS), and time to tumour progression (TTP) were evaluated. Adverse events were also recorded.
The median duration of follow-up was 12.1 months, and the median time of treatment was 6.7 months for all patients. The median OS, median PFS, and median TTP for the whole cohort were 19.3 months, 11.6 months, and 11.6 months, respectively. The overall response rate (ORR) and disease control rate (DCR) for the whole cohort were 23.8% and 85.7%, respectively. Of the 42 evaluable individuals, two (4.8%) had hyperprogressive disease. The most common adverse events (AEs) were pain (n = 6; 14.3%), anorexia (n = 4; 9.5%), hypertension (n = 4; 9.5%), pyrexia (n = 3; 7.1%), cough (n = 3; 7.1%), and hypothyroidism (n = 3; 7.1%). The median OS of patients with albumin-bilirubin (ALBI) grade 1 was longer than that of patients with ALBI grade 2 (19.3 months vs. 14.7 months). The median PFS did not show a significant difference between ALBI grade 1 and grade 2 patients (13.6 months vs. 6.9 months).
PD-1-targeted immunotherapy showed promising efficacy and safety in advanced ICC patients.
Key messages
PD-1-targeted immunotherapy is a safe and effective treatment for advanced ICC patients.
This study provides therapeutic strategy for advanced ICC patients.
We aimed to describe the molecular epidemiological characteristics and clinical treatment outcome of typhoid fever in Ningbo, China during 2005–2014. Eighty-eight Salmonella Typhi isolates were ...obtained from 307 hospitalized patients. Three prevalent pulsed-field gel electrophoresis (PFGE) patterns of 54 isolates from 3 outbreaks were identified. Overall, there were 64 (72.7%) isolates from clustered cases and 24 (27.3%) isolates from sporadic cases. Resistance to nalidixic acid (NAL) (n = 47; 53.4%) and ampicillin (AMP) (n = 40; 45.4%) and rare resistance to tetracycline (TET) (n = 2; 2.3%) and gentamicin (GEN) (n = 2; 2.3%) were observed. No isolates resistant to cefotaxime (CTX), chloramphenicol (CL), ciprofloxacin (CIP), and trimethoprim-sulfamethoxazole (SXT) were found. The occurrence of reduced sensitivity to CIP was 52.3% (n = 46). The medians of fever clearance time in cases with and without complications were 7 (interquartile range (IQR): 4–10) and 5 (IQR: 3–7) days (P = 0.001), respectively, when patients were treated with CIP or levofloxacin (LEV) and/or third-generation cephalosporins (CEP). Rates of serious complications were at low levels: peritonitis (2.3%), intestinal hemorrhage (6.8%), and intestinal perforation (1.1%). The present study revealed a long-term clustering trend with respect to PFGE patterns, occasional outbreaks, and the rapid spread of AMP resistance and decreased CIP susceptibility among S. Typhi isolates in recent years.
Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in ...providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response.
The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment.
TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo.
Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological ...significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear.
Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients' progression-free survival (PFS).
The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (
0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (
< 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (
< 0.001). Patients in the risk subgroups reported similar overall response rates (
0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively,
0.002).
The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.
Background Lack of opportunity for radical surgery and postoperative tumor recurrence are challenges for surgeons and hepatocellular carcinoma (HCC) patients. This study aimed to develop nomograms to ...predict recurrence risk and recurrence-free survival (RFS) probability after conversion hepatectomy for patients previously receiving transarterial interventional therapy. Methods In total, 261 HCC patients who underwent conversion liver resection and previously received transarterial interventional therapy were retrospectively enrolled. Nomograms to predict recurrence risk and RFS were developed, with discriminative ability and calibration evaluated by C-statistics, calibration plots, and the Area under the Receiver Operator Characteristic (AUROC) curves. Results Univariate/multivariable logistic regression and Cox regression analyses were used to identify predictive factors for recurrence risk and RFS, respectively. The following factors were selected as predictive of recurrence: age, tumor number, microvascular invasion (MVI) grade, preoperative alpha-fetoprotein (AFP), preoperative carbohydrate antigen 19-9 (CA19-9), and Eastern Cooperative Oncology Group performance score (ECOG PS). Similarly, age, tumor number, postoperative AFP, postoperative protein induced by vitamin K absence or antagonist-II (PIVKA-II), and ECOG PS were incorporated for the prediction of RFS. The discriminative ability and calibration of the nomograms revealed good predictive ability. Calibration plots showed good agreement between the nomogram predictions of recurrence and RFS and the actual observations. Conclusions A pair of reliable nomograms was developed to predict recurrence and RFS in HCC patients after conversion resection who previously received transarterial interventional therapy. These predictive models can be used as guidance for clinicians to help with treatment strategies. Keywords: Hepatocellular carcinoma, Conversion, Hepatectomy, Recurrence, Nomogram
In recent years, the development of BMSCs-derived exosomes (EXO) for the treatment of osteosarcoma (OS) is a safe and promising modality for OS treatment, which can effectively deliver drugs to tumor ...cells in vivo. However, the differences in the drugs carried, and the binding of EXOs to other organs limit their therapeutic efficacy. Therefore, improving the OS-targeting ability of BMSCs EXOs and developing new drugs is crucial for the clinical application of targeted therapy for OS. In this study, we constructed a potential therapeutic nano platform by modifying BMSCs EXOs using the bone-targeting peptide SDSSD and encapsulated capreomycin (CAP) within a shell. These constructed nanoparticles (NPs) showed the ability of homologous targeting and bone-targeting exosomes (BT-EXO) significantly promotes cellular endocytosis in vitro and tumor accumulation in vivo. Furthermore, our results revealed that the constructed NPs induced ferroptosis in OS cells by prompting excessive accumulation of reactive oxygen species (ROS), Fe.sup.2+ aggregation, and lipid peroxidation and further identified the potential anticancer molecular mechanism of ferroptosis as transduced by the Keap1/Nrf2/GPX4 signaling pathway. Also, these constructed NP-directed ferroptosis showed significant inhibition of tumor growth in vivo with no significant side effects. These results suggest that these constructed NPs have superior anticancer activity in mouse models of OS in vitro and in vivo, providing a new and promising strategy for combining ferroptosis-based chemotherapy with targeted therapy for OS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Vessels that encapsulate tumor cluster (VETC) is associated with poor prognosis in hepatocellular carcinoma (HCC). Vessels that encapsulate tumor cluster estimation before initial ...treatment is helpful for clinical doctors. We aimed to construct a novel predictive model for VETC, using preoperatively accessible clinical parameters and imagine features.
Methods
Totally, 365 HCC patients who received curative hepatectomy in the Sun Yat-Sen University Cancer Center from 2013 to 2014 were enrolled in this study. Vessels that encapsulate tumor cluster pattern was confirmed by immunochemistry staining. 243 were randomly assigned to the training cohort while the rest was assigned to the validation cohort. Independent predictive factors for VETC estimation were determined by univariate and multivariate logistic analysis. We further constructed a predictive nomogram for VETC in HCC. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curve, and calibration curve. Besides, the decision curve was plotted to evaluate the clinical usefulness. Ultimately, Kaplan–Meier survival curves were utilized to confirm the association between the nomogram and survival.
Results
Immunochemistry staining revealed VETC in 87 patients (23.8%). lymphocyte to monocyte ratio (>7.75, OR = 4.06), neutrophil (>7, OR = 4.48), AST to ALT ratio (AAR > .86, OR = 2.16), ALT to lymphocyte ratio index (BLRI > 21.73, OR = 2.57), alpha-fetoprotein (OR = 1.1), and tumor diameter (OR = 2.65) were independent predictive factors. The nomogram incorporating these predictive factors performed well with an area under the curve (AUC) of .746 and .707 in training and validation cohorts, respectively. Calibration curves indicated the predicted probabilities closely corresponded with the actual VETC status. Moreover, the decision curve proved our nomogram could provide clinical benefits with patients. Finally, low probability of VETC group had significantly longer recurrence free survival (RFS) and overall survival (OS) than the high probability of the VETC group (all P < .001).
Conclusion
A novel predictive nomogram integrating clinical indicators and image characteristics shows strong predictive VETC performance and might provide standardized net clinical benefits.
In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor ...microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.
We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including
,
,
,
,
, and
, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.
We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.
The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.
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