Elevated serum 25-hydroxyvitamin D: a potential indicator of remission in Takayasu arteritis patients with normal ESR and CRP levels.

OBJECTIVE: The goal of the present study was to investigate the correlation between serum 25-hydroxyvitamin D [25(OH)D] levels and disease remission in Takayasu arteritis (TAK) patients. METHODS: This retrospective study included 59 patients in the study group and 80 patients in the validation cohort with TAK. After 6 months of therapy, patients were re-evaluated, and serum 25(OH)D levels were compared before and after treatment. Correlations between changes in 25(OH)D levels and changes in disease activity scores (NIH, ITAS2010, ITAS.A) were analyzed. Additionally, a predictive cut-off value for disease remission was determined. RESULTS: After 6 months of therapy, serum 25(OH)D levels in TAK patients significantly increased compared to baseline [(18.33 ± 7.25)µg/L vs (11.77 ± 4.14) µg/L] (P < 0.001). Positive correlations were observed between the increasing changes in the 25(OH)D level and the decreasing changes in the reduced NIH, ITAS2010, and ITAS.A scores (r = 0.455, P < 0.001; r = 0.495, P < 0.001; and r = 0.352 P = 0.006, respectively). A change of 8.45 µg/L in 25(OH)D level was identified as the predictive cut-off value for TAK remission (sensitivity 54.1%, specificity 90.9%, area under the curve = 0.741). Similarly for patients with normal baseline ESR, sensitivity is 68.0%, specificity is 92.3%, and area under the curve is 0.831, and for patients with normal baseline CRP, sensitivity is 58.3%, specificity is 90.0%, and area under the curve is 0.748. Validation in an additional 80 patients demonstrated a higher remission rate in those with a 25(OH)D level change > 8.45 µg/L. CONCLUSION: Serum 25(OH)D levels significantly increased after treatment in TAK patients, and an increase of ≥ 8.45 µg/L was predictive of disease remission, especially in individuals with normal baseline ESR and/or CRP levels. Key Points • Following treatment, there was a significant increase in serum 25(OH)D levels among TAK patients. • The elevated changes in 25(OH)D levels before and after treatment demonstrated a positive correlation with the reduction in disease activity scores. • In patients with TAK before and after treatment, an elevation in serum 25(OH)D levels exceeding 8.45 µg/L serves as an indicator for disease remission, particularly prominent in individuals with normal baseline ESR and/or CRP levels.

Coronary artery calcification in Takayasu's arteritis: clinical characteristics and risk factors.

OBJECTIVES: Coronary artery calcification (CAC) is frequently observed in Takayasu's arteritis (TAK). Our objective is to calculate the prevalence and severity of CAC in TAK, while evaluating the influence of traditional cardiovascular risk factors, glucocorticoid exposure, and disease activity on CAC. METHODS: This retrospective study involved 155 TAK patients. We measured the Agatston score by coronary computed tomography angiography (CCTA) and categorised all patients into groups with or without CAC (41 vs. 114) to compare clinical characteristics and ancillary findings between the two groups. RESULTS: Among the TAK patients, a total of 41 TAK patients (26.45%) exhibited CAC. Age of onset, disease duration, history of hypertension, history of hyperlipidaemia, Numano V and glucocorticoid use emerged as the independent risk factors for developing CAC in TAK (OR [95% CI] 1.084[1.028-1.142], p=0.003; 1.005 [1.001-1.010], p=0.020; 4.792 [1.713-13.411], p=0.003; 4.199 [1.087-16.219], p=0.037; 3.287 [1.070-10.100], p=0.038; 3.558[1.269-9.977], p=0.016). Nonetheless, CAC was not associated with disease activity. Moreover, the extent of calcification score in TAK showed a positive correlation with the number of traditional cardiovascular risk factors. CONCLUSIONS: We recommend CCTA screening for Numano V classified TAK patients. Glucocorticoid usage significantly escalates the risk of CAC. Therefore, in cases of effectively controlled disease, the inclusion of immunosuppressants aimed at reducing glucocorticoid dosage is advisable.

Long Non-coding RNA RP11-252C15.1 is a Potential Biomarker of Prognosis and Hallmark for Leukemogenesis in Children with B-cell Precursor Acute Lymphoblastic Leukemia.

INTRODUCTION: Improved understanding of the prognostic biomarkers associated with childhood acute lymphoblastic leukemia (ALL) is needed for accurate risk group stratification. This study aimed to identify potential long-non coding RNA (lncRNA) markers and evaluate their prognostic value in children with ALL. METHODS: We selected 50 children with newly diagnosed ALL and 20 age-matched patients with idiopathic immune thrombocytopenia (controls). RNA sequencing was performed to identify differentially expressed lncRNAs between the ALL and control groups. Correlation analysis was performed to determine the relationships between candidate lncRNAs, clinical features, and the risk of leukemogenesis. RESULTS: A total of 1,019 differentially expressed lncRNAs were identified between the ALL and control groups. Reverse-transcriptase (RT-qPCR) revealed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 were significantly upregulated in patients with ALL. Furthermore correlation analysis showed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 represent potential predictors of leukemogenesis; however, only lncRNA RP11-252C15.1 was associated with clinical features and outcome in children with B-cell precursor ALL (BCP-ALL). In vitro experiments confirmed that lncRNA RP11-252C15.1 was significantly overexpressed in BCP-ALL cell lines and promoted proliferation, and repressed apoptosis in MHH-CALL-3 cells. CONCLUSION: LncRNA RP11-252C15.1 is a potential oncogene in BCP-ALL pathogenesis and a prognostic biomarker in children with BCP-ALL.

Clinical features and management of germline CEBPA-mutated carriers.

Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.

Decreased IL-4 is the risk factor of depression in patients with Takayasu arteritis.

Objective: Depression is a common complication in Takayasu arteritis (TA). Disorders of the immune system play an important role in both diseases. This study aimed to clarify the feature of cytokines in TA patients with depression. Methods: In this cross-sectional study, serum cytokines were tested in 40 TA patients and 11 healthy controls using the Bio-Plex Magpix System (Bio-Rad®). The state of depression was measured by the Zung Self-Rating Depression Scale (SDS) in TA patients. Logistic regression analysis was performed to find the risk factors of depression in patients with TA. Results: TA patients with depression had higher ESR, hsCRP, NIH, and ITAS.A than patients without depression (16.00 [10.00, 58.50]mm/H vs. 7.50 [4.50, 17.75]mm/H, p = 0.013; 7.60 [2.32, 46.52]mg/L vs. 0.71 [0.32, 4.37]mg/L, p = 0.001; 2.00 [2.00, 3.00] vs. 1.00 [0.00, 2.00], p = 0.007; 7.00 [4.00, 9.50] vs. 1.50 [0.00, 5.75], p = 0.012, respectively). Additionally, the lower age of onset and levels of IL-4, IL-13, eotaxin, and IP-10 were observed in the depressed group compared with the non-depressed (23.50 [19.25, 32.50]pg./ml vs. 37.00 [23.25, 42.50]pg./ml, p = 0.017; 2.80 [2.17, 3.18]pg./ml vs. 3.51 [3.22, 4.66]pg./ml, p < 0.001; 0.66 [0.60, 1.12]pg./ml vs. 1.04 [0.82, 1.25]pg./ml, p = 0.008; 46.48 [37.06, 61.75]pg./ml vs. 69.14 [59.30, 92.80]pg./ml, p = 0.001; 184.50 [138.23, 257.25]pg./ml vs. 322.32 [241.98, 412.60]pg./ml, p = 0.005, respectively). The lower level of IL-4 and age of onset were the independent risk factors for depression in TA patients (OR [95% CI] 0.124 [0.018, 0.827], p = 0.031; 0.870 [0.765, 0.990], p = 0.035, respectively). Conclusion: Our data suggested that lower cytokine levels, especially IL-4, might be involved in the development of TA patients with depression. Clinicians can probably use serum IL-4 level testing as a potential indicator of depression in TA.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

A bioorthogonal cell sorting strategy for isolation of desired cell phenotypes.

Here we describe a cost-effective and simplified cell sorting method using tetrazine bioorthogonal chemistry. We successfully isolated SKOV3 cells from complex mixtures, demonstrating efficacy in separating mouse lymphocytes expressing interferon and HeLa cells expressing virally transduced green fluorescent protein post-infection.

Prognostic significance of multiparametric flow cytometry minimal residual disease at two time points after induction in pediatric acute myeloid leukemia.

BACKGROUND: Prompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses. METHODS: MFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol. RESULTS: Using a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy. CONCLUSIONS: The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

Intracellular and extracellular synergistic therapy for restoring macrophage functions via anti-CD47 antibody-conjugated bifunctional nanoparticles in atherosclerosis.

Atherosclerosis is a significant contributor to global cardiovascular disease. Reducing the formation of atherosclerotic plaque effectively can lead to a decrease in cardiovascular diseases. Therefore, controlling macrophage function is crucial. This study presents the creation of a bifunctional nanoparticle that is specific to macrophages to achieve intracellular and extracellular synergistic therapy for restoring macrophage functions. The nanoparticle is conjugated with anti-CD47 antibody to modulate extracellular CD47-SIRPα phagocytic signaling axis on the outer surface of macrophages and encapsulates the NLRP3 inhibitor (CY-09) to regulate intracellular inflammation response of macrophages. The results showed that the nanoparticles accumulate in the atherosclerotic plaque, alter macrophage phagocytosis, inhibit NLRP3 inflammasome activation, and decrease the plaque burden in Apoe-/- mice whilst ensuring safety. Examination of single-cell RNA sequencing indicates that this multifunctional nanoparticle decreases the expression of genes linked to inflammation and manages inflammatory pathways in the plaque lesion. This study proposes a synergistic therapeutic approach that utilizes a bifunctional nanoparticle, conjugated with anti-CD47, to regulate the microenvironment of plaques.

A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.

The evaluation of four nano-formulations loaded-Elsinochrome A on characteristics and in vitro cytotoxicity effect.

Elsinochrome A (EA) is a naturally occurring photosensitizer with potential applications in photodynamic therapy (PDT) for various malignancies. Despite its promising therapeutic properties, the poor solubility of EA hampers its effective utilization in clinical settings. To circumvent this limitation, we engineered four distinct nano-formulations: PLGA/EA nanoparticles (NPs), CMC-PLGA/EA NPs, mPEG-PCL/EA nanomicelles (NMs), and LHP-CHOL/EA nanoliposomes (NLs), all designed to enhance the solubility of EA. A comparative evaluation of these formulations, based on metrics such as particle size, Zeta potential, drug loading efficiency, and encapsulation efficiency, identified PLGA/EA NPs and mPEG-PCL/EA NMs as the most efficacious candidates. Subsequent in vitro investigations into the drug release kinetics under varying pH conditions and the impact on cell viability and apoptosis in A549 and MCF-7 cell lines were conducted. Remarkably, the maximum drug release for PLGA/EA NPs and mPEG-PCL/EA NMs was recorded at 62.5% and 70.8% in an acidic environment (pH 5.7), respectively. Upon exposure to 460 nm light, PLGA/EA NPs induced a significant reduction in A549 cell viability to 13.8% and an apoptosis rate of 93.8%, whereas mPEG-PCL/EA NMs elicited a decrease in MCF-7 cell viability to 12.8% and an apoptosis rate of 73.0%.

Prognostic value of serum albumin level in patients with diffuse large B cell lymphoma.

OBJECTIVE: To investigate the prognostic value of serum albumin (SA) levels before chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) after receiving chemotherapy. METHODS: This is a retrospective study, and 127 patients with DLBCL including 71 males (55.9%) and 56 females (44.1%) were included. Patients' gender, age, Ann Arbor staging, eastern cooperative oncology group (ECOG) score, treatment options, international prognostic index, response rate, overall survival (OS), and progression-free survival (PFS) were obtained for statistical analysis. RESULTS: Univariate analysis showed that SA≤34 g/L, Ann Arbor III-IV, B symptoms, ECOG≥2, and bone marrow involvement suggest a poor prognosis in patients with DLBCL. Patients with persistent SA>34 g/L had significantly longer OS than patients with persistent SA≤34 g/L (P=0.020). Multivariate analysis showed that SA≤34 g/L (HR=0.48, 95% CI=0.26-0.90, P=0.022) and R-CHOP-like treatment regimen (HR=0.43, 95% CI=0.24-0.76, P=0.004) are independent factors that could affect the prognosis of patients with DLBCL. CONCLUSION: SA can be used as an indicator of prognosis in patients with DLBCL before the first chemotherapy. DLBCL patients with SA≤34 g/L are associated with short OS and poor prognosis, which may potentially provide guidance for the clinician to pay more attention to this population before the first chemotherapy.

Right Ventricular Function in Takayasu's Arteritis Patients With Pulmonary Artery Involvement Using MRI Feature Tracking.

BACKGROUND: Pulmonary artery involvement (PAI) is not rare in Takayasu arteritis (TA). Persistently elevated pulmonary arterial pressure in TA-PAI patients leads to pulmonary hypertension (PH), and eventually cardiac death. Thus, the early detection of right ventricular dysfunction before the onset of PH is important. PURPOSE: To explore the potential of right ventricular global peak longitudinal and circumferential strain (RVGLS and RVGCS, respectively) in detecting right ventricular myocardial damage in TA-PAI patients without PH. STUDY TYPE: Retrospective. POPULATION: One hundred and six TA patients (39.6 ± 13.9 years), of whom 52 were non-PAI and 54 were PAI patients (36 without PH and 18 with PH), along with 58 sex- and age-matched healthy volunteers (HVs) (36.7 ± 13.2 years). The involved arteries were validated by aorta magnetic resonance (MR) angiography and pulmonary artery computed tomography angiography. FIELD STRENGTH/SEQUENCE: 3 T/Cine imaging sequence with a steady-state free precession readout. ASSESSMENT: Cardiac MRI-derived parameters measured by two radiologists independently were compared among HVs, and TA patients with and without PAI. In addition, these indices were further compared among HVs, and TA-PAI patients with and without PH. STATISTICAL TESTS: Student's t test, one-way ANOVA analysis, Pearson and Spearman correlation analysis, and reproducibility analysis. A P-value of <0.05 was considered statistically significant. RESULTS: Although the TA-PAI patients without PH had a similar RV ejection fraction (RVEF) with HV (P = 0.348), RVGLS (non-PH 20.6 ± 3.7% vs. HV 24.0 ± 3.1%) was significantly lower and RVGCS (non-PH 14.8 ± 3.9% vs. HV 13.0 ± 2.7%) higher. The TA-PAI patients with PH had significantly poorer RVGLS (PH 13.5 ± 3.8% vs. non-PH 20.6 ± 3.7%) and RVGCS (PH 10.9 ± 3.2% vs. non-PH 14.8 ± 3.9%) than those without PH. DATA CONCLUSION: Right ventricular dysfunction was detected in the TA-PAI patients without PH. MR-feature tracking may be an effective method for detecting early cardiac damage in the TA-PAI patients without PH. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

High-throughput sequencing reveals the change of TCR α chain CDR3 with Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TAK) is an inflammatory disease of blood vessels, and its pathogenesis is not clear at present. In this study, we explored the immunological characteristics of T cell receptor (TCR) α-chain complementarity-determining region 3 (CDR3) in patients with TAK. METHODS: Five untreated patients with TAK were collected from June 2019 to December 2019. Four healthy blood samples were matched as the control group. The blood mononuclear cells were separated, and RNA was extracted for reverse transcription to obtain complementary DNA. Then high-throughput sequencing was performed. The quality of samples was evaluated by principal component analysis. We compared the diversity and expression of TCR α-chain between TAK group and control group. R software was used for statistical analysis and drawing, and Mann-Whitney U test was used to analyze the differences between the two groups. RESULTS: The results showed that there was a significant difference in the diversity of TCR α-chain CDR3 between the two groups. Three V region genes expression significantly higher in the TAK patients than in the control group. A total of 196 VJ rearrangement genes are significantly different between the two groups, of which 149 rearrangement genes in the TAK group are lower than those in the control group, and 47 rearrangement genes in the TAK group are higher than those in the control group. CONCLUSION: Patients with TAK have a unique TCR α-chain CDR3 library. These characteristic genes may be a marker for early diagnosis and provide a new theoretical basis for treating TAK.

Erythropoietin relieves neuronal apoptosis in epilepsy rats via TGF-ß/Smad signaling pathway.

This study aimed to investigate the influence of recombinant human erythropoietin (rHuEPO) on pentylenetetrazol (PTZ)-induced neuronal apoptosis in epilepsy rats, and to explore the signaling pathways related to the action. Healthy Sprague-Dawley rats aged 8 weeks old were randomly divided into 5 groups, namely, control group, PTZ model group, PTZ + rHuEPO intervention group, PTZ + SB431542 + rHuEPO intervention group and PTZ + SB431542 (TGF-ß/Smad inhibitor) intervention group. The expressions of apoptotic proteins [tumor necrosis factor receptor 1 (TNFR1) and caspase-3] and the transforming growth factor-beta (TGF-ß)/Smad signaling pathway-related proteins [phosphorylated smad3 (p-smad3) and TGF-ß1] in the brain tissues were determined via Western blotting (WB). Epilepsy was successfully induced by PTZ in the rats. The results of the TUNEL assay showed that the intervention with rHuEPO could remarkably reduce the number of PTZ-induced apoptotic neurons in the hippocampus, while SB431542 inhibitor could attenuate the protective effect of rHuEPO against neuronal apoptosis (P<0.05). In addition, the intraperitoneal injection of 50 µg/kg rHuEPO could activate the TGF-ß/Smad signaling pathway, markedly up-regulate the expressions of TGF-ß1 and p-smad3 (P<0.05), down-regulate the expressions of apoptotic proteins TNFR1 and caspase-3 (P<0.01) and reduce neuronal apoptosis. Moreover, SB431542 was able to notably repress the protective effect of rHuEPO against neuronal apoptosis, and down-regulate the expressions of p-smad3 and TGF-ß1 (P<0.01). In conclusion, the inhibitory effect of rHuEPO on nerve cell apoptosis in epilepsy rats may be realized by activating the TGF-ß/Smad signaling pathway, thus relieving neuronal apoptosis and ameliorating the symptoms of epilepsy.

Metformin reduces hepatocarcinogenesis by inducing downregulation of Cyp26a1 and CD8+ T cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated. METHODS: Fah-/-  mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8+ T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin. RESULTS: RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah-/- mice. Metformin prevented the formation of non-diabetic HCC in Fah-/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8+  T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah-/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45ß/JNK/c-Jun pathway. CONCLUSIONS: Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8+ T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC.

Individualized PEEP without Recruitment Maneuvers Improves Intraoperative Oxygenation: A Randomized Controlled Study.

Individualized positive end-expiratory pressure (PEEP) combined with recruitment maneuvers improves intraoperative oxygenation in individuals undergoing robot-assisted prostatectomy. However, whether electrical impedance tomography (EIT)-guided individualized PEEP without recruitment maneuvers can also improve intraoperative oxygenation is unknown. To test this, fifty-six male patients undergoing elective robot-assisted laparoscopic prostatectomy were randomly assigned to either individualized PEEP (Group PEEPIND, n = 28) or a control with a fixed PEEP of 5 cm H2O (Group PEEP5, n = 28). Individualized PEEP was guided by EIT after placing the patients in the Trendelenburg position and performing intraperitoneal insufflation. Patients in Group PEEPIND maintained individualized PEEP without intermittent recruitment maneuvers, and those in Group PEEP5 maintained a PEEP of 5 cm H2O intraoperatively. Both groups were extubated in a semi-sitting position once the extubation criteria were met. The primary outcome was arterial oxygen partial pressure (PaO2)/inspiratory oxygen fraction (FiO2) prior to extubation. Other outcomes included intraoperative driving pressure, plateau pressure and dynamic, respiratory system compliance, and the incidence of postoperative hypoxemia in the post-operative care unit (PACU). Our results showed that the intraoperative median for PEEPIND was 16 cm H2O (ranging from 12 to 18 cm H2O). EIT-guided PEEPIND was associated with higher PaO2/FiO2 before extubation compared to PEEP5 (71.6 ± 10.7 vs. 56.8 ± 14.1 kPa, p = 0.003). Improved oxygenation extended into the PACU with a lower incidence of postoperative hypoxemia (3.8% vs. 26.9%, p = 0.021). Additionally, PEEPIND was associated with lower driving pressures (12.0 ± 3.0 vs. 15.0 ± 4.4 cm H2O, p = 0.044) and better compliance (44.5 ± 12.8 vs. 33.6 ± 9.1 mL/cm H2O, p = 0.017). Our data indicated that individualized PEEP guided by EIT without intraoperative recruitment maneuvers also improved perioperative oxygenation in patients undergoing robot-assisted laparoscopic radical prostatectomy, which could benefit patients with the risk of intraoperative hemodynamic instability caused by recruitment maneuvers. Trial registration: China Clinical Trial Registration Center Identifier: ChiCTR2100053839. This study was registered on 1 December 2021. The first patient was recruited on 15 December 2021.

Effects of somatostatin analogs on uptake of radiolabeled somatostatin analogs on imaging: a systematic review and meta-analysis.

Background: The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients. Methods: The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. Results: A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe1-Tyr3-Thr8-octreotide (68Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 vs. 7.62±2.12, P=0.001) and spleen (25.74±7.14 vs. 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique. Conclusions: Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.

Analysis of coronary computed tomography angiography-derived pericoronary fat attenuation index characteristics in the diagnostic assessment of patients with Takayasu arteritis.

Background: The clinical value of pericoronary adipose tissue in assessing Takayasu arteritis (TAK) with coronary artery involvement (CAI) is yet to be determined. The purpose of this study was to investigate the characteristics of pericoronary fat attenuation index (FAI) derived from coronary computed tomography angiography (CTA) in patients with TAK. Methods: This is a retrospective study involving enrollment of 111 consecutive patients (mean age, 33.92±12.48 years) who were diagnosed as TAK, of which 52 patients had coronary artery involvement (TAK-CAI) and 59 patients without coronary artery involvement (TAK-nonCAI). Based on the extent of coronary artery lesion, the TAK-CAI group was further classified into localized group (n=25) and diffused group (n=27). Furthermore, patients with TAK were divided into active group (n=33) and inactive group (n=78). Meanwhile, 51 gender-matched individuals with normal appearance in coronary CTA examination were enrolled as the control group. The pericoronary FAI was quantitatively evaluated on each coronary CTA examination groups. The diagnostic value of pericoronary FAI was determined using the area under the curve (AUC) of the receiver operating characteristic. Results: A higher pericoronary FAI was found in TAK-nonCAI group than control group with normal coronary arteries (P<0.001). Multivariate analysis showed that the FAI is an independent risk factor for coronary involvement in TAK patients [odds ratio (OR): 1.23, 95% confidence interval (CI): 1.13-1.35, P<0.001]. With the best cut-off value of -86.50, the pericoronary FAI identified coronary involvement with 67.8% sensitivity and 74.5% specificity (AUC: 0.794, 95% CI: 0.713-0.875, P<0.001). Multivariate analysis showed that the pericoronary FAI is an independent risk factor for determination of active TAK patients (OR: 1.57, 95% CI: 1.25-1.97, P<0.001). With the best cut-off value of -79.50, the pericoronary FAI identified active inflammation with 93.9% sensitivity and 74.4% specificity (AUC: 0.911, 95% CI: 0.860-0.962, P<0.001). Conclusions: Coronary CTA-derived FAI is significantly increased in patients with TAK and can be used as a reliable biomarker to distinguish TAK patients from those with normal coronary arteries, and determine the extent of TAK inflammation.

Effect of perioperative application of dexmedetomidine on post-operative stress reaction, pain and prognostic adverse effects in patients undergoing gynaecological laparoscopy.

Introduction: The aim of this study was to analyse the effect of perioperative dexmedetomidine (DEX) application on stress response, post-operative pain and prognosis in patients undergoing gynaecologic laparoscopy. Patients and Methods: One hundred and sixty-eight patients admitted for gynaecologic laparoscopic surgery from May 2020 to November 2022 were included in the study. The patients were randomly divided into pre-operative DEX group (n = 56), intraoperative DEX group (n = 56) and post-operative DEX group (n = 56) according to the application of DEX in the perioperative period. The visual analogue scale (VAS), time awake, extubation time, pneumoperitoneum time, post-anaesthesia care unit (PACU) stay time and Richmond agitation-sedation scale score (RASS) were recorded. Results: Patients in both the pre-operative and intraoperative DEX groups had substantially shorter wakeup and extubation times than those in the post-operative DEX group. Patients in the pre-operative DEX group had considerably shorter wakeup and extubation times than those in the intraoperative DEX group, and their pneumoperitoneum time was significantly shorter than that of the post-operative DEX group (P < 0.001). The RASS scores of the pre-operative DEX group and intraoperative DEX group were significantly lower than those of the post-operative DEX group at 1 h, 6 h and 12 h after surgery. Meanwhile, at all time periods, the RASS scores of patients in the pre-operative DEX group were considerably lower than those in the intraoperative DEX group (P < 0.01). The VAS scores of patients in the pre-operative DEX group and intraoperative DEX group were evidently lower than those in the post-operative DEX group at 0.5 h, 2 h and 12 h postoperatively, and the VAS scores of patients in the pre-operative DEX group were markedly lower than those in the intraoperative DEX group (P < 0.001). The incidence of nausea and vomiting was significantly lower in the pre-operative DEX group than in the intraoperative DEX group and the post-operative DEX group at 0-2 h, >2-12 h and >12-24 h postoperatively (P < 0.001). The incidence of nausea and vomiting in the intraoperative DEX group was significantly lower than that in the post-operative DEX group from 0 to 2 h after surgery (P < 0.05). The incidence of adverse reactions was not significantly different amongst the three groups of patients (P > 0.05). Conclusion: Pre-operative and intraoperative application of DEX can help reduce post-operative pain and stress responses, help patients recover quickly after surgery and improve patient prognosis, especially the pre-operative application of DEX.