Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: The Food and Drug Administration of the United States has approved several drugs for treating advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for first-line therapy include monotherapy or combination therapy. However, selecting a suitable first-line and second-line treatments to improve overall survival remains an unresolved issue. OBJECTIVE: To evaluate the overall survival (OS) and progression-free survival (PFS) of patients with metastatic clear cell renal cell carcinoma (mRCC). Patients were divided into several grouped according to the treatment sequence of TKI and anti PD-1 administration. The overall survival benefit was evaluated based on the order of administration of anti PD-1 and TKI. PATIENTS AND METHODS: In this retrospective propensity-matched cohort study, we identified 135 patients with mRCC treated at the Affiliated Cancer Hospital of Shandong First Medical University from January 1, 2017, to December 31, 2022. These patients had received anti PD-1 treatment as part of their first or second line of therapy. Statistical analysis was performed from June 1, 2023, to August 1, 2023. The primary outcome measure was OS, from the date of diagnosis to death or the last follow-up. PFS was monitored during treatment. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. By comparing the complete treatment course of patients, the survival of patients in different groups was compared according to the number of immunotherapy lines. RESULTS: The final cohort comprised 135 patients, of whom 84 received first-line therapy with anti PD-1 (include 6 patients treated with anti PD-1 (tislelizumab, carrelizumab, toripalimab or sintilizumab) alone and 78 patients treated with anti PD-1 combined with anti-vascular TKI (axitinib, sunitinib, solfanitinib or pazopanib)). The remaining 51 patients were treated with anti PD-1 as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether anti PD-1 were used in the first-line treatment. It was observed that the OS of patients receiving first-line targeted therapy was higher than those receiving first-line immunotherapy, with a median OS of 33 months versus 15 months. To investigate this outcome further, we refined the patient groups based on the administration sequence of anti PD-1 and TKIs in the treatment regimen. We found that the median PFS of patients with first-line treatments of TKI combined with anti PD-1 was 3.5 months, compared to 14.5 months when TKI combined with anti PD-1 followed first-line TKI (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS was 16.66 months and 31.88 months, respectively (p=0.008). CONCLUSIONS: This study indicates that administering immunotherapy following anti-vascular therapy significantly enhances both OS and PFS compared to other sequences of therapies. This finding provides valuable insights and robust data support for clinical decision-making regarding treatment sequencing.

Effects of integrated management on surgical outcomes and mental health of patients following endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a less invasive local treatment for diseases throughout the gastrointestinal tract. AIM: To develop an integrated management protocol and analyze its effects on surgical outcomes and mental health of patients after ESD. METHODS: The study population consisted of patients undergoing ESD before implementation of integrated management and those undergoing ESD by the same pool of surgeons after implementation of integrated management. RESULTS: The management group exhibited shortened fasting time and length of hospital stay compared to the control group (P < 0.05). The management group exhibited a higher incidence rate of postoperative complications than the control group (3 cases vs 11 cases; P = 0.043). The management group exhibited a lower uncertainty score for disease knowledge compared to the control group 12 h after surgery (P < 0.05). The management group gave more scores on the domains of patient familiarity to the responsible nurses, professional skills of responsible nurses, and general evaluation compared to the control group. The management group had a higher total score of patient satisfaction towards the responsible nurses in term of health care than the control group (P < 0.01). The management group exhibited lower Self-Rating Anxiety Scale and Self-Rating Depression Scale scores compared to the control group 12 h after surgery (P < 0.01). CONCLUSION: The study demonstrates that integrated management could improve surgical outcomes and mental health of patients undergoing ESD.

Salvianolic acids from Salvia miltiorrhiza Bunge and their anti-inflammatory effects through the activation of α7nAchR signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease (CVD) is a serious disease with a high incidence rate and mortality. Inflammation is closely related to the occurrence of CVDs. As an essential medicine of promoting blood circulation and removing blood stasis in China, Salvia miltiorrhiza Bunge (Danshen) is widely used to treat CVDs due to its anti-inflammatory and cardiovascular protective effects. Salvianolic acids are the most abundant component in the water extract of S. miltiorrhiza, which has a significant effect on the treatment of CVDs. However, due to the complex composition of salvianolic acids, the active molecules and their underlying mechanisms have not been fully explored. AIM OF THIS STUDY: The present study aims to isolate and identify salvianolic acids from Danshen with anti-inflammatory activity and explore the potential mechanisms of isolates. METHODS: The structures of isolated salvianolic acids were elucidated by UV, IR, NMR, MS and electronic circular dichroism (ECD) calculations. Then anti-inflammatory activities of isolates were screened out by the zebrafish inflammation models. The most active compound was further used to explore the anti-inflammatory mechanisms on LPS-stimulated RAW 264.7 cells. The key inflammatory cytokines IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of STAT3, p-STAT3 (Tyr705), NF-κB p65, IκBα, p-IκBα (Ser32) and α7nAchR were determined by Western blotting. The nuclear translocation of p-STAT3 (Tyr705) and NF-κB p65 was evaluated by immunofluorescence assays. Finally, the in vivo anti-inflammatory mechanisms were investigated by observation of neutrophil migration, H&E staining, survival analysis and quantitative PCR (Q-PCR) in LPS-microinjected zebrafish. RESULTS: Two new and four known compounds were isolated from Danshen. Among them, isosalvianolic acid A-1 (C1) and ethyl lithospermate (C5) inhibited neutrophil migrations in three zebrafish inflammation models and C1 with the best activities decreased the secretion of IL-6 and TNF-α and inhibited the expression level of p-IκBα (Ser32) in LPS stimulated RAW 264.7 cells. In addition, C1 also reduced the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Moreover, C1 significantly upregulated the protein expression of α7nAchR, and the knockdown of α7nAchR counteracted the effects of C1 on the production of IL-6 and TNF-α and the expression levels of p-STAT3 (Tyr705), NF-κB p65 and p-IκBα (Ser32). In vivo experiments, C1 decreased the migration and infiltration of inflammatory cells, increased the survival ratio and inhibited the mRNA level of IL-6, TNF-α, STAT3, NF-κB and IκBα in LPS-microinjected zebrafish. CONCLUSION: Two new and four known compounds were isolated from Danshen. Among them, C1 exerted anti-inflammatory activities by activating α7nAchR signaling and subsequently inhibiting STAT3 and NF-κB pathways. This study provided evidence for the clinical application of Danshen and contributed to the development of C1 as a novel in the treatment of cardiovascular disease.

Efficacy and safety of angiogenesis inhibitors plus immune checkpoint inhibitors in advanced soft tissue sarcoma: a real-world, single-center study.

Angiogenesis inhibitors (AIs) and immune checkpoint inhibitors (ICIs) are new treatment options for advanced soft tissue sarcoma (STS) patients. This study evaluated the efficacy and safety of AIs plus ICIs in patients with advanced STS. A retrospective cohort study was performed on STS patients treated with AIs and ICIs at Shandong Cancer Hospital and Institute between August 2020 and December 2021. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and adverse events. Thirty-three patients were enrolled; 27 were evaluable for objective response. The ORR and DCR were 48.1% (95% CI 30.7-66.0%) and 85.2% (95% CI 67.5-94.1%). With a median follow-up of 7.6 months (range, 0.8-25.5), the median PFS for all 33 patients was 8.90 months (95% CI 5.98-11.82). The median OS was not reached. The most common treatment-related adverse events (TRAEs) of any grade were hypertension (50.0%), ECG T-wave abnormality (30.0%), hypothyroidism (26.7%), elevated alanine aminotransferase or aspartate aminotransferase (23.3%), elevated thyroid-stimulating hormone (23.3%), and fatigue (16.7%). The most common grade 3-4 TRAE was hypertension (27.3%). Three serious TRAEs (two myocarditis and one rapid atrial fibrillation) were recorded. This study suggests that adding AIs to ICIs is beneficial in STS.

Association between bone marrow fluorodeoxyglucose uptake and recurrence after curative surgical resection in patients with T1-2N0M0 lung adenocarcinoma: a retrospective cohort study.

BACKGROUND: Evidence regarding the relationship between fluorodeoxyglucose (FDG) uptake in the bone marrow of patients with lung adenocarcinoma and prognosis is limited. This study aimed to identify whether bone marrow FDG uptake is a risk factor for recurrence in patients after curative surgical resection of T1-2N0M0 lung adenocarcinoma. METHODS: From January 2012 to December 2016, we retrospectively enrolled 195 pT1-2N0M0 lung adenocarcinoma patients who underwent both preoperative FDG positron emission tomography/computed tomography (PET/CT) and surgical resection from the lung adenocarcinoma database maintained by the PET/CT department at our hospital. After surgical resection, patients were followed up mainly through regular outpatient examinations. The maximum standardized uptake value (SUVmax) of the primary tumor, the mean FDG uptake of bone marrow (BM SUV), bone marrow-liver uptake ratio (BLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured from the pretreatment FDG PET/CT images. Multi-adjusted Cox proportional hazards models were built to evaluate the independent prognostic value of BLR in predicting recurrence-free survival (RFS). A restricted cubic spline regression model was conducted to provide more precise estimates and examine the shape of the associations between BLR and the risk of recurrence. RESULTS: The follow-up results showed that 30 of the 195 patients (15.4%) had tumor recurrence. Compared with non-recurrent patients, the primary tumor size in recurrent patients was larger, and the SUVmax, TLG, and serum C-reactive protein (CRP) levels were higher. Univariate analysis showed that BLR, tumor size, SUVmax, TLG, and CRP were significantly correlated with postoperative tumor recurrence. After adjustment for conventional confounding factors, the hazard ratio of BLR was 5.01 (95% CI, 1.32, 18.98) for the highest tertile of BLR compared with the lowest tertile. The multi-adjusted spline regression showed that BLR had a linear relationship with log relative risk (RR) for recurrence when BLR was lower than 0.7. Over this level, the effect stabilized, suggesting a saturation effect for BLR at a level of approximately 0.7 at recurrence. CONCLUSIONS: BLR was an independent risk factor for predicting RFS in T1-2N0M0 lung adenocarcinoma patients after curative surgical resection. BLR can be used as a biomarker for evaluating the risk of lung cancer recurrence.

Arabidopsis thaliana constitutively active ROP11 interacts with the NADPH oxidase respiratory burst oxidase homologue F to regulate reactive oxygen species production in root hairs.

Reactive oxygen species (ROS) play a key signalling role in cells. Plant NADPH oxidases, also known as respiratory burst oxidase homologues (Rbohs), are well characterised ROS-generating systems. In this study, we found that the constitutively active small guanosine triphosphatase (GTPase) ROP11 (CA-ROP11) interacted with RbohF by using a yeast two-hybrid analysis, a pull-down assay and an in vivo bimolecular fluorescence complementation assay. The mutation of amino acid L336 or L337 in RbohF abolished its interaction with CA-ROP11. Coexpression of CA-ROP11 and wild-type RbohF in Nicotiana benthamiana Domin enhanced ROS production compared with coexpression of CA-ROP11 and mutant RbohF or of dominant negative ROP11 and wild-type RbohF. Moreover, CA-ROP11 overexpression resulted in ROS accumulation and a swollen root hair phenotype in Arabidopsis thaliana (L.) Heynh. The deletion of RbohF partially reduced the increase in ROS in Arabidopsis plants overexpressing CA-ROP11. These results suggest that Arabidopsis ROP11 modulates ROS production by interacting with RbohF in root hairs.

Platinum particles-modified electrode for HPLC with pulsed amperometric detection of thiols in rat striatum.

A new chemically modified electrode based on the immobilization of Pt particles is fabricated and exhibits electrocatalytic oxidation for L-cysteine (L-Cys), glutathione (GSH) and penicillamine (PEN) with relatively high sensitivity. It is also adaptable to HPLC for pulsed amperometric detection (PAD) of these thiols. PAD largely improves the detection sensitivity because the alternated polarizations can effectively clean and reactivate the electrode surface. It is shown that the peak currents of L-Cys, GSH and PEN are linear to their concentrations, with the calculated detection limit of 1.1 x 10(-7), 1.8 x 10(-7) and 3.8 x 10(-7) mol L(-1), respectively (S/N = 3). The method has been successfully applied to assess the contents of L-Cys and GSH in rat striatal microdialysates. The average contents of the two analytes in rat striatum are 2.6 x 10(-6) and 2.8 x 10(-6) mol L(-1), respectively.