NIR-responsive CN-Pt-GEM hydrogel induces necroptosis and immunotherapeutic responses prevent postoperative recurrence and wound infection in lung carcinoma.

BACKGROUND: Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse. RESULTS: The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection. CONCLUSIONS: These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.

Hyperprogressive disease under anti-PD-1 rechallenge after initial response to anti-PD-1 treatment for non-small cell lung cancer: a case report.

Background: Hyperprogressive disease is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis. The rechallenge of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors can be a treatment option in non-small cell lung cancer (NSCLC) patients who once responded to them. Here, we reported the hyperprogressive phenomenon after PD-1/PD-L1 rechallenge in a patient with NSCLC. Case Description: This case report described a patient with recurrent large cell lung cancer undergoing hyperprogressive disease with pleural and pericardial dissemination shortly after the pembrolizumab rechallenge, although he had a favorable response to the initial pembrolizumab treatment. A lower ratio of CD8+ T cells to Foxp3+ regulatory T cells was distributed in the cell blocks of pleural and pericardial effusion which were taken after hyperprogressive disease, compared to the resected tumor microenvironment. Neutrophil-to-lymphocyte ratio (NLR) was lower in peripheral blood when the disease was controlled and it rose when the disease progressed. Notably, NLR increased dramatically when hyperprogression occurred. Conclusions: For the first time, we reported that a patient who showed a favorable response to initial anti-PD-1 treatment underwent hyperprogressive disease when rechallenging the same immunotherapy. The increased Foxp3+ regulatory T cells in the tumor microenvironment and the longitudinal change of NLRs in peripheral blood were suggested to be associated with hyperprogressive disease.

Electroacupuncture stimulation enhances the permeability of the blood-brain barrier: A systematic review and meta-analysis of preclinical evidence and possible mechanisms.

An important cellular barrier to maintain the stability of the brain's internal and external environment is the blood-brain barrier (BBB). It also prevents harmful substances from entering brain tissue through blood circulation while providing protection for the central nervous system. It should be noted, however, that the intact BBB can be a barrier to the transport of most drugs into the brain via the conventional route of administration, which can prevent them from reaching effective concentrations for the treatment of disorders affecting the central nervous system. Electroacupuncture stimulation has been shown to be effective at opening the BBB in a series of experimental studies. This study systematically analyzes the possibility and mechanism by which electroacupuncture opens the BBB. In PubMed, Web of Science, VIP Database, Wanfang Database, and the Chinese National Knowledge Infrastructure, papers have been published for nearly 22 years aimed at opening the BBB and its associated structures. A comparison of EB content between electroacupuncture and control was selected as the primary outcome. There were also results on vascular endothelial growth factor (VEGF), nerve growth factor (NGF), P-Glycoprotein (P-gp), Matrix Metalloproteinase 9 (MMP-9), and glial fibrillary acidic protein (GFAP). We utilized Review Manager software analysis to analyze correlations between studies with a view to exploring the mechanisms of similarity. Evans Blue infiltration forest plot: pooled effect size of 2.04, 95% CI: 1.21 to 2.87, P < 0.01. These results indicate that electroacupuncture significantly increases EB penetration across the BBB. Most studies have reported that GFAP, MMP-9, and VEGF were upregulated after treatment. P-gp expression decreased as well. Electroacupuncture can open the BBB, and the sparse-dense wave is currently the most effective electroacupuncture frequency for opening the BBB. VEGF plays an important role in opening the BBB. It is also important to regulate the expression of MMP-9 and GFAP and inhibit the expression of P-gp.

Efficacy of acupuncture therapy on cancer-related insomnia: a systematic review and network meta-analysis.

Objectives: Cancer-related insomnia (CRI) takes a toll on many cancer survivors, causing distressing symptoms and deteriorating the quality of life. Acupuncture therapy has been used for CRI already. However, it is still uncertain which acupuncture regime is best for CRI. The primary objective of this review is to conduct a comparative evaluation and ranking of the effectiveness of different acupuncture therapies for CRI. Methods: Randomized controlled trials (RCTs) that were published up to July 31, 2023, from 8 databases (PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and China Biology Medicine disc) were integrated in this study. Trials that met the inclusion criteria were evaluated the risk of bias. Pittsburgh sleep quality index (PSQI) was used to assess the efficacy of different acupuncture therapies as the primary outcome. Then, STATA 15, R, and OpenBUGS were applied to perform the network meta-analysis. PRISMA statements were followed in this network meta-analysis. Results: A total of 37 studies were included in this review, involving 16 interventions with 3,246 CRI participants. Auriculotherapy + moxibustion [surface under the cumulative ranking curve (SUCRA) 98.98%] and auriculotherapy (SUCRA 77.47%) came out top of the ranking, which were more effective than control, medicine, usual care and sham acupuncture. Conclusion: Auriculotherapy + moxibustion and auriculotherapy + acupuncture emerged as the top two acupuncture regimes for CRI and future studies should pay more attention to CRI. Clinical trial registration: https://clinicaltrials.gov/, identifier INPLASY202210095.

Effect of Specific mode electroacupuncture stimulation combined with NGF during the ischaemic stroke: Study protocol for a randomized controlled trial

ABSTRACT Background: The emergence of the Nerve Growth Factor (NGF) has promoted the development of neuroprotective therapy; however, it has little effect on cerebral ischemia because of its poor Blood-Brain Barrier (BBB) permeability. Specific Mode Electroacupuncture Stimulation (SMES) can open BBB safely and effectively; however, it has shown inconclusive clinical effects and indirect clinical evidence in the recovery phase. Hence, the authors conducted a multicentre, randomized, placebo-controlled, assessor-blinded clinical trial to assess the effectiveness and safety of SMES combined with NGF treatment used during ischaemic stroke recovery. Methods: A total of 288 stroke patients from three hospitals will be recruited and randomly allocated to four groups: acupuncture + placebo, acupuncture + NGF, SMES + placebo, and SMES + NGF, in a 1:1:1:1 ratio. Assessment data will be collected at baseline, 2-weeks, and 4-weeks during the treatment period, as well as at the 4-week and 8-week follow-up after treatment completion. The primary outcome measure will be the basic cure rate. The secondary outcome measures include the simplified Modified Barthel Index, Timed Up and Go Test, Fugl-Meyer Assessment of Motor Function Score, Tinetti Performance Oriented Mobility Assessment, Montreal Cognitive Assessment, and Loewenstein Occupational Therapy Cognitive Assessment. Moreover, resting-state functional magnetic resonance imaging and Functional near-infrared spectroscopy can detect changes in cerebral blood flow and brain function and investigate the relationship between the clinical efficacy and mechanism of the prescribed interventions. Conclusion: This study will provide clinical evidence for the efficacy and safety of SMES combined with NGF in the treatment of stroke patients.

Early Detection of Therapeutic Benefit from PD-1/PD-L1 Blockade in Advanced Lung Cancer by Monitoring Cachexia-Related Circulating Cytokines.

Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients.

Integrated Analysis of Ferroptosis and Immunity-Related Genes Associated with Intestinal Ischemia/Reperfusion Injury.

Purpose: Intestinal ischemia/reperfusion (I/R) injury is an unresolved clinical challenge due to its high prevalence, difficulty in diagnosis, and lack of clinically effective therapeutic agents. Ferroptosis is a novel form of cell-regulated death that has been shown to play a role in various I/R models and has been shown to be immune-related. Further unraveling the molecular mechanisms associated with ferroptosis and immunity in intestinal I/R injury may lead to the discovery of potentially effective drugs. Methods: We obtained differentially expressed mRNAs (DEGs) in mouse intestinal tissues following intestinal I/R injury or sham surgery. Then, we extracted ferroptosis-related DEGs (FRGs) and immune-related DEGs (IRGs) from the DEGs. In addition, we performed functional analysis of FRGs and IRGs. Next, we used transcriptome sequencing from patients with intestinal I/R injury to validate the results. Then, we constructed transcription factors (TFs)-gene networks and gene-drug networks using mouse and human co-expressed FRGs (coFRG) and mouse and human co-expressed IRGs (coIRG). We also analyzed the composition of immune cells to reveal correlations between FRGs signatures and immune cells in the mouse and human gut. Finally, we validated these results through animal experiments. Results: We extracted 61 FRGs and 294 IRGs from mouse samples and performed PPI and functional analyses. We extracted 45 FRGs and 200 IRGs from human samples for validation, and identified 24 coFRGs,100 coIRGs and 6 hub genes (HSPA5, GDF15, TNFAIP3, HMOX1, CXCL2 and IL6) in both. We also predicted potential TF-gene networks for coFRGs and coIRGs, as well as predicted gene-drug pairs for hub genes. In addition, we found that the immune cells were altered in the early stages of intestinal I/R injury and that FRGs were closely associated with immune cells in mice and humans. Finally, we validated the hub genes in mouse samples. Conclusion: In conclusion, we identified ferroptosis and immunity-related genes to predict their correlations in intestinal I/R injury. We also predicated potential TF-genes network and potential therapeutic targets (HSPA5, GDF15, TNFAIP3, HMOX1, CXCL2 and IL6) to provide clues for further investigation of intestinal I/R injury.

A novel adipokine WISP1 attenuates lipopolysaccharide-induced cell injury in 3T3-L1 adipocytes by regulating the PI3K/Akt pathway.

BACKGROUND: To study the effect of WISP1 on lipopolysaccharide (LPS)-induced cell injury in 3T3-L1 adipocytes. METHOD: Lentivirus was transiently transfected into log phase 3T3-L1 adipocytes, which were then treated with LPS at a concentration of 10 µg/mL for 24 h. The cells were divided into the following groups: group A (control, untreated cells); group B (LPS-treated cells); group C (GFP), cells transfected with lentivirus-containing GFP; group D (GFP+LPS), group C treated with LPS;group E (WISP1OE), cells transfected with lentivirus, group F (shNC+LPS), cells transfected with lentivirus-containing nshRNA treated with LPS; group G (shWISP1 +LPS), cells transfected with lentivirus-containing shRNA treated with LPS; group H (WISP1OE+LPS), group E treated with LPS; group I (WISP1OE+LPS+LY294002), group E treated with LPS followed by LY294002 for 24 h. RESULTS: WISP1 overexpression notably ameliorated cell apoptosis, accompanied with the increased expression of bcl-2, the decreased expressions of bax and cleaved-caspase-3, and promoted the release of inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-treated 3T3-L1 adipocytes. WISP1 knockdown exhibited the opposite results. In addition, WISP1 stimulated Akt phosphorylation and reduced nuclear translocation of Fork head box protein O3 (FoxO3a) in 3T3-L1 adipocytes treated by LPS. The inhibition of the PI3K/Akt signaling pathway diminished the protective effect of WISP1. CONCLUSION: WISP1 prevents 3T3-L1 adipocytes from being injured by LPS by regulating the PI3K/Akt pathway.

Heterogeneous Outcomes of Immune Checkpoint Inhibitor Rechallenge in Patients With NSCLC: A Systematic Review and Meta-Analysis.

Introduction: Outcomes of immune checkpoint inhibitor (ICI) rechallenge in NSCLC remain uncertain. This study estimated the safety and efficacy of ICI rechallenge and compared rechallenge benefit among different reasons of initial ICI discontinuation in NSCLC. Methods: PubMed, EMBASE, and Cochrane Library were searched for studies on NSCLC retreated with ICI. Immune-related adverse events (irAEs), overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) at initial ICI and rechallenge were analyzed. Results: A total of 15 studies including 442 patients between 2018 and 2022 were eligible for meta-analysis. The incidence of grade 3 or 4 irAE was lower in rechallenge than initial ICI (8.6% versus 17.8%, p < 0.001). Patients rechallenged with ICI had lower ORR and DCR than initial ICI (13.2% versus 42.4%, p < 0.001; 51.1% versus 74.0%, p < 0.001). The ORR and DCR to ICI rechallenge were both higher in patients who experienced disease progression after stopping ICI or irAE than patients with disease progression during ICI treatment (ORR: 46.2% versus 20% versus 11.4%, p = 0.003; DCR: 84.6% versus 90.0% versus 55.0%, p = 0.002). In addition, 34.7% of 69 patients with individual response to ICI and PFS experienced the same or better response to ICI rechallenge in comparison with initial ICI, although PFS in initial ICI was longer than that in ICI rechallenge (median: 8.90 versus 3.67 mo, hazard ratio = 0.44, 95% confidence interval: 0.33-0.59). Conclusions: ICI rechallenge had less severe toxicity than initial ICI treatment. Patients undergoing disease progression after ICI cessation or ICI discontinuation owing to irAE are more likely to benefit from ICI rechallenge in NSCLC.

Survival past five years with advanced, EGFR-mutated or ALK-rearranged non-small cell lung cancer-is there a "tail plateau" in the survival curve of these patients?

BACKGROUND: The prognosis of patients with NSCLC harboring oncogenic driver gene alterations, such as EGFR gene mutations or ALK fusion, has improved dramatically with the advent of corresponding molecularly targeted drugs. As patients were followed up for about five years in most clinical trials, the long-term outcomes beyond 5 years are unclear. The objectives of this study are to explore the clinical course beyond five years of chemotherapy initiation and to investigate factors that lead to long-term survival. METHODS: One hundred and seventy-seven patients with advanced, EGFR-mutated or ALK-rearranged NSCLC who received their first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and according to subgroups of patients' characteristics. RESULTS: Median OS in the total cohort was 40.6 months, the one-year survival rate was 89%, the three-year survival rate was 54%, and the five-year survival rate was 28%. Median OS was 36.9 months in EGFR-mutated patients and 55.4 months in ALK-rearranged patients. The OS curve seemed to plateau after 72 months, and most of the patients who were still alive after more than five years are on treatment. Female sex, age under 75 years, an ECOG PS of 0 to 1, ALK rearrangement, postoperative recurrence, and presence of brain metastasis were significantly associated with longer OS. CONCLUSIONS: A tail plateau was found in the survival curves of patients with advanced, EGFR-mutated and ALK-rearranged NSCLC, but most were on treatment, especially with EGFR-mutated NSCLC.

Comparative efficacy of different acupuncture therapies on cancer-related insomnia: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Cancer-related insomnia (CRI), as a common complication in cancer survivors, may further lead to depression, anxiety and other symptoms. Acupuncture therapy is a promising therapeutic strategy for CRI. The effectiveness of acupuncture therapy on CRI has been validated by several relevant meta-analyses. Questions remain, however, including which acupuncture regimen is optimal. We aim to conduct the first network meta-analysis to compare different acupuncture therapies, rank their effectiveness and assess which approach could be optimal for treatment of CRI. METHODS AND ANALYSIS: A comprehensive search of PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Database, VIP Database (China Science and Technology Journal Database), and China Biology Medicine (from inception until 1 March 2022) will be carried out to identify randomised controlled trials (RCTs) of acupuncture therapy for insomnia in cancer survivors, reported in English or Chinese. Reviews, animal studies, non-RCT studies, editorials and other secondary insomnia studies will be excluded. The primary outcome measure will be the Pittsburgh Sleep Quality Index. Pairwise meta-analysis will be performed in Stata and network meta-analysis by OpenBUGS, R and Stata. Network plots and funnel plots will be used to show the scale of studies and participants for each intervention and the potential publication bias, respectively. Both heterogeneity and consistency will be evaluated by R. ORs with 95% CIs and mean differences with 95% CI will be calculated in OpenBUGS and transformed into league figure and surface under the cumulative ranking by Stata to visualise the results. ETHICS AND DISSEMINATION: Ethical committee approval for this review is unnecessary since the data used will be extracted from pre-existing literature. The results will be submitted for publication in a peer-reviewed journal and presented at international academic conferences.

[Root shape changes of impacted upper central incisor before and after orthodontic traction].

PURPOSE: Changes of root shape of impacted upper central incisor before and after orthodontic traction were observed with dental cone-beam CT(CBCT), the timing for traction of impacted upper central incisor was investigated. METHODS: Ten impacted maxillary central incisors were diagnosed via panoramic radiograph. CBCT images were taken preoperatively for accurate localization. Following combined treatment of dental surgery and orthodontic traction, ten impacted maxillary central incisors were guided out and aligned well. Final treatment results and the root development status were evaluated via CBCT. RESULTS: Ten impacted maxillary central incisors were tracted to normal position. CBCT images before and after treatment showed that the root of impacted incisors with completed root apex had no change in shape, while the root of impacted incisors with uncompleted root apex developed continually with obviously improved shape and length. CONCLUSIONS: Optimistic results can be achieved if the traction of impacted upper central incisor is carried out before root development completed.